Table 1:
Promising Pre-clinical Studies of TRAIL-induced Apoptosis in Cancer Therapeutics.
| Category | Sensitizing Agent | Cancer Type | Mechanism |
|---|---|---|---|
| DNA Damaging Agent | Radiation therapy | Breast cancer, Prostate cancer, Lung cancer, Colorectal cancer, Head and Neck cancer, T-lymphoblastic leukemia [86] | Irradiation-induced activation of p53 and subsequent p53-dependent up-regulation of pro-apoptotic proteins such as DR4/5. |
| DNA Damaging Agent | Cisplatin, gemcitabine and many more (e.g. 5-FU or topoisomerase inhibitor Irinotecan and Etoposide) | NSCLC, Esophageal cancer, mesothelioma, Leukemia [54][87] | DNA Damage-induced activation of p53 and upregulated caspase-8 |
| Manipulation or Recovery of p53 | Ad-p53, p53R3 Nutlin-3 | Glioma, myeloma, Lung cancer, Leukemia, lymphoma, sarcoma [87] | Stabilization and activation of p53 and subsequent upregulation of DR5 |
| Natural Compound | Polyphenols (e.g. wogonin, resveratrol) | Colorectal cancer hepatoblastoma, medulloblastoma, glioblastoma, pancreatic cancer etc. [87] | Pro-oxidant effect that generates ROS-mediated p53 activation and pro-apoptotic protein PUMA and DR5 upregulation |
| Natural Compound | Terpenoids (e.g. nimbolide, andrographolide) | Colon cancer, hepatoma, cervical cancer [87] | ROS production & ERK activation (causing DR4/5 upregulation), downregulation of several anti-apoptotic proteins and stabilization of p53 through phosphorylation |
| Natural Compound | Vitamin-related products (e.g. Vitamin E and related compounds, vitamin A analogs, CD437 retinoid) | Colon cancer, mesothelioma, lung cancer [87] | ROS production & ERK activation and DR4/5 upregulation, enhanced Bid cleavage and mitochondrial apoptosis pathway |
| Epigenetics Modification | HDAC inhibitors (e.g. SAHA, CBHA, TSA and VPA) | Breast cancer, lung cancer, colon cancer, prostate cancer, renal cell carcinoma, melanoma [88] | Upregulation of DR4/5, upregulation of pro-apoptotic Bcl-2 family proteins, reduce cytoprotective autophagy, distribute DR4/5 into lipid raft, downregulation of anti-apoptotic proteins and suppression of c-myc |
| Epigenetics Modification | DNMT inhibitors (e.g. Zeb, decitabine | Breast cancer, lung cancer [88] | Enhancing DR5 fucosylation, caspase-8 upregulation, downregulation of XIAP |
| Molecule mimetics of BH3-only proteins | ABT-737, ABT-199, ABT-263 and Smac-mimetics | Chronic Lymphocytic leukemia, follicular lymphoma, ovarian cancer [54][88] | Mimics the activity of pro-apoptotic protein Bad and suppression of anti-apoptotic Bcl-2 and IAP family proteins |
| Small molecules | Multi-kinase inhibitor (e.g. Sorafenib) | Malignant pleural mesothelioma, colon cancer [89,90] | Shut down MAPK signaling, PI3K/Akt signaling and NF-kB signaling, downregulation of mcl-1, c-FLIP and IAP family proteins |
| Small molecules | PI3K/Akt/mTORC1 inhibitors | Neuroblastoma, breast cancer, leukemia [91] | Suppression of autophagy and proliferation |
| Antibodies | Single-chain variable fragment (scFv) nanobodies | NSCLC, colon cancer, glioma, B-lymphoblastic leukemia, chronic-B-lymphocytic leukemia [66,67] | Simultaneous targeting of proliferation and apoptosis pathway, selective induction of apoptosis, target angiogenesis |
| Immunotherapy | Tumor antigen-specific, MHC-restricted T cells with PD-L1 nanobodies | Melanoma, chronic lymphocytic leukemia [71] | Downregulation of c-FLIP, converting suppressive macrophages/DCs into pro-apoptotic effector cells and IFN-gamma production |
| Immunotherapy | CD3/CD7 fusion with stimulatory TRAIL antibody on T-cells | Pan-carcinoma [72] | Cytolytic granzyme/perforin pathway activation induced by even low DR5 expression |
| Immunotherapy | scFv:CD70-TNC-TRAIL fusion protein | Lymphoma, melanoma, bladder cancer, colon cancer [70] | Cytotoxic T-cells and activate granulocytes, monocytes and DCs |