Traditional Chinese medicines and their active ingredients sensitize cancer cells to TRAIL-induced apoptosis

Traditional Chinese medicines and their active ingredients sensitize cancer cells to TRAIL-induced apoptosis 中药及其有效成分对TRAIL引起肿瘤细胞凋亡具有增敏作用 2 3 equal first-author 5 equal 5 6 7 8 corresp Wulin WEN, richard8207@126.com Wulin WEN, richard8207@126.com richard8207@126.com 1 4 corresp Ming HONG, hongming530@126.com Ming HONG, hongming530@126.com hongming530@126.com https://orcid.org/0000-0003-3989-8543 Institute of Advanced Diagnostic and Clinical Medicine, Zhongshan People’s Hospital, Guangzhou University & Zhongshan People’s Hospital Joint Biomedical Institute, Zhongshan528400, China Institute of Advanced Diagnostic and Clinical Medicine, Zhongshan People’s Hospital, Guangzhou University & Zhongshan People’s Hospital Joint Biomedical Institute, Zhongshan528400, China Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou510006, China Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou510006, China Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou510006, China Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou510006, China Dongguan & Guangzhou University of Chinese Medicine Cooperative Academy of Mathematical Engineering for Chinese Medicine, Dongguan523000, China Dongguan & Guangzhou University of Chinese Medicine Cooperative Academy of Mathematical Engineering for Chinese Medicine, Dongguan523000, China Research Center of Chinese Herbal Resource Science and Engineering, Guangzhou University of Traditional Chinese Medicine, Guangzhou510006, China Research Center of Chinese Herbal Resource Science and Engineering, Guangzhou University of Traditional Chinese Medicine, Guangzhou510006, China Department of Pharmacology & Toxicology, University of Kansas, Lawrence, KS66105, USA Department of Pharmacology & Toxicology, University of Kansas, Lawrence, KS66105, USA Zhongshan People’s Hospital, Zhongshan528400, China Zhongshan People’s Hospital, Zhongshan528400, China ENT & HN Surgery Department, the Second Affiliated Hospital of Ningxia Medical University, Yinchuan750000, China ENT & HN Surgery Department, the Second Affiliated Hospital of Ningxia Medical University, Yinchuan750000, China The rapidly developing resistance of cancers to chemotherapy agents and the severe cytotoxicity of such agents to normal cells are major stumbling blocks in current cancer treatments. Most current chemotherapy agents have significant cytotoxicity, which leads to devastating adverse effects and results in a substandard quality of life, including increased daily morbidity and premature mortality. The death receptor of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can sidestep p53-dependent pathways to induce tumor cell apoptosis without damaging most normal cells. However, various cancer cells can develop resistance to TRAIL-induced apoptosis via different pathways. Therefore, it is critical to find an efficient TRAIL sensitizer to reverse the resistance of tumor cells to TRAIL, and to reinforce TRAIL’s ability to induce tumor cell apoptosis. In recent years, traditional Chinese medicines and their active ingredients have shown great potential to trigger apoptotic cell death in TRAIL-resistant cancer cell lines. This review aims to collate information about Chinese medicines that can effectively reverse the resistance of tumor cells to TRAIL and enhance TRAIL’s ability to induce apoptosis. We explore the therapeutic potential of TRAIL and provide new ideas for the development of TRAIL therapy and the generation of new anti-cancer drugs for human cancer treatment. This study involved an extensive review of studies obtained from literature searches of electronic databases such as Google Scholar and PubMed. “TRAIL sensitize” and “Chinese medicine” were the search keywords. We then isolated newly published studies on the mechanisms of TRAIL-induced apoptosis. The name of each plant was validated using certified databases such as The Plant List. This study indicates that TRAIL can be combined with different Chinese medicine components through intrinsic or extrinsic pathways to promote cancer cell apoptosis. It also demonstrates that the active ingredients of traditional Chinese medicines enhance the sensitivity of cancer cells to TRAIL-mediated apoptosis. This provides useful information regarding traditional Chinese medicine treatment, the development of TRAIL-based therapies, and the treatment of cancer. 肿瘤坏死因子相关凋亡诱导配体（TRAIL）的死亡受体可以避开P53依赖的途径来诱导肿瘤细胞凋亡而不会损害大多数正常细胞。但是，各种癌细胞可以通过不同途径对TRAIL诱导的细胞凋亡产生抗性。因此找到一种有效的TRAIL敏化剂，以逆转肿瘤细胞对TRAIL的抵抗力至关重要。同时，中药及其有效成分对治疗肿瘤方面显示出巨大的潜力。这篇综述归纳了可有效逆转肿瘤细胞对TRAIL的耐药性并增强TRAIL诱导凋亡能力的中药及其有效成分的信息，为TRAIL治疗的发展和用于人类癌症治疗的新型抗癌药物的产生提供新思路。 Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) Cancer therapy Chinese medicine Apoptosis 肿瘤坏死因子相关凋亡诱导配体（TRAIL） 癌症治疗 中药 细胞凋亡 1 Introduction 1 Apoptosis is a physiological pattern of cell death. It not only regulates tissue homeostasis, but also is a host mechanism that eliminates undesirable cell clones. For example, apoptosis is considered the final result of antitumor immune surveillance. Like other members of the tumor necrosis factor (TNF) family, TNF-related apoptosis-inducing ligand (TRAIL) is a homotrimer expressed as a type II transmembrane protein that can be proteolytically cleaved from the cell surface and released in a soluble form ( Holland, 2013 Holland, 2013 ). TRAIL induces apoptosis through two well-known apoptotic pathways: an intrinsic pathway involving interaction with its receptors, and an extrinsic pathway ( Falschlehner et al., 2007 Falschlehner et al., 2007 ). TRAIL triggers extrinsic apoptotic pathways through its receptors death receptor 4 (DR4) and DR5. The trimerization of DR4 and DR5 occurs due to TRAIL linkage of TRAIL. By recruiting Fas-associated death domain (FADD) proteins, these multiple protein complexes are assembled into a death-inducing signaling complex (DISC) ( Wang and El-Deiry, 2003 Wang and El-Deiry, 2003 ) ( Fig. 1 Fig. 1 ). An adaptor protein is translocated to DISC, and its death domains (DDs) interact directly with the DD of the death receptors ( Trivedi and Mishra, 2015 Trivedi and Mishra, 2015 ). This protein complex assembly then begins to recruit caspase-8 and/or caspase-10, which belong to the starting caspases. These caspases, also known as apoptotic promoters, are activated automatically via proteolysis and subsequently transmit apoptotic signals to an effector caspase, such as caspase-3. Several cellular proteins dissociate from activated caspase-3 and constitute a signal cascade, leading to the biochemical and morphological features of apoptosis ( Johnstone et al., 2008 Johnstone et al., 2008 ). In most cancer cell lines, in addition to the extrinsic pathway, researchers have found that activating an intrinsic apoptotic pathway via the mitochondrial pathway regulated by B-cell lymphoma 2 (Bcl-2) can enhance TRAIL-induced apoptotic signals ( Gonzalvez and Ashkenazi, 2010 Gonzalvez and Ashkenazi, 2010 ) ( Fig. 2 Fig. 2 ). Bcl-2 homeodomain 3 interaction domain death agonist (Bid) is a substrate of caspase-8 ( Li et al., 1998 Li et al., 1998 ) that leads to an activated truncated Bid (tBid). Next, tBid interacts with Bcl-2 homologous antagonist/killer (Bak) and Bcl-2-associated X protein (Bax), which belong to the pro-apoptotic Bcl-2 family, leading to their oligomerization in the mitochondrial membrane. This causes a loss of mitochondrial membrane potential, directing the release of mitochondrial proteins, such as cytochrome c and second mitochondrial-derived activator of caspase/direct inhibitor of apoptosis protein-binding protein with low pI (SMAC/DIABLO), which participates in the pro-apoptotic process ( de Miguel et al., 2016 de Miguel et al., 2016 ). Cytochrome c bonds to pepsin-9 and apoptotic protease activating factor 1 (APAF-1) to form apoptotic bodies, causing the activation of caspase-9. Therefore, in the apoptotic effectors of caspase-3, -6, and -7, the apoptotic signal reaches a vertex, leading to apoptosis and cell death ( Almasan and Ashkenazi, 2003 Almasan and Ashkenazi, 2003 ). Although TRAIL is expressed in multifarious tissues ( Daniels et al., 2005 Daniels et al., 2005 ), it is expressed mainly in cells of the immune system, and plays a key role in inducing apoptosis of virally and oncogenically transformed cells ( Hayakawa et al., 2004 Hayakawa et al., 2004 ). TRAIL interacts with five receptors: TRAIL-R1 (DR4), TRAIL-R2 (DR5) ( Pan et al., 1997 Pan et al., 1997 ), TRAIL-R3 (DcR1/TRID/LIT), TRAIL-R4 (DcR2/TRUNND), and osteoprotegerin (OPG) ( Kwilas et al., 2016 Kwilas et al., 2016 ). DR4 and DR5 each contain a conserved DD motif and function in apoptotic signaling. TRAIL-induced apoptosis can be inhibited by the overexpression of these proteins, which act as "decoys." Although DcR2 has a truncated non-functional cytoplasmic DD, DcR1 lacks a cytoplasmic region. The physiological relevance of OPG as a TRAIL receptor is unclear ( Wang and El-Deiry, 2003 Wang and El-Deiry, 2003 ). Because DR4 and DR5 are expressed mainly in cancer cells, rather than in most untransformed cells, selective apoptosis can be triggered without significant tissue toxicity. This makes using other agonists or TRAIL for cancer treatment by DR4/DR5 a promising methodology ( de Miguel et al., 2016 de Miguel et al., 2016 ). As previously mentioned, Bcl-2 family proteins also play significant roles in apoptosis induced by TRAIL. A subset of these proteins routinely governs the intrinsic apoptotic pathway. In addition to the Bcl homologous domain 3 (BH-3) only proteins, there are four BHs (BH1‍–‍4) ( Lemke et al., 2014 Lemke et al., 2014 ). These include: the anti-apoptotic proteins Bcl-2, Bcl-xL, Bcl-B, Bcl-w, myeloid cell leukemia-1 (Mcl-1), and A1; the pro-apoptotic proteins Bax, Bak, and Bcl-2-related ovarian killer (Bok); and the BH-3 only proteins Bid, Bcl-2-interacting mediator of cell death (Bim), p53 up-regulated modulator of apoptosis (Puma), Bik, and Noxa ( Yamaguchi et al., 2019 Yamaguchi et al., 2019 ). Structural studies have shown the importance of the interaction of these protein domains to anti-apoptotic and pro-apoptotic effects. For example, anti-apoptotic activity is neutralized by pro-apoptotic proteins, thus breaking down the obstacle to apoptosis induction during cytotoxic stress. Similarly, increasing the activation of Bak and Bax further guides caspase activation and enhances the apoptosis process ( Delbridge and Strasser, 2015 Delbridge and Strasser, 2015 ). During cytotoxic stress, caspase-8 activation leads to Bid rupture and the formation of tBid, directs the oligomerization of Bak and Bax, and subsequently causes mitochondrial outer membrane permeability (MOMP), which is a marker of the intrinsic apoptotic pathway. Intermembrane space proteins such as cytochrome c are subsequently released. This triggers the activation of the caspase cascade, resulting in cell death ( Kalkavan and Green, 2018 Kalkavan and Green, 2018 ). However, the existence of anti-apoptotic proteins inhibits apoptosis by maintaining mitochondrial membrane integrity against Bax and Bak activity ( Seervi et al., 2018 Seervi et al., 2018 ). Because Bcl-2 plays an important role in regulating apoptosis, TRAIL's regulation of the intrinsic apoptotic pathway is strictly dependent on cell type. TRAIL can induce wild-type cytochrome c release and apoptosis, which proves the importance of these two molecules in apoptosis. It takes place in Bax -/- or Bak -/- mouse embryonic fibroblasts, but not in double-knockout Bax -/- /Bak -/- cells ( Zhang and Fang, 2005 Zhang and Fang, 2005 ). The impact of Bcl-2 in regulating apoptosis has been further proved by knockout studies of pro-apoptotic proteins, as has the mechanism by which the absence of Bcl-2 reverses the difficulty in inducing apoptosis ( Huang and Sinicrope, 2008 Huang and Sinicrope, 2008 ). The level of Bcl-2 anti-apoptosis protein can be inhibited by compound management, thereby eliminating the blocking of TRAIL-induced apoptosis ( Kisim et al., 2012 Kisim et al., 2012 ). In summary, the resistance to apoptosis induced by TRAIL can be reduced via the following mechanisms: upregulation of death receptors (DR5 or DR4); downregulation of cell survival proteins such as Bcl-2, Bcl-xL, survivin, the X-linked inhibitor of apoptosis protein (XIAP), and Mcl-1, as well as cellular FADD-like interleukin-1β (IL-1β)-converting enzyme (FLICE)-like inhibitory proteins (c-FLIP, a caspase-8 inhibitor also known as I-FLICE); or upregulation of pro-apoptotic proteins and downregulation of TRAIL-binding antagonistic decoy receptors that lack the functional domains necessary for transduction of apoptosis signals ( Gupta et al., 2013 Gupta et al., 2013 ) ( Fig. 3 Fig. 3 ). In theory, TRAIL can be used as an inducing factor in many human cancers and is an ideal target for cancer treatments. However, there are many tumor cells that show insensitivity or even resistance to it. This has become a major problem for scientists. The clinical effects of TRAIL, when applied individually, are often unsatisfactory ( Kretz et al., 2018 Kretz et al., 2018 ). Therefore, it is very important to find effective TRAIL sensitizers to reverse the resistance of tumor cells to TRAIL and enhance the ability of TRAIL to induce tumor cell apoptosis. The combination of some traditional Chinese medicines (TCMs) and TRAIL is a promising way to reverse acquired TRAIL resistance, and also a very promising treatment option. Many studies have demonstrated that in cancer treatment, the combination of Chinese herbal medicine with chemotherapy, radiation therapy, or targeted therapy can be used to enhance the efficacy and reduce the side effects and complications caused by the therapies ( Wang et al., 2018 Wang et al., 2018 ). The compounds of TCM have shown characteristics of low toxicity and high efficiency, and have multiple targets. Furthermore, their corresponding anti-tumor sensitizing effects have attracted increasing attention, rendering TCM an important source of new anti-tumor drugs ( Singh et al., 2014 Singh et al., 2014 ). In this review, we summarize the role of TCMs and their ingredients capable of actively sensitizing TRAIL to induce cancer cell apoptosis. 2 Combining TRAIL with traditional Chinese medicine to promote tumor cell apoptosis 1 2.1 Compounds used in Chinese medicine induce apoptosis by upregulating DR5 in cancer 2 Auriculasin (AC), sourced for example from roots of Flemingia macrophylla (Willd.) Merr., is found in various food ingredients as a prenylated isoflavone ( Wang et al., 2013 Wang et al., 2013 ). AC can lead to cellular apoptosis and thus reduce tumor growth by targeting reactive oxygen species (ROS)-mediated caspase-independent pathways and inhibiting phosphoinositide-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling ( Cho et al., 2018 Cho et al., 2018 ). Prostate cancer is the most common cancer globally, and an important cause of cancer-induced death in males. Co-treatment with TRAIL and non-cytotoxic concentrations of AC can increase the apoptosis of RC-58T/h/SA#4 cells, which have observable resistance to TRAIL. AC can also effectively reduce the expression of apoptosis-related proteins and AC-TRAIL-induced cell death by pretreatment with a chimeric blocking antibody against DR5. This indicates that non-toxic concentrations of AC make TRAIL-resistant primary prostate cancer cells sensitive to TRAIL-mediated apoptosis by upregulating downstream signaling pathways and DR5 ( Cho et al., 2019 Cho et al., 2019 ). Clematis flammula L. (CFI) is an herb native to North Africa and Southern Europe, and is widely used in TCM. CFI is used by the Chinese to treat rheumatism. In recent reports, its component, boehmenan, has been confirmed to induce lung cancer cell apoptosis by regulating epidermal growth factor (EGF)-dependent pathways ( Pan et al., 2016 Pan et al., 2016 ). Clematis hederagenin saponin (CHS), another compound extracted from CFI, can also induce apoptosis through the mitochondrial pathway in breast cancer cells ( Cheng et al., 2018 Cheng et al., 2018 ). In another experiment, HCT116 cells of colon cancer were treated by a combination of CFI and TRAIL. Compared to cells treated with CFI or TRAIL alone, it was found that CFI synergizes with TRAIL by downregulating the expression of cell survival proteins involved in apoptosis. The results showed that CF1 sensitizes TRAIL-resistant cells to apoptosis by activating DR5-expressing mitogen-activated protein kinase (MAPK), SP1, and CCAAT/enhancer-binding protein homologous protein (CHOP) ( Guesmi et al., 2019 Guesmi et al., 2019 ). Luteolin is an important family member of the flavonoids and is highly distributed in vegetables, fruits, tea, olive oil, honeycomb propolis, and red wine ( Mittra et al., 2000 Mittra et al., 2000 ). It exists in the form of glycoside in Chinese herbal medicines such as Lonicera japonica Thunb, Perilla frutescens (L.) Britton, and Dendranthema morifolium (Ramat.) Tzvelev ( Hempel et al., 1999 Hempel et al., 1999 ). Luteolin is effective against oxidation, inflammation, and cancer, and has an ability to reverse multidrug resistance (MDR) in many types of cancer cells ( Ou et al., 2013 Ou et al., 2013 ). It can also weaken the cytotoxicity caused by various chemotherapeutic drugs ( Lin et al., 2008 Lin et al., 2008 ). Luteolin can directly induce apoptosis by activating c-Jun NH 2 -terminal kinase (JNK), thereby inhibiting TNF-‍α‍-mediated nuclear factor-‍κB (NF-‍κB) p65 to nuclear ( Cai et al., 2011 Cai et al., 2011 ). It has been proven that luteloin can inhibit gastric cancer (GC) progression by suppressing Notch1 signaling and reversing epithelial-mesenchymal transition (EMT) ( Zang et al., 2017 Zang et al., 2017 ). Furthermore, it has been demonstrated that luteolin, as a flavonoid, can cross the blood–brain barrier ( Youdim et al., 2004 Youdim et al., 2004 ). In hepatocellular carcinoma (HCC) cells, treatment with TRAIL or luteolin alone causes little or no cell death, while co-treatment with TRAIL and an increasing concentration of luteolin can significantly reduce cell viability as well as increase apoptotic bodies. Luteolin induces autophagy and sensitizes cells to TRAIL‑induced apoptosis, and its treatments significantly upregulate microtubule-associated protein light chain 3 (LC3)‑II and downregulate p62 expression, which is consistent with DR5 upregulation. These outcomes suggest that luteolin sensitizes TRAIL-induced apoptosis by upregulating DR5 expression ( Nazim and Park, 2019 Nazim and Park, 2019 ). It has been reported that tetrandine (TET), a natural compound isolated from Stephania tetrandra S. Moore, has been used to treat inflammation and hypertension in China for hundreds of years. It has shown a variety of pharmacological activities, including immunosuppressive, antihypertensive, and antitumor activities ( Wang et al., 2004 Wang et al., 2004 ). In recent years, TET's novel antitumor effects have been extensively studied. Impressively, TET affects various biological activities of cancer cells, including inhibition of invasion, migration, proliferation, and angiogenesis. It induces autophagy and apoptosis, and also enhances radiation sensitivity and MDR ( Liu T et al., 2016 Liu T et al., 2016 ). TET derivative H1 exerts anti-MDR activity by inhibiting the activation of Erk1/2, Akt1/2, and an intrinsic apoptotic pathway ( Wei et al., 2011 Wei et al., 2011 ). In prostate cancer, TET treatment leads to increased levels of DR5 and DR4 proteins. To clarify the functions of DR5 and DR4 in sensitizing TET to TRAIL in LNCaP cells, researchers used a lentiviral short hairpin RNA (shRNA) construct to knock down TET and TRAIL. Based on western blot analysis results, DK cells (lentivirus shRNA-transfected LNCaP cells infected simultaneously with DR4 and DR5) showed a significant reduction in the levels of DR4/DR5 protein, but TET treatment failed to affect their protein levels (20 μmol/L for 24 h). Next, researchers figured out the concentration-dependent effect of TET on DR4/DR5 protein levels in DK cells and LNCaP shRNA control (scrl)-control cells. In LNCaP scrl-control cells, they discovered that TET treatment led to a time-dependent increase in the levels of DR4 and DR5 mRNA, yet this effect was not seen in DK cells. Therefore, DR4 and DR5 are necessary for inducing PCa cells to sensitize TRAIL by TET ( Shishodia et al., 2018 Shishodia et al., 2018 ). Ginsenoside is the main active ingredient from Panax ginseng C.A. Meyer. The protopanaxadiol-type ginsenosides include CK, CMc, CMc1, CO, CY, Rb1, Rb2, Rc, Rd, F2, Rg3, and Rh2. CK is regarded as the major ginsenoside metabolite in blood and urine ( Hasegawa et al., 1997 Hasegawa et al., 1997 ). It is reported that CK enhances the apoptosis induced by γ rays by generating ROS in human lung cancer cells and destroying mitochondrial membranes ( Chae et al., 2009 Chae et al., 2009 ). CK can also induce apoptosis and autophagy by activating JNK and producing ROS in human colon cancer cells ( Kim et al., 2013 Kim et al., 2013 ). TRAIL can also induce apoptosis in colon cancer cells. In an experiment examining the effect of CK on the expression of TRAIL DRs, the results showed that DR5 and DcR2 were upregulated in a dose-dependent manner. Additionally, CK treatment can increase cell surface expression and DR5 transcription, which coincides with protein changes. To further substantiate these findings, the expression of DR5 can be silenced by applying two specific small interfering RNAs (siRNAs). The silencing of DR5 reduced the percentage of cell apoptosis induced by CK, as indicated by flow cytometry analysis. This evidence indicates that DR5 plays a decisive role in enhancing the influence of CK on TRAIL-induced apoptosis ( Chen et al., 2016 Chen et al., 2016 ). Triptolide is a diterpenoid compound isolated from the Chinese herbal medicine Tripterygium wilfordii Hook F., which can effectively induce apoptosis and autophagy in a variety of cancer types, including neuroblastoma ( Antonoff et al., 2009 Antonoff et al., 2009 ; Krosch et al., 2013 Krosch et al., 2013 ), pancreatic cancer ( Mujumdar et al., 2010 Mujumdar et al., 2010 ), and colon cancer ( Dudeja et al., 2009 Dudeja et al., 2009 ). It can also sensitize a variety of solid tumor cells to TRAIL-induced cell death ( Clawson et al., 2010 Clawson et al., 2010 ). Research indicates that triptolide can sensitize various cancer cells to apoptosis induced by the TRAIL-induced death receptor pathway. Triptolide treatment can result in p53 accumulation and inhibit the Akt/Hdm2 signaling pathway, which upregulates DR5 expression and makes prostate cancer cells significantly more sensitive to TRAIL-mediated apoptosis ( Hu and Sun, 2012 Hu and Sun, 2012 ). In pancreatic cancer, it increases the death receptor DR5 levels and the pre-survival c-FLIP is decreased, thus promoting the activation of caspase-8. This combination further results in cell death ( Chen ZY et al., 2014 Chen ZY et al., 2014 ). In vivo treatment of mice bearing renal cell carcinoma (RCC) in situ showed that TRAIL induced increases in apoptosis and death of human RCC cells in the presence of triptolide. Treatment of Renca mice with Minnelide and anti-DR5 monoclonal antibody (mAb) was able to significantly reduce the tumor burden and prolong survival time ( Brincks et al., 2015 Brincks et al., 2015 ). Andrographolide (Andro) is a diterpene lactone isolated from the traditional herbal medicine Andrographis paniculata (Burm. F.) Nees. It is known that the compound exerts anti-inflammatory activity primarily by inhibiting the nuclear transcription factor NF-‍κB ( Xia et al., 2004 Xia et al., 2004 ). According to a research report, Andro is able to induce apoptosis of human cancer cells via the DR-mediated apoptosis pathway. Through the p53-dependent transcriptional upregulation of DR4 to achieve this sensitization, this process is mediated by multiple consecutive events, including the production of ROS, the activation of JNK, and p53 stabilization and phosphorylation ( Zhou et al., 2008 Zhou et al., 2008 ). In bladder cancer, co-therapy by TRAIL and Andro can inhibit the growth of T24 cells, reduce proliferation and colony formation, inhibit migration, and promote caspase-mediated apoptosis. Andro's sensitization is achieved by upregulating DR4 and DR5 in a p53-dependent manner. Additionally, Andro is able to inactivate the NF-‍κB signaling pathway by downregulating p65/RelA, which further contributes to TRAIL-mediated cytotoxicity ( Deng et al., 2019 Deng et al., 2019 ). Moreover, Andro increases p53 expression in prostate cancer cells, and also leads to ROS production in cells. At low toxic concentrations, Andro preferentially increases the sensitivity of PCa cells to TRAIL-induced apoptosis, and the regulatory mechanism is related to the increase in DR4 ( Wei et al., 2018 Wei et al., 2018 ). 2.2 Compounds used in Chinese medicine sensitize TRAIL-induced apoptosis through intrinsic pathways in cancer 2 Curcumin (Cur), found in the rhizomes of TCM Zingiber officinale Roscoe, is a highly pleiotropic molecule ( Devassy et al., 2015 Devassy et al., 2015 ). Cur has shown strong antioxidative, anti-inflammatory, antiangiogenic, anticancer, and pro-apoptosis properties ( Aggarwal et al., 2003 Aggarwal et al., 2003 ). In nanoparticles (TRAIL-Cur-NPs), TRAIL is used as both a therapeutic agent and an active targeting ligand. Cur can upregulate DR4 and DR5 to enhance the apoptosis-inducing effect of TRAIL ( Yang et al., 2017 Yang et al., 2017 ). Extensive research has shown that Cur has chemopreventive properties, mainly because it has the ability to prevent the cancer cell cycle when used independently or in combination with radiation therapy or chemotherapy. Cur also induces cancer cell apoptosis by regulating a variety of important cellular signaling pathways, including JNK, NF-κB, Janus kinase/signal transducers and activators of transcription (JAK/STAT), PI3K/Akt, Notch-1, and TRAIL. Cur is known to induce apoptosis of cancer cells and activate cell death signals, and inhibit tumor progression without affecting normal cells ( Chen J et al., 2014 Chen J et al., 2014 ). It has been shown to sensitize TRAIL-resistant cells to apoptosis. Treatment with Cur can produce intracellular ROS and inhibit Akt activity, thereby increasing the quantity of DR5 after activating NF-κB ( Deeb et al., 2004 Deeb et al., 2004 ). Cur inhibits NF-κB by inhibiting the pro-survival Akt signaling pathway, thereby making human prostate cancer cells sensitive to TRAIL-induced apoptosis ( Deeb et al., 2007 Deeb et al., 2007 ). Research also shows that Cur sensitizes breast cancer cells to TRAIL-induced apoptosis by regulating apoptosis-related proteins. Data suggest that Cur-induced Mcl-1 in MCF-7 cells may reduce the Cur-induced sensitization to TRAIL, while Cur downregulates Mcl-1 in SK-BR-3 and T47D cells, which may help sensitize cancer cells to TRAIL ( Park et al., 2013 Park et al., 2013 ). Magnolol is a biologically active compound extracted from Magnolia officinalis Rehder. It has many pharmacological effects, such as anti-depressive, antioxidant, anti-inflammatory, and anti-tumor properties ( Chuang et al., 2011 Chuang et al., 2011 ). Evidence suggests that magnolol may be applied as a therapeutic agent for a variety of cancers, such as breast, lung, prostate, and colon cancers. For lung cancer, magnolol or polyphenol mixture (PM) treatment increased the expression of the pro-apoptotic protein Bax significantly, while it inhibited the expression of the anti-apoptotic protein Bcl-2. Moreover, in A549 and H1299 cells, magnolol and PM treatments significantly increased capsase-3, as well as the levels of PARP cleavage protein and caspase-3 cleavage ( Liu YT et al., 2016 Liu YT et al., 2016 ). Honokiol is also a natural biochenolic compound extracted from the Magnolia plant. It can activate caspase-3, -8, and -9 through TRAIL treatment, whereas its upregulation of DR5 does not participate in the increase of TRAIL sensitivity. In addition, honokiol reduces survivin and c-FLIP to increase TRAIL sensitivity ( Woo et al., 2019 Woo et al., 2019 ). Bakuchiol, a pre-cured phenolic monomer isolated from the seeds of the pine cell Cullen corylifolium (L.) Medik, is commonly used in traditional folk medicine in India and China as a nephrogenic agent to relieve diarrhea, osteoporosis, and asthma ( Lim et al., 2009 Lim et al., 2009 ; Chen et al., 2010 Chen et al., 2010 ; Xu et al., 2014 Xu et al., 2014 ). A previous study has shown that bakuchiol can activate JNK and then transfer Bax to the mitochondria of rat liver fibroblasts to induce caspase-3-dependent apoptosis ( Park et al., 2005 Park et al., 2005 ). Also, bakuchiol exerts an anti-tumor effect in lung cancer cells through activating caspase-9/3 and p53, arresting cells in S-phase, upregulating Bax, and downregulating Bcl-2 through apoptosis, which is related to ROS ( Chen et al., 2010 Chen et al., 2010 ). Further research may prove that bakuchiol can enhance the anti-tumor activity of TRAIL. In colon cancer, experiments show that only HCT116 cells are sensitive to TRAIL. Even at concentrations as high as 50 or 100 ng/mL, HT-29 and HCT116 cancer cells are resistant to TRAIL (data not shown). However, when bakuchiol was combined with TRAIL, it enhanced TRAIL-induced cytotoxicity in TRAIL-resistant HT-29 cells and TRAIL-sensitive HCT116 cells. The experimental results indicated that bakuchiol reduced the expression of Bcl-2, survivin, XIAP, and c-FLIP via the overexpression of DR4 and DR5 to overcome TRAIL resistance ( Park et al., 2016 Park et al., 2016 ). Shikonin is a crude ingredient from the roots of Lithospermum erythrorhizon Siebold & Zucc. that has for centuries been widely used in China to treat many diseases ( Huang et al., 2014 Huang et al., 2014 ; Wang et al., 2019 Wang et al., 2019 ). Shikonin has been demonstrated to have antiproliferative ability ( Gong and Li, 2011 Gong and Li, 2011 ; Gorrini et al., 2013 Gorrini et al., 2013 ). It can enhance cytotoxicity and reverse drug resistance to chemotherapy ( Huang, 2007 Huang, 2007 ; Lee et al., 2015 Lee et al., 2015 ; He et al., 2016 He et al., 2016 ), and has the ability to inhibit the invasion and migration of cancer cells and kill certain cancer cells, while causing less cytotoxicity to normal cells ( Goncharenko-Khaider et al., 2010 Goncharenko-Khaider et al., 2010 ; Li et al., 2014 Li et al., 2014 ; He et al., 2016 He et al., 2016 ). In cholangiocarcinoma cells, ROS-triggered JNK contributes to the TRAIL-induced antiproliferative activity of shikonin and induces apoptosis ( Zhou et al., 2017 Zhou et al., 2017 ). In the same way, the AKT, JNK, and signal transducer and activator of transcription 3 (STAT3) pathways are engaged in shikonin-mediated sensitization of TRAIL in A549 cells. More importantly, cotreatment with shikonin and TRAIL can inhibit the expression of anti-apoptotic proteins such as Bcl-2, Bcl-xL, Mcl-1, XIAP, and c-FLIP. This can enhance Bid expression, but has no effect on Bax expression ( Guo et al., 2018 Guo et al., 2018 ). Recently, a study also found that in HepG2 cells, acetylshikonin, a shikonin derivative, was able to combine with TRAIL to activate the caspase signaling pathway. Furthermore, Bax promotes the apoptosis induced by TRAIL and acetylshikonin ( Hong et al., 2019 Hong et al., 2019 ). Irigenin is an isoflavonoid ( Jung et al., 2002 Jung et al., 2002 ) isolated from the rhizomes of Iris domestica (L.) Goldblatt & Mabb. ( Wozniak et al., 2010 Wozniak et al., 2010 ). I. domestica (L.) Goldblatt & Mabb. has long been used as an antidote, expectorant, antiphlogistic, analgesic, and antipyretic agent, and is a TCM ( Zhang et al., 2016 Zhang et al., 2016 ). Irigenin has been found to have an antiproliferative effect on cancer cells ( Morrissey et al., 2004 Morrissey et al., 2004 ). A recent study showed that irigenin can sensitize GC cells to TRAIL-regulated cell death. When irigenin was combined with TRAIL, the expression of Bax, FADD, and DR5 was greatly enhanced, while the expression of survivin, c-FLIP, and Bcl-2 was strongly reduced. The results show that irigenin sensitizes GC cells to TRAIL-induced apoptosis by increasing pro-apoptotic proteins and reducing anti-apoptotic proteins ( Xu et al., 2018 Xu et al., 2018 ). Berberine, a natural alkaloid, is isolated from many medicinal herbs, such as the Chinese herbs Berberis vulgaris L., Berberis aquifolium Pursh, and Coptis chinensis Franch. ( Eom et al., 2008 Eom et al., 2008 ). Studies have shown that berberine targets multiple pathways to induce apoptosis in cultured human colon cancer cells ( Murthy et al., 2012 Murthy et al., 2012 ; Guamán Ortiz et al., 2014 Guamán Ortiz et al., 2014 ). TRAIL enhances berberine-mediated p38 activation and counteraction ( Refaat et al., 2015 Refaat et al., 2015 ). In the murine 4T1 breast cancer model, the combined treatment of DR5 and berberine can effectively inhibit primary tumor growth and metastasis ( Refaat et al., 2013 Refaat et al., 2013 ). Also, DR5 participates in the apoptosis caused by the TRAIL-berberine combination ( Ke et al., 2018 Ke et al., 2018 ). Furthermore, berberine can enhance TRAIL-induced apoptosis in human renal cancer cells through ROS-mediated downregulation of Mcl-1 and c-FLIP proteins ( Lee et al., 2011 Lee et al., 2011 ). 3 Conclusions 1 This review briefly summarizes the apoptotic effects of activated TRAIL when combined with different TCM components through intrinsic or extrinsic pathways ( Table 1 Table 1 ), and also reveals its physiological role in cancer. Various reports have shown that different compounds derived from Chinese herbal medicines can make tumor cells sensitive to TRAIL by directly activating intrinsic apoptotic pathways or regulating multiple non-apoptotic pathways to upregulate DR. Bcl-2: B-cell lymphoma 2, an anti-apoptotic protein; Bax: Bcl-2-associated X protein, a pro-apoptotic protein; c-FLIP: cellular FADD-like interleukin-1β (IL-1β)-converting enzyme (FLICE)-like inhibitory protein; DR4: death receptor 4, a receptor of TRAIL (TRAIL-R1); DR5: a receptor of TRAIL (TRAIL-R2); FADD: Fas-associated death domain (DD); Mcl-1: an anti-apoptotic protein; survivin, a member of the inhibitor of apoptosis protein (IAP) family with caspase activation inhibition functions; TRAIL: tumor necrosis factor-related apoptosis-inducing ligand; XIAP: X-linked IAP protein. Compound Source of Chinese herbal medicine(s) Tumor cell type Mechanism of action Auriculasin Flemingia macrophylla (Willd.) Merr. Prostate cancer DR5↑ Boehmenan, Clematis hederagenin saponin Clematis flammula L. Colon cancer DR5↑ Luteolin Lonicera japonica Thunb, Perilla frutescens (L.) Britton, Dendranthema morifolium (Ramat.) Tzvelev Hepatocellular carcinoma DR5↑ Tetrandine Stephania tetrandra S. Moore Prostate cancer DR4↑, DR5↑ Ginsenoside Panax ginseng C.A. Meyer Colon cancer DR5↑ Triptolide Tripterygium wilfordii Hook F. Pancreatic cancer DR5↑, c-FLIP↓ Andrographolide Andrographis paniculata (Burm. F.) Nees Prostate cancer DR4↑ Curcumin Zingiber officinale Roscoe Breast cancer Mcl-1↓ Magnolol Magnolia officinalis Rehder Lung cancer Bax↑, Bcl-2↓ Bakuchiol Cullen corylifolium (L.) Medik Colon cancer Bcl-2↓, survivin↓, XIAP↓, c-FLIP↓ Shikonin Lithospermum erythrorhizon Siebold & Zucc. Lung cancer Bcl-2↓, Bcl-xL↓, Mcl-1↓, XIAP↓,c-FLIP↓ Irigenin Iris domestica (L.) Goldblatt & Mabb. Gastric cancer Bax↑, Bcl-2↓, survivin↓, c-FLIP↓ Berberine Berberis vulgaris L., Berberis aquifolium Pursh, Coptis chinensis Franch. Renal cancer Mcl-1↓, c-FLIP↓ Nevertheless, most of the studies were performed in preclinical mouse models or cell lines of cancer. Therefore, more clinical evidence is needed to confirm whether these Chinese herbal medicine derivatives can also synergize with TRAIL in cancer patients. Some other challenges remain. For instance, TRAIL can selectively induce apoptosis of tumor cells or transformed cells, but the mechanism of insensitivity to TRAIL in normal cells is still not completely clear. The molecular mechanisms that cause TRAIL resistance in tumor cells have also not been elucidated. Thus, more work is needed to address the mechanism of TRAIL resistance, which could lead to the development of new treatments to restore TRAIL sensitivity. In addition, TRAIL is known to induce tumor metastasis and activate survival pathways ( Trauzold et al., 2001 Trauzold et al., 2001 ; Hartwig et al., 2017 Hartwig et al., 2017 ), although the detailed functions of the TRAIL pathway in drug resistance and tumor metastasis are not yet fully understood. In recent years, the influence of TRAIL on cancer treatment has attracted increasing attention. With advancements in understanding of the mechanism of TRAIL and the elucidation of TRAIL-sensitive biomarkers, new TRAIL sensitizers will be discovered. This progress will be useful for the development of therapies based on TRAIL and new types of anticancer drugs to treat human cancers. References Aggarwal BB , Kumar A , Bharti AC , 2003 . Anticancer potential of curcumin: preclinical and clinical studies . Anticancer Res , 23 ( 1A ): 363 - 398 . Anticancer potential of curcumin: preclinical and clinical studies Almasan A , Ashkenazi A , 2003 . Apo2L/TRAIL: apoptosis signaling, biology, and potential for cancer therapy . Cytokine Growth Factor Rev , 14 ( 3-4 ): 337 - 348 . https://doi.org/10.1016/S1359-6101(03)00029-7 https://doi.org/10.1016/S1359-6101(03)00029-7 Apo2L/TRAIL: apoptosis signaling, biology, and potential for cancer therapy Antonoff MB , Chugh R , Borja-Cacho D , et al. , 2009 . Triptolide therapy for neuroblastoma decreases cell viability in vitro and inhibits tumor growth in vivo . Surgery , 146 ( 2 ): 282 - 290 . https://doi.org/10.1016/j.surg.2009.04.023 https://doi.org/10.1016/j.surg.2009.04.023 Triptolide therapy for neuroblastoma decreases cell viability in vitro and inhibits tumor growth in vivo Brincks EL , Kucaba TA , James BR , et al. , 2015 . Triptolide enhances the tumoricidal activity of TRAIL against renal cell carcinoma . FEBS J , 282 ( 24 ): 4747 - 4765 . https://doi.org/10.1111/febs.13532 https://doi.org/10.1111/febs.13532 Triptolide enhances the tumoricidal activity of TRAIL against renal cell carcinoma Cai XT , Ye TM , Liu C , et al. , 2011 . Luteolin induced G2 phase cell cycle arrest and apoptosis on non-small cell lung cancer cells . Toxicol in Vitro , 25 ( 7 ): 1385 - 1391 . https://doi.org/10.1016/j.tiv.2011.05.009 https://doi.org/10.1016/j.tiv.2011.05.009 Luteolin induced G2 phase cell cycle arrest and apoptosis on non-small cell lung cancer cells Chae S , Kang KA , Chang WY , et al. , 2009 . Effect of compound K, a metabolite of ginseng saponin, combined with γ-ray radiation in human lung cancer cells in vitro and in vivo . J Agric Food Chem , 57 ( 13 ): 5777 - 5782 . https://doi.org/10.1021/jf900331g https://doi.org/10.1021/jf900331g Effect of compound K, a metabolite of ginseng saponin, combined with γ-ray radiation in human lung cancer cells in vitro and in vivo Chen J , Wang FL , Chen WD , 2014 . Modulation of apoptosis-related cell signalling pathways by curcumin as a strategy to inhibit tumor progression . Mol Biol Rep , 41 ( 7 ): 4583 - 4594 . https://doi.org/10.1007/s11033-014-3329-9 https://doi.org/10.1007/s11033-014-3329-9 Modulation of apoptosis-related cell signalling pathways by curcumin as a strategy to inhibit tumor progression Chen L , Meng Y , Sun Q , et al. , 2016 . Ginsenoside compound K sensitizes human colon cancer cells to TRAIL-induced apoptosis via autophagy-dependent and -independent DR5 upregulation . Cell Death Dis , 7 ( 8 ): e2334 . https://doi.org/10.1038/cddis.2016.234 https://doi.org/10.1038/cddis.2016.234 Ginsenoside compound K sensitizes human colon cancer cells to TRAIL-induced apoptosis via autophagy-dependent and -independent DR5 upregulation Chen Z , Jin K , Gao LY , et al. , 2010 . Anti-tumor effects of bakuchiol, an analogue of resveratrol, on human lung adenocarcinoma A549 cell line . Eur J Pharmacol , 643 ( 2 - 3 ): 170 - 179 . https://doi.org/10.1016/j.ejphar.2010.06.025 https://doi.org/10.1016/j.ejphar.2010.06.025 Anti-tumor effects of bakuchiol, an analogue of resveratrol, on human lung adenocarcinoma A549 cell line Chen ZY , Sangwan V , Banerjee S , et al. , 2014 . Triptolide sensitizes pancreatic cancer cells to TRAIL-induced activation of the Death Receptor pathway . Cancer Lett , 348 ( 1-2 ): 156 - 166 . https://doi.org/10.1016/j.canlet.2014.03.016 https://doi.org/10.1016/j.canlet.2014.03.016 Triptolide sensitizes pancreatic cancer cells to TRAIL-induced activation of the Death Receptor pathway Cheng L , Shi L , Wu J , et al. , 2018 . A hederagenin saponin isolated from Clematis ganpiniana induces apoptosis in breast cancer cells via the mitochondrial pathway . Oncol Lett , 15 ( 2 ): 1737 - 1743 . https://doi.org/10.3892/ol.2017.7494 https://doi.org/10.3892/ol.2017.7494 A hederagenin saponin isolated from Clematis ganpiniana induces apoptosis in breast cancer cells via the mitochondrial pathway Cho HD , Lee JH , Moon KD , et al. , 2018 . Auriculasin-induced ROS causes prostate cancer cell death via induction of apoptosis . Food Chem Toxicol , 111 : 660 - 669 . https://doi.org/10.1016/j.fct.2017.12.007 https://doi.org/10.1016/j.fct.2017.12.007 Auriculasin-induced ROS causes prostate cancer cell death via induction of apoptosis Cho HD , Gu IA , Won YS , et al. , 2019 . Auriculasin sensitizes primary prostate cancer cells to TRAIL-mediated apoptosis through up-regulation of the DR5-dependent pathway . Food Chem Toxicol , 126 : 223 - 232 . https://doi.org/10.1016/j.fct.2019.02.030 https://doi.org/10.1016/j.fct.2019.02.030 Auriculasin sensitizes primary prostate cancer cells to TRAIL-mediated apoptosis through up-regulation of the DR5-dependent pathway Chuang TC , Hsu SC , Cheng YT , et al. , 2011 . Magnolol down-regulates HER2 gene expression, leading to inhibition of HER2-mediated metastatic potential in ovarian cancer cells . Cancer Lett , 311 ( 1 ): 11 - 19 . https://doi.org/10.1016/j.canlet.2011.06.007 https://doi.org/10.1016/j.canlet.2011.06.007 Magnolol down-regulates HER2 gene expression, leading to inhibition of HER2-mediated metastatic potential in ovarian cancer cells Clawson KA , Borja-Cacho D , Antonoff MB , et al. , 2010 . Triptolide and TRAIL combination enhances apoptosis in cholangiocarcinoma . J Surg Res , 163 ( 2 ): 244 - 249 . https://doi.org/10.1016/j.jss.2010.03.067 https://doi.org/10.1016/j.jss.2010.03.067 Triptolide and TRAIL combination enhances apoptosis in cholangiocarcinoma Daniels RA , Turley H , Kimberley FC , et al. , 2005 . Expression of TRAIL and TRAIL receptors in normal and malignant tissues . Cell Res , 15 ( 6 ): 430 - 438 . https://doi.org/10.1038/sj.cr.7290311 https://doi.org/10.1038/sj.cr.7290311 Expression of TRAIL and TRAIL receptors in normal and malignant tissues de Miguel D , Lemke J , Anel A , et al. , 2016 . Onto better TRAILs for cancer treatment . Cell Death Differ , 23 ( 5 ): 733 - 747 . https://doi.org/10.1038/cdd.2015.174 https://doi.org/10.1038/cdd.2015.174 Onto better TRAILs for cancer treatment Deeb D , Jiang H , Gao XH , et al. , 2004 . Curcumin sensitizes prostate cancer cells to tumor necrosis factor-related apoptosis-inducing ligand/Apo2L by inhibiting nuclear factor-κB through suppression of IκBα phosphorylation . Mol Cancer Ther , 3 ( 7 ): 803 - 812 . Curcumin sensitizes prostate cancer cells to tumor necrosis factor-related apoptosis-inducing ligand/Apo2L by inhibiting nuclear factor-κB through suppression of IκBα phosphorylation Deeb D , Jiang H , Gao XH , et al. , 2007 . Curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)-1-6-heptadine-3,5-dione;C21H 20 O 6 ] sensitizes human prostate cancer cells to tumor necrosis factor-related apoptosis-inducing ligand/Apo2L-induced apoptosis by suppressing nuclear factor-κB via inhibition of the prosurvival Akt signaling pathway . J Pharmacol Exp Ther , 321 ( 2 ): 616 - 625 . https://doi.org/10.1124/jpet.106.117721 https://doi.org/10.1124/jpet.106.117721 Curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)-1-6-heptadine-3,5-dione;C21H20O6] sensitizes human prostate cancer cells to tumor necrosis factor-related apoptosis-inducing ligand/Apo2L-induced apoptosis by suppressing nuclear factor-κB via inhibition of the prosurvival Akt signaling pathway Delbridge ARD , Strasser A , 2015 . The BCL-2 protein family, BH3-mimetics and cancer therapy . Cell Death Differ , 22 ( 7 ): 1071 - 1080 . https://doi.org/10.1038/cdd.2015.50 https://doi.org/10.1038/cdd.2015.50 The BCL-2 protein family, BH3-mimetics and cancer therapy Deng YY , Bi R , Guo HR , et al. , 2019 . Andrographolide enhances TRAIL-induced apoptosis via p53 -mediated death receptors up-regulation and suppression of the NF-κB pathway in bladder cancer cells . Int J Biol Sci , 15 ( 3 ): 688 - 700 . https://doi.org/10.7150/ijbs.30847 https://doi.org/10.7150/ijbs.30847 Andrographolide enhances TRAIL-induced apoptosis via p53-mediated death receptors up-regulation and suppression of the NF-κB pathway in bladder cancer cells Devassy JG , Nwachukwu ID , Jones PJH , 2015 . Curcumin and cancer: barriers to obtaining a health claim . Nutr Rev , 73 ( 3 ): 155 - 165 . https://doi.org/10.1093/nutrit/nuu064 https://doi.org/10.1093/nutrit/nuu064 Curcumin and cancer: barriers to obtaining a health claim Dudeja V , Mujumdar N , Phillips P , et al. , 2009 . Heat shock protein 70 inhibits apoptosis in cancer cells through simultaneous and independent mechanisms . Gastroenterology , 136 ( 5 ): 1772 - 1782 . https://doi.org/10.1053/j.gastro.2009.01.070 https://doi.org/10.1053/j.gastro.2009.01.070 Heat shock protein 70 inhibits apoptosis in cancer cells through simultaneous and independent mechanisms Eom KS , Hong JM , Youn MJ , et al. , 2008 . Berberine induces G1 arrest and apoptosis in human glioblastoma T98G cells through mitochondrial/caspases pathway . Biol Pharm Bull , 31 ( 4 ): 558 - 562 . https://doi.org/10.1248/bpb.31.558 https://doi.org/10.1248/bpb.31.558 Berberine induces G1 arrest and apoptosis in human glioblastoma T98G cells through mitochondrial/caspases pathway Falschlehner C , Emmerich CH , Gerlach B , et al. , 2007 . TRAIL signalling: decisions between life and death . Int J Biochem Cell Biol , 39 ( 7-8 ): 1462 - 1475 . https://doi.org/10.1016/j.biocel.2007.02.007 https://doi.org/10.1016/j.biocel.2007.02.007 TRAIL signalling: decisions between life and death Goncharenko-Khaider N , Lane D , Matte I , et al. , 2010 . The inhibition of Bid expression by Akt leads to resistance to TRAIL-induced apoptosis in ovarian cancer cells . Oncogene , 29 ( 40 ): 5523 - 5536 . https://doi.org/10.1038/onc.2010.288 https://doi.org/10.1038/onc.2010.288 The inhibition of Bid expression by Akt leads to resistance to TRAIL-induced apoptosis in ovarian cancer cells Gong K , Li WH , 2011 . Shikonin, a Chinese plant-derived naphthoquinone, induces apoptosis in hepatocellular carcinoma cells through reactive oxygen species: a potential new treatment for hepatocellular carcinoma . Free Radic Biol Med , 51 ( 12 ): 2259 - 2271 . https://doi.org/10.1016/j.freeradbiomed.2011.09.018 https://doi.org/10.1016/j.freeradbiomed.2011.09.018 Shikonin, a Chinese plant-derived naphthoquinone, induces apoptosis in hepatocellular carcinoma cells through reactive oxygen species: a potential new treatment for hepatocellular carcinoma Gonzalvez F , Ashkenazi A , 2010 . New insights into apoptosis signaling by Apo2L/TRAIL . Oncogene , 29 ( 34 ): 4752 - 4765 . https://doi.org/10.1038/onc.2010.221 https://doi.org/10.1038/onc.2010.221 New insights into apoptosis signaling by Apo2L/TRAIL Gorrini C , Harris IS , Mak TW , 2013 . Modulation of oxidative stress as an anticancer strategy . Nat Rev Drug Discov , 12 ( 12 ): 931 - 947 . https://doi.org/10.1038/nrd4002 https://doi.org/10.1038/nrd4002 Modulation of oxidative stress as an anticancer strategy Guamán Ortiz LM , Tillhon M , Parks M , et al. , 2014 . Multiple effects of berberine derivatives on colon cancer cells . Biomed Res Int , 2014 : 924585 . https://doi.org/10.1155/2014/924585 https://doi.org/10.1155/2014/924585 Multiple effects of berberine derivatives on colon cancer cells Guesmi F , Hmed MB , Prasad S , et al. , 2019 . In vivo pathogenesis of colon carcinoma and its suppression by hydrophilic fractions of Clematis flammula via activation of TRAIL death machinery (DRs) expression . Biomed Pharmacother , 109 : 2182 - 2191 . https://doi.org/10.1016/j.biopha.2018.11.052 https://doi.org/10.1016/j.biopha.2018.11.052 In vivo pathogenesis of colon carcinoma and its suppression by hydrophilic fractions of Clematis flammula via activation of TRAIL death machinery (DRs) expression Guo ZL , Li JZ , Ma YY , et al. , 2018 . Shikonin sensitizes A549 cells to TRAIL-induced apoptosis through the JNK, STAT3 and AKT pathways . BMC Cell Biol , 19 : 29 . https://doi.org/10.1186/s12860-018-0179-7 https://doi.org/10.1186/s12860-018-0179-7 Shikonin sensitizes A549 cells to TRAIL-induced apoptosis through the JNK, STAT3 and AKT pathways Gupta SC , Francis SK , Nair MS , et al. , 2013 . Azadirone, a limonoid tetranortriterpene, induces death receptors and sensitizes human cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) through a p53 protein-independent mechanism: evidence for the role of the ROS-ERK-CHOP-death receptor pathway . J Biol Chem , 288 ( 45 ): 32343 - 32356 . https://doi.org/10.1074/jbc.M113.455188 https://doi.org/10.1074/jbc.M113.455188 Azadirone, a limonoid tetranortriterpene, induces death receptors and sensitizes human cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) through a p53 protein-independent mechanism: evidence for the role of the ROS-ERK-CHOP-death receptor pathway Hartwig T , Montinaro A , von Karstedt S , et al. , 2017 . The TRAIL-induced cancer secretome promotes a tumor-supportive immune microenvironment via CCR2 . Mol Cell , 65 ( 4 ): 730 - 742. e5. https://doi.org/10.1016/j.molcel.2017.01.021 https://doi.org/10.1016/j.molcel.2017.01.021 The TRAIL-induced cancer secretome promotes a tumor-supportive immune microenvironment via CCR2 Hasegawa H , Sung JH , Huh JH , 1997 . Ginseng intestinal bacterial metabolite IH901 as a new anti-metastatic agent . Arch Pharm Res , 20 ( 6 ): 539 - 544 . https://doi.org/10.1007/BF02975208 https://doi.org/10.1007/BF02975208 Ginseng intestinal bacterial metabolite IH901 as a new anti-metastatic agent Hayakawa Y , Screpanti V , Yagita H , et al. , 2004 . NK cell TRAIL eliminates immature dendritic cells in vivo and limits dendritic cell vaccination efficacy . J Immunol , 172 ( 1 ): 123 - 129 . https://doi.org/10.4049/jimmunol.172.1.123 https://doi.org/10.4049/jimmunol.172.1.123 NK cell TRAIL eliminates immature dendritic cells in vivo and limits dendritic cell vaccination efficacy He GD , He GL , Zhou RY , et al. , 2016 . Enhancement of cisplatin-induced colon cancer cells apoptosis by shikonin, a natural inducer of ROS in vitro and in vivo . Biochem Biophys Res Commun , 469 ( 4 ): 1075 - 1082 . https://doi.org/10.1016/j.bbrc.2015.12.100 https://doi.org/10.1016/j.bbrc.2015.12.100 Enhancement of cisplatin-induced colon cancer cells apoptosis by shikonin, a natural inducer of ROS in vitro and in vivo Hempel J , Pforte H , Raab B , et al. , 1999 . Flavonols and flavones of parsley cell suspension culture change the antioxidative capacity of plasma in rats . Nahrung , 43 ( 3 ): 201 - 204 . https://doi.org/10.1002/(SICI)1521-3803(19990601)43:3<201::AID-FOOD201>3.0.CO;2-1 https://doi.org/10.1002/(SICI)1521-3803(19990601)43:3<201::AID-FOOD201>3.0.CO;2-1 Flavonols and flavones of parsley cell suspension culture change the antioxidative capacity of plasma in rats Holland PM , 2013 . Targeting Apo2L/TRAIL receptors by soluble Apo2L/TRAIL . Cancer Lett , 332 ( 2 ): 156 - 162 . https://doi.org/10.1016/j.canlet.2010.11.001 https://doi.org/10.1016/j.canlet.2010.11.001 Targeting Apo2L/TRAIL receptors by soluble Apo2L/TRAIL Hong M , Li JK , Li SY , et al. , 2019 . Acetylshikonin sensitizes hepatocellular carcinoma cells to apoptosis through ROS-mediated caspase activation . Cells , 8 ( 11 ): 1466 . https://doi.org/10.3390/cells8111466 https://doi.org/10.3390/cells8111466 Acetylshikonin sensitizes hepatocellular carcinoma cells to apoptosis through ROS-mediated caspase activation Hu XW , Sun Y , 2012 . Triptolide sensitizes TRAIL-induced apoptosis in prostate cancer cells via p53-mediated DR5 up-regulation . Mol Biol Rep , 39 ( 9 ): 8763 - 8770 . https://doi.org/10.1007/s11033-012-1737-2 https://doi.org/10.1007/s11033-012-1737-2 Triptolide sensitizes TRAIL-induced apoptosis in prostate cancer cells via p53-mediated DR5 up-regulation Huang SB , Sinicrope FA , 2008 . BH3 mimetic ABT-737 potentiates TRAIL-mediated apoptotic signaling by unsequestering Bim and Bak in human pancreatic cancer cells . Cancer Res , 68 ( 8 ): 2944 - 2951 . https://doi.org/10.1158/0008-5472.CAN-07-2508 https://doi.org/10.1158/0008-5472.CAN-07-2508 BH3 mimetic ABT-737 potentiates TRAIL-mediated apoptotic signaling by unsequestering Bim and Bak in human pancreatic cancer cells Huang SY , 2007 . Regulation of metastases by signal transducer and activator of transcription 3 signaling pathway: clinical implications . Clin Cancer Res , 13 ( 5 ): 1362 - 1366 . https://doi.org/10.1158/1078-0432.CCR-06-2313 https://doi.org/10.1158/1078-0432.CCR-06-2313 Regulation of metastases by signal transducer and activator of transcription 3 signaling pathway: clinical implications Huang WR , Zhang Y , Tang X , 2014 . Shikonin inhibits the proliferation of human lens epithelial cells by inducing apoptosis through ROS and caspase-dependent pathway . Molecules , 19 ( 6 ): 7785 - 7797 . https://doi.org/10.3390/molecules19067785 https://doi.org/10.3390/molecules19067785 Shikonin inhibits the proliferation of human lens epithelial cells by inducing apoptosis through ROS and caspase-dependent pathway Johnstone RW , Frew AJ , Smyth MJ , 2008 . The TRAIL apoptotic pathway in cancer onset, progression and therapy . Nat Rev Cancer , 8 ( 10 ): 782 - 798 . https://doi.org/10.1038/nrc2465 https://doi.org/10.1038/nrc2465 The TRAIL apoptotic pathway in cancer onset, progression and therapy Jung SH , Lee YS , Lee S , et al. , 2002 . Isoflavonoids from the rhizomes of Belamcanda chinensis and their effects on aldose reductase and sorbitol accumulation in streptozotocin induced diabetic rat tissues . Arch Pharm Res , 25 ( 3 ): 306 - 312 . https://doi.org/10.1007/BF02976631 https://doi.org/10.1007/BF02976631 Isoflavonoids from the rhizomes of Belamcanda chinensis and their effects on aldose reductase and sorbitol accumulation in streptozotocin induced diabetic rat tissues Kalkavan H , Green DR , 2018 . MOMP, cell suicide as a BCL-2 family business . Cell Death Differ , 25 ( 1 ): 46 - 55 . https://doi.org/10.1038/cdd.2017.179 https://doi.org/10.1038/cdd.2017.179 MOMP, cell suicide as a BCL-2 family business Ke R , Vishnoi K , Viswakarma N , et al. , 2018 . Involvement of AMP-activated protein kinase and death receptor 5 in TRAIL-berberine-induced apoptosis of cancer cells . Sci Rep , 8 ( 1 ): 5521 . https://doi.org/10.1038/s41598-018-23780-x https://doi.org/10.1038/s41598-018-23780-x Involvement of AMP-activated protein kinase and death receptor 5 in TRAIL-berberine-induced apoptosis of cancer cells Kim AD , Kang KA , Kim HS , et al. , 2013 . A ginseng metabolite, compound K, induces autophagy and apoptosis via generation of reactive oxygen species and activation of JNK in human colon cancer cells . Cell Death Dis , 4 ( 8 ): e750 . https://doi.org/10.1038/cddis.2013.273 https://doi.org/10.1038/cddis.2013.273 A ginseng metabolite, compound K, induces autophagy and apoptosis via generation of reactive oxygen species and activation of JNK in human colon cancer cells Kisim A , Atmaca H , Cakar B , et al. , 2012 . Pretreatment with AT-101 enhances tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis of breast cancer cells by inducing death receptors 4 and 5 protein levels . J Cancer Res Clin Oncol , 138 ( 7 ): 1155 - 1163 . https://doi.org/10.1007/s00432-012-1187-1 https://doi.org/10.1007/s00432-012-1187-1 Pretreatment with AT-101 enhances tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis of breast cancer cells by inducing death receptors 4 and 5 protein levels Kretz AL , von Karstedt S , Hillenbrand A , et al. , 2018 . Should we keep walking along the trail for pancreatic cancer treatment? Revisiting TNF-related apoptosis-inducing ligand for anticancer therapy . Cancers , 10 ( 3 ): 77 . https://doi.org/10.3390/cancers10030077 https://doi.org/10.3390/cancers10030077 Should we keep walking along the trail for pancreatic cancer treatment? Revisiting TNF-related apoptosis-inducing ligand for anticancer therapy Krosch TCK , Sangwan V , Banerjee S , et al. , 2013 . Triptolide-mediated cell death in neuroblastoma occurs by both apoptosis and autophagy pathways and results in inhibition of nuclear factor-kappa B activity . Am J Surg , 205 ( 4 ): 387 - 396 . https://doi.org/10.1016/j.amjsurg.2013.01.008 https://doi.org/10.1016/j.amjsurg.2013.01.008 Triptolide-mediated cell death in neuroblastoma occurs by both apoptosis and autophagy pathways and results in inhibition of nuclear factor-kappa B activity Kwilas AR , Ardiani A , Gameiro SR , et al. , 2016 . Androgen deprivation therapy sensitizes triple negative breast cancer cells to immune-mediated lysis through androgen receptor independent modulation of osteoprotegerin . Oncotarget , 7 ( 17 ): 23498 - 23511 . https://doi.org/10.18632/oncotarget.8274 https://doi.org/10.18632/oncotarget.8274 Androgen deprivation therapy sensitizes triple negative breast cancer cells to immune-mediated lysis through androgen receptor independent modulation of osteoprotegerin Lee DH , Sung KS , Bartlett DL , et al. , 2015 . HSP90 inhibitor NVP-AUY922 enhances TRAIL-induced apoptosis by suppressing the JAK2-STAT3-Mcl-1 signal transduction pathway in colorectal cancer cells . Cell Signal , 27 ( 2 ): 293 - 305 . https://doi.org/10.1016/j.cellsig.2014.11.013 https://doi.org/10.1016/j.cellsig.2014.11.013 HSP90 inhibitor NVP-AUY922 enhances TRAIL-induced apoptosis by suppressing the JAK2-STAT3-Mcl-1 signal transduction pathway in colorectal cancer cells Lee SJ , Noh HJ , Sung EG , et al. , 2011 . Berberine sensitizes TRAIL-induced apoptosis through proteasome-mediated downregulation of c-FLIP and Mcl-1 proteins . Int J Oncol , 38 ( 2 ): 485 - 492 . https://doi.org/10.3892/ijo.2010.878 https://doi.org/10.3892/ijo.2010.878 Berberine sensitizes TRAIL-induced apoptosis through proteasome-mediated downregulation of c-FLIP and Mcl-1 proteins Lemke J , von Karstedt S , Zinngrebe J , et al. , 2014 . Getting TRAIL back on track for cancer therapy . Cell Death Differ , 21 ( 9 ): 1350 - 1364 . https://doi.org/10.1038/cdd.2014.81 https://doi.org/10.1038/cdd.2014.81 Getting TRAIL back on track for cancer therapy Li HL , Zhu H , Xu CJ , et al. , 1998 . Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis . Cell , 94 ( 4 ): 491 - 501 . https://doi.org/10.1016/S0092-8674(00)81590-1 https://doi.org/10.1016/S0092-8674(00)81590-1 Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis Li WJ , Liu J , Jackson K , et al. , 2014 . Sensitizing the therapeutic efficacy of taxol with shikonin in human breast cancer cells . PLoS ONE , 9 ( 4 ): e94079 . https://doi.org/10.1371/journal.pone.0094079 https://doi.org/10.1371/journal.pone.0094079 Sensitizing the therapeutic efficacy of taxol with shikonin in human breast cancer cells Lim SH , Ha TY , Kim SR , et al. , 2009 . Ethanol extract of Psoralea corylifolia L. and its main constituent, bakuchiol, reduce bone loss in ovariectomised Sprague-Dawley rats , Br J Nutr , 101 ( 7 ): 1031 - 1039 . https://doi.org/10.1017/S0007114508066750 https://doi.org/10.1017/S0007114508066750 Ethanol extract of Psoralea corylifolia L. and its main constituent, bakuchiol, reduce bone loss in ovariectomised Sprague-Dawley rats Lin Y , Shi RX , Wang X , et al. , 2008 . Luteolin, a flavonoid with potential for cancer prevention and therapy . Curr Cancer Drug Targets , 8 ( 7 ): 634 - 646 . https://doi.org/10.2174/156800908786241050 https://doi.org/10.2174/156800908786241050 Luteolin, a flavonoid with potential for cancer prevention and therapy Liu T , Liu X , Li WH , 2016 . Tetrandrine, a Chinese plant-derived alkaloid, is a potential candidate for cancer chemotherapy . Oncotarget , 7 ( 26 ): 40800 - 40815 . https://doi.org/10.18632/oncotarget.8315 https://doi.org/10.18632/oncotarget.8315 Tetrandrine, a Chinese plant-derived alkaloid, is a potential candidate for cancer chemotherapy Liu YT , Tong YL , Yang X , et al. , 2016 . Novel histone deacetylase inhibitors derived from Magnolia officinalis significantly enhance TRAIL-induced apoptosis in non-small cell lung cancer . Pharmacol Res , 111 : 113 - 125 . https://doi.org/10.1016/j.phrs.2016.05.028 https://doi.org/10.1016/j.phrs.2016.05.028 Novel histone deacetylase inhibitors derived from Magnolia officinalis significantly enhance TRAIL-induced apoptosis in non-small cell lung cancer Mittra B , Saha A , Chowdhury AR , et al. , 2000 . Luteolin, an abundant dietary component is a potent anti-leishmanial agent that acts by inducing topoisomerase II-mediated kinetoplast DNA cleavage leading to apoptosis . Mol Med , 6 ( 6 ): 527 - 541 . Luteolin, an abundant dietary component is a potent anti-leishmanial agent that acts by inducing topoisomerase II-mediated kinetoplast DNA cleavage leading to apoptosis Morrissey C , Bektic J , Spengler B , et al. , 2004 . Phytoestrogens derived from Belamcanda chinensis have an antiproliferative effect on prostate cancer cells in vitro . J Urol , 172 ( 6 Pt 1 ): 2426 - 2433 . https://doi.org/10.1097/01.ju.0000143537.86596.66 https://doi.org/10.1097/01.ju.0000143537.86596.66 Phytoestrogens derived from Belamcanda chinensis have an antiproliferative effect on prostate cancer cells in vitro Mujumdar N , Mackenzie TN , Dudeja V , et al. , 2010 . Triptolide induces cell death in pancreatic cancer cells by apoptotic and autophagic pathways . Gastroenterology , 139 ( 2 ): 598 - 608 . https://doi.org/10.1053/j.gastro.2010.04.046 https://doi.org/10.1053/j.gastro.2010.04.046 Triptolide induces cell death in pancreatic cancer cells by apoptotic and autophagic pathways Murthy KNC , Jayaprakasha GK , Patil BS , 2012 . The natural alkaloid berberine targets multiple pathways to induce cell death in cultured human colon cancer cells . Eur J Pharmacol , 688 ( 1-3 ): 14 - 21 . https://doi.org/10.1016/j.ejphar.2012.05.004 https://doi.org/10.1016/j.ejphar.2012.05.004 The natural alkaloid berberine targets multiple pathways to induce cell death in cultured human colon cancer cells Nazim UM , Park SY , 2019 . Luteolin sensitizes human liver cancer cells to TRAIL-induced apoptosis via autophagy and JNK-mediated death receptor 5 upregulation . Int J Oncol , 54 ( 2 ): 665 - 672 . https://doi.org/10.3892/ijo.2018.4633 https://doi.org/10.3892/ijo.2018.4633 Luteolin sensitizes human liver cancer cells to TRAIL-induced apoptosis via autophagy and JNK-mediated death receptor 5 upregulation Ou YC , Kuan YH , Li JR , et al. , 2013 . Induction of apoptosis by luteolin involving Akt inactivation in human 786-O renal cell carcinoma cells . Evid Based Complement Alternat Med , 2013 : 109105 . https://doi.org/10.1155/2013/109105 https://doi.org/10.1155/2013/109105 Induction of apoptosis by luteolin involving Akt inactivation in human 786-O renal cell carcinoma cells Pan GH , Ni J , Wei YF , et al. , 1997 . An antagonist decoy receptor and a death domain-containing receptor for TRAIL . Science , 277 ( 5327 ): 815 - 818 . https://doi.org/10.1126/science.277.5327.815 https://doi.org/10.1126/science.277.5327.815 An antagonist decoy receptor and a death domain-containing receptor for TRAIL Pan LL , Wang XL , Zhang QY , et al. , 2016 . Boehmenan, a lignan from the Chinese medicinal plant Clematis armandii , induces apoptosis in lung cancer cells through modulation of EGF-dependent pathways . Phytomedicine , 23 ( 5 ): 468 - 476 . https://doi.org/10.1016/j.phymed.2016.02.006 https://doi.org/10.1016/j.phymed.2016.02.006 Boehmenan, a lignan from the Chinese medicinal plant Clematis armandii, induces apoptosis in lung cancer cells through modulation of EGF-dependent pathways Park EJ , Zhao YZ , Kim YC , et al. , 2005 . Protective effect of ( S )-bakuchiol from Psoralea corylifolia on rat liver injury in vitro and in vivo . Planta Med , 71 ( 6 ): 508 - 513 . https://doi.org/10.1055/s-2005-864150 https://doi.org/10.1055/s-2005-864150 Protective effect of (S)-bakuchiol from Psoralea corylifolia on rat liver injury in vitro and in vivo Park MH , Kim JH , Chung YH , et al. , 2016 . Bakuchiol sensitizes cancer cells to TRAIL through ROS- and JNK-mediated upregulation of death receptors and downregulation of survival proteins . Biochem Biophys Res Commun , 473 ( 2 ): 586 - 592 . https://doi.org/10.1016/j.bbrc.2016.03.127 https://doi.org/10.1016/j.bbrc.2016.03.127 Bakuchiol sensitizes cancer cells to TRAIL through ROS- and JNK-mediated upregulation of death receptors and downregulation of survival proteins Park S , Cho DH , Andera L , et al. , 2013 . Curcumin enhances TRAIL-induced apoptosis of breast cancer cells by regulating apoptosis-related proteins . Mol Cell Biochem , 383 ( 1-2 ): 39 - 48 . https://doi.org/10.1007/s11010-013-1752-1 https://doi.org/10.1007/s11010-013-1752-1 Curcumin enhances TRAIL-induced apoptosis of breast cancer cells by regulating apoptosis-related proteins Refaat A , Abdelhamed S , Yagita H , et al. , 2013 . Berberine enhances tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in breast cancer . Oncol Lett , 6 ( 3 ): 840 - 844 . https://doi.org/10.3892/ol.2013.1434 https://doi.org/10.3892/ol.2013.1434 Berberine enhances tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in breast cancer Refaat A , Abdelhamed S , Saiki I , et al. , 2015 . Inhibition of p38 mitogen-activated protein kinase potentiates the apoptotic effect of berberine/tumor necrosis factor-related apoptosis-inducing ligand combination therapy . Oncol Lett , 10 ( 3 ): 1907 - 1911 . https://doi.org/10.3892/ol.2015.3494 https://doi.org/10.3892/ol.2015.3494 Inhibition of p38 mitogen-activated protein kinase potentiates the apoptotic effect of berberine/tumor necrosis factor-related apoptosis-inducing ligand combination therapy Seervi M , Rani A , Sharma AK , et al. , 2018 . ROS mediated ER stress induces Bax-Bak dependent and independent apoptosis in response to Thioridazine . Biomed Pharmacother , 106 : 200 - 209 . https://doi.org/10.1016/j.biopha.2018.06.123 https://doi.org/10.1016/j.biopha.2018.06.123 ROS mediated ER stress induces Bax-Bak dependent and independent apoptosis in response to Thioridazine Shishodia G , Koul S , Dong Q , et al. , 2018 . Tetrandrine (TET) induces death receptors Apo TRAIL R1 (DR4) and Apo TRAIL R2 (DR5) and sensitizes prostate cancer cells to TRAIL-induced apoptosis . Mol Cancer Ther , 17 ( 6 ): 1217 - 1228 . https://doi.org/10.1158/1535-7163.MCT-17-1157 https://doi.org/10.1158/1535-7163.MCT-17-1157 Tetrandrine (TET) induces death receptors Apo TRAIL R1 (DR4) and Apo TRAIL R2 (DR5) and sensitizes prostate cancer cells to TRAIL-induced apoptosis Singh S , Singh PP , Roberts LR , et al. , 2014 . Chemopreventive strategies in hepatocellular carcinoma . Nat Rev Gastroenterol Hepatol , 11 ( 1 ): 45 - 54 . https://doi.org/10.1038/nrgastro.2013.143 https://doi.org/10.1038/nrgastro.2013.143 Chemopreventive strategies in hepatocellular carcinoma Trauzold A , Wermann H , Arlt A , et al. , 2001 . CD95 and TRAIL receptor-mediated activation of protein kinase C and NF-κB contributes to apoptosis resistance in ductal pancreatic adenocarcinoma cells . Oncogene , 20 ( 31 ): 4258 - 4269 . https://doi.org/10.1038/sj.onc.1204559 https://doi.org/10.1038/sj.onc.1204559 CD95 and TRAIL receptor-mediated activation of protein kinase C and NF-κB contributes to apoptosis resistance in ductal pancreatic adenocarcinoma cells Trivedi R , Mishra DP , 2015 . Trailing TRAIL resistance: novel targets for TRAIL sensitization in cancer cells . Front Oncol , 5 : 69 . https://doi.org/10.3389/fonc.2015.00069 https://doi.org/10.3389/fonc.2015.00069 Trailing TRAIL resistance: novel targets for TRAIL sensitization in cancer cells Wang FF , Yao XS , Zhang YW , et al. , 2019 . Synthesis, biological function and evaluation of shikonin in cancer therapy . Fitoterapia , 134 : 329 - 339 . https://doi.org/10.1016/j.fitote.2019.03.005 https://doi.org/10.1016/j.fitote.2019.03.005 Synthesis, biological function and evaluation of shikonin in cancer therapy Wang G , Lemos JR , Iadecola C , 2004 . Herbal alkaloid tetrandrine: from an ion channel blocker to inhibitor of tumor proliferation . Trends Pharmacol Sci , 25 ( 3 ): 120 - 123 . https://doi.org/10.1016/j.tips.2004.01.009 https://doi.org/10.1016/j.tips.2004.01.009 Herbal alkaloid tetrandrine: from an ion channel blocker to inhibitor of tumor proliferation Wang SL , El-Deiry WS , 2003 . TRAIL and apoptosis induction by TNF-family death receptors . Oncogene , 22 ( 53 ): 8628 - 8633 . https://doi.org/10.1038/sj.onc.1207232 https://doi.org/10.1038/sj.onc.1207232 TRAIL and apoptosis induction by TNF-family death receptors Wang Y , Curtis-Long MJ , Yuk HJ , et al. , 2013 . Bacterial neuraminidase inhibitory effects of prenylated isoflavones from roots of Flemingia philippinensis . Bioorg Med Chem , 21 ( 21 ): 6398 - 6404 . https://doi.org/10.1016/j.bmc.2013.08.049 https://doi.org/10.1016/j.bmc.2013.08.049 Bacterial neuraminidase inhibitory effects of prenylated isoflavones from roots of Flemingia philippinensis Wang ZX , Qi FH , Cui YG , et al. , 2018 . An update on Chinese herbal medicines as adjuvant treatment of anticancer therapeutics . BioSci Trends , 12 ( 3 ): 220 - 239 . https://doi.org/10.5582/bst.2018.01144 https://doi.org/10.5582/bst.2018.01144 An update on Chinese herbal medicines as adjuvant treatment of anticancer therapeutics Wei N , Liu GT , Chen XG , et al. , 2011 . H1, a derivative of Tetrandrine, exerts anti-MDR activity by initiating intrinsic apoptosis pathway and inhibiting the activation of Erk1/2 and Akt1/2 . Biochem Pharmacol , 82 ( 11 ): 1593 - 1603 . https://doi.org/10.1016/j.bcp.2011.08.012 https://doi.org/10.1016/j.bcp.2011.08.012 H1, a derivative of Tetrandrine, exerts anti-MDR activity by initiating intrinsic apoptosis pathway and inhibiting the activation of Erk1/2 and Akt1/2 Wei RJ , Zhang XS , He DL , 2018 . Andrographolide sensitizes prostate cancer cells to TRAIL-induced apoptosis . Asian J Androl , 20 ( 2 ): 200 - 204 . https://doi.org/10.4103/aja.aja_30_17 https://doi.org/10.4103/aja.aja_30_17 Andrographolide sensitizes prostate cancer cells to TRAIL-induced apoptosis Woo SM , Seo SU , Kubatka P , et al. , 2019 . Honokiol enhances TRAIL-mediated apoptosis through STAMBPL1-induced survivin and c-FLIP degradation . Biomolecules , 9 ( 12 ): 838 . https://doi.org/10.3390/biom9120838 https://doi.org/10.3390/biom9120838 Honokiol enhances TRAIL-mediated apoptosis through STAMBPL1-induced survivin and c-FLIP degradation Wozniak D , Janda B , Kapusta I , et al. , 2010 . Antimutagenic and anti-oxidant activities of isoflavonoids from Belamcanda chinensis (L.) DC . Mutat Res/Genet Toxicol Environ Mutagen , 696 ( 2 ): 148 - 153 . https://doi.org/10.1016/j.mrgentox.2010.01.004 https://doi.org/10.1016/j.mrgentox.2010.01.004 Antimutagenic and anti-oxidant activities of isoflavonoids from Belamcanda chinensis (L.) DC Xia YF , Ye BQ , Li YD , et al. , 2004 . Andrographolide attenuates inflammation by inhibition of NF-‍κB activation through covalent modification of reduced cysteine 62 of p50 . J Immunol , 173 ( 6 ): 4207 - 4217 . https://doi.org/10.4049/jimmunol.173.6.4207 https://doi.org/10.4049/jimmunol.173.6.4207 Andrographolide attenuates inflammation by inhibition of NF-‍κB activation through covalent modification of reduced cysteine 62 of p50 Xu Y , Li PZ , Zhang X , et al. , 2014 . In vitro evidence for bakuchiol’s influence towards drug metabolism through inhibition of UDP-glucuronosyltransferase (UGT) 2B7 . Afr Health Sci , 14 ( 3 ): 564 - 569 . https://doi.org/10.4314/ahs.v14i3.10 https://doi.org/10.4314/ahs.v14i3.10 In vitro evidence for bakuchiol’s influence towards drug metabolism through inhibition of UDP-glucuronosyltransferase (UGT) 2B7 Xu Y , Gao CC , Pan ZG , et al. , 2018 . Irigenin sensitizes TRAIL-induced apoptosis via enhancing pro-apoptotic molecules in gastric cancer cells . Biochem Biophys Res Commun , 496 ( 3 ): 998 - 1005 . https://doi.org/10.1016/j.bbrc.2018.01.003 https://doi.org/10.1016/j.bbrc.2018.01.003 Irigenin sensitizes TRAIL-induced apoptosis via enhancing pro-apoptotic molecules in gastric cancer cells Yamaguchi R , Lartigue L , Perkins G , 2019 . Targeting Mcl-1 and other Bcl-2 family member proteins in cancer therapy . Pharmacol Ther , 195 : 13 - 20 . https://doi.org/10.1016/j.pharmthera.2018.10.009 https://doi.org/10.1016/j.pharmthera.2018.10.009 Targeting Mcl-1 and other Bcl-2 family member proteins in cancer therapy Yang X , Li ZJ , Wu QJ , et al. , 2017 . TRAIL and curcumin codelivery nanoparticles enhance TRAIL-induced apoptosis through upregulation of death receptors . Drug Deliv , 24 ( 1 ): 1526 - 1536 . https://doi.org/10.1080/10717544.2017.1384863 https://doi.org/10.1080/10717544.2017.1384863 TRAIL and curcumin codelivery nanoparticles enhance TRAIL-induced apoptosis through upregulation of death receptors Youdim KA , Qaiser MZ , Begley DJ , et al. , 2004 . Flavonoid permeability across an in situ model of the blood-brain barrier . Free Radic Biol Med , 36 ( 5 ): 592 - 604 . https://doi.org/10.1016/j.freeradbiomed.2003.11.023 https://doi.org/10.1016/j.freeradbiomed.2003.11.023 Flavonoid permeability across an in situ model of the blood-brain barrier Zang MD , Hu L , Fan ZY , et al. , 2017 . Luteolin suppresses gastric cancer progression by reversing epithelial-mesenchymal transition via suppression of the Notch signaling pathway . J Transl Med , 15 : 52 . https://doi.org/10.1186/s12967-017-1151-6 https://doi.org/10.1186/s12967-017-1151-6 Luteolin suppresses gastric cancer progression by reversing epithelial-mesenchymal transition via suppression of the Notch signaling pathway Zhang L , Wei KH , Xu JP , et al. , 2016 . Belamcanda chinensis (L.) DC—an ethnopharmacological, phytochemical and pharmacological review . J Ethnopharmacol , 186 : 1 - 13 . https://doi.org/10.1016/j.jep.2016.03.046 https://doi.org/10.1016/j.jep.2016.03.046 Belamcandachinensis (L.) DC—an ethnopharmacological, phytochemical and pharmacological review Zhang LD , Fang BL , 2005 . Mechanisms of resistance to TRAIL-induced apoptosis in cancer . Cancer Gene Ther , 12 ( 3 ): 228 - 237 . https://doi.org/10.1038/sj.cgt.7700792 https://doi.org/10.1038/sj.cgt.7700792 Mechanisms of resistance to TRAIL-induced apoptosis in cancer Zhou GY , Yang ZQ , Wang XD , et al. , 2017 . TRAIL enhances shikonin induced apoptosis through ROS/JNK signaling in cholangiocarcinoma cells . Cell Physiol Biochem , 42 ( 3 ): 1073 - 1086 . https://doi.org/10.1159/000478758 https://doi.org/10.1159/000478758 TRAIL enhances shikonin induced apoptosis through ROS/JNK signaling in cholangiocarcinoma cells Zhou J , Lu GD , Ong CS , et al. , 2008 . Andrographolide sensitizes cancer cells to TRAIL-induced apoptosis via p53-mediated death receptor 4 up-regulation . Mol Cancer Ther , 7 ( 7 ): 2170 - 2180 . https://doi.org/10.1158/1535-7163.Mct-08-0071 https://doi.org/10.1158/1535-7163.Mct-08-0071 Andrographolide sensitizes cancer cells to TRAIL-induced apoptosis via p53-mediated death receptor 4 up-regulation Ming HONG, Wulin WEN, and Jiawei WANG conducted this review. Bingyu SUN, Yongqiang LIU, Danhua HE, and Jinke LI contributed in the writing and editing of the manuscript. All authors have read and approved the final manuscript and, therefore, have full access to all the data in the study and take responsibility for the integrity and security of the data. This study was supported by the Guangdong Basic and Applied Basic Research Foundation (No. 2019A1515110167), China. 10.1631/jzus.B2000497 1673-1581（2021）03-0190-14 2020-08-24 2020-11-19 2021-02-24 2021-03-15 2022-05-09 © Zhejiang University Press 2021 Bingyu SUN, Yongqiang LIU, Danhua HE, Jinke LI, Jiawei WANG, Wulin WEN, and Ming HONG declare that they have no conflict of interest. This article does not contain any studies with human or animal subjects performed by any of the authors. Compliance with ethics guidelines 浙江大学学报（英文版）（B辑：生物医学和生物技术） 3 22