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

Abstract

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.

Keywords: Apoptosis; Cancer therapy; Chinese medicine; Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL).

Fig. 1. Apoptosis induction at the level of TRAIL DISC. TRAIL binds to DR4 or DR5 to form a trimer of the receptor, thereby recruiting the receptor molecule FADD and pre-caspase-8 to jointly form DISC. The pre-caspase-8 is activated at the level of the DISC, which in turn activates downstream caspase-3, inducing apoptosis. Arrows denote activation, and blunt arrows indicate inhibition. c-FLIP: cellular FADD-like interleukin-1β (IL-1β)-converting enzyme (FLICE)-like inhibitory proteins; DISC: death induction signal complex; DR: death receptor; FADD: Fas-associated death domain (DD); NF-‍κB: nuclear factor-‍κB; TRAIL: tumor necrosis factor-related apoptosis-inducing ligand.

Fig. 2. TRAIL induces apoptosis by intracellular apoptosis (mitochondrial pathway). Overexpression of anti-apoptosis proteins (Bcl-2, Bcl-xL, Mcl-1), as well as dysregulation of pro-apoptosis proteins (Bax and Bak), can lead to hindrance of apoptosis. In addition, members of the apoptosis-inhibiting protein IAP family (like survivin) can inhibit the function of caspase-9 and caspase-3 directly and prevent the transmission of apoptosis signals. Arrows denote activation, and blunt arrows indicate inhibition. Bak: B-cell lymphoma 2 (Bcl-2) homologous antagonist/killer; Bax: Bcl-2-associated X protein; c-FLIP: cellular FADD-like interleukin-1β (IL-1β)-converting enzyme (FLICE)-like inhibitory proteins； DIABLO: direct inhibitor of apoptosis protein-binding protein with low pI; FADD: Fas-associated death domain (DD); IAP: inhibitor of apoptosis protein; Mcl-1: myeloid cell leukemia-1; SMAC: second mitochondrial-derived activator of caspase; tBid: truncated Bcl-2 homeodomain 3 interaction domain death agonist (Bid); TRAIL: tumor necrosis factor-related apoptosis-inducing ligand.

Fig. 3. TRAIL-induced apoptosis is out of balance during carcinogenesis. The mechanisms that inhibit the execution of apoptosis include: (1) destruction of the balance between anti-apoptotic and pro-apoptotic proteins, causing apoptosis imbalance in affected cells due to lower expression of pro-apoptotic proteins (such as Bid, Bak, and Bax) or overexpression of anti-apoptotic proteins (such as Bcl-xL, Bcl-2, c-FLIP, and Mcl-1); (2) inhibition of apoptosis by reducing caspase function; (3) impaired death receptor signal transduction attributed to a decrease in glycosylation, leading to escape from extrinsic apoptotic pathways and lower receptor surface expression. Bak: B-cell lymphoma 2 (Bcl-2) homologous antagonist/killer; Bax: Bcl-2-associated X protein; Bid: Bcl-2 homeodomain 3 interaction domain death agonist; c-FLIP: cellular FADD-like interleukin-1β (IL-1β)-converting enzyme (FLICE)-like inhibitory proteins; FADD: Fas-associated death domain (DD); Mcl-1: myeloid cell leukemia-1; TRAIL: tumor necrosis factor-related apoptosis-inducing ligand.