Table 1.
Death-inducing cancer therapies
| Therapy | Mechanism | Primary PCD induced | Cancers tested | Status | Ref. |
|---|---|---|---|---|---|
| BH3 mimetics | Antagonize antiapoptotic BCL-2 proteins, sensitizing cells to proapoptotic signals | Apoptosis | Lymphomas, CLL, AML, ALL, MM, SCLC | Clinical and preclinical trials | [94] |
| SMAC mimetics | Bind to cIAPs and XIAP, blocking endogenous inhibitors of caspases. Also relieves repression of RIPK1/RIPK3 | Apoptosis | HNSCC, solid tumors | Phase I/II clinical trials | [95] |
| Anthracyclines (doxorubicin) | Intercalates DNA/RNA strands leading to irreparable DNA damage | Immunogenic apoptosis | Solid tumors, MM, leukemias and lymphomas | Commonly prescribed | [96] |
| Bortezomib | Protease inhibitor, induction dependent on BH3 proteins | Immunogenic apoptosis | MM, MCL | Commonly prescribed | [97] |
| Platinum derivatives (cisplatin, oxaliplatin) | Cross-links DNA inhibiting synthesis and transcription | Immunogenic apoptosis, necroptosis | Solid tumors | Commonly prescribed | [98] |
| Gamma-irradiation | Direct and indirect DNA damage | Immunogenic apoptosis, necrosis, other? | Solid tumors | Commonly prescribed | [99] |
| Hypericin-photodynamic therapy | Cellular sensitization to light and ROS production leading to cellular damage | Immunogenic apoptosis | Solid tumors | Phase I/II clinical trials | [100] |
| HPA3P | Increased levels of RIPK3 expression | Necroptosis | CRC (HT-29, SW480 HCT116 p53+/+) | Preclinical | [111] |
| Shikonin | Downregulation of procaspase-8 | Necroptosis | BRC (MCF-7), APML (HL60) | Preclinical | [83, 112–114] |
| SMAC mimetics + IFNy | Relieved repression of RIPK1/RIPK3; IRF1-dependent downstream of IFNy | Necroptosis | CRC (HT-29), BRC (EFM-192A), AML (MV4-11, Molm-13) | Preclinical | [115] |
| SMAC mimetics + caspase inhibition | Relieved repression of RIPK1/RIPK3; caspase inhibition allows for ripoptosome formation | Necroptosis | OVC (OVCAR3) | Preclinical | [116] |
| SMAC mimetics + demethylating agents + caspase inhibition | Relieved repression of RIPK1/RIPK3 + demethylation to inhibit prosurvival NF-κB signaling + inhibit caspase to skew from apoptotic to necroptotic death | Necroptosis | AML (MV4-11, NB4) | Preclinical | [117] |
Cancer types: ALL acute lymphocytic leukemia, AML acute monocytic leukemia, APML acute promyelocytic leukemia, BRC breast cancer, CRC colorectal cancer, HNSCC head and neck squamous cell carcinoma, MM multiple myeloma, MCL mantle cell lymphoma, OVC ovarian cancer, SCLC small cell lung cancer. Specific cell lines listed in parentheses.