review · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Chemotherapy drugs have traditionally been recognised as triggers of apoptosis, a form of cell death that avoids activating the immune system. However, multiple approved cancer treatments, including cisplatin, doxorubicin, etoposide, 5-fluorouracil, gemcitabine, paclitaxel, vinblastine, and cyclosporine, also induce alternative pathways known as necroptosis and pyroptosis. Each cell death pathway carries distinct advantages and disadvantages when activated by therapeutic agents. A detailed assessment of the molecular mechanisms behind each type reveals notable crosstalk between these pathways. Comparing how these agents induce apoptosis, necroptosis, and pyroptosis provides a framework to assess additional chemotherapies. Understanding the specific cell death pathways activated by distinct drugs can help reduce adverse side effects and guide the identification of novel drug combinations that yield synergistic therapeutic effects alongside low systemic toxicity.
Standard cancer treatments often rely on apoptosis to destroy tumours, but cancer cells frequently develop resistance to this silent pathway. Recognising that established therapies also activate alternative, inflammatory mechanisms like necroptosis and pyroptosis opens new possibilities for treatment design. Better understanding these pathways helps researchers select drug combinations that eliminate resistant tumours while minimising harmful side effects and systemic toxicity for patients.
This early-stage research provides mechanistic insights for pharmaceutical researchers and oncology drug developers. By mapping how existing treatments induce necroptosis and pyroptosis, the findings can aid the development of synergistic combination therapies with reduced toxicity. As the work synthesises fundamental biological pathways of existing molecules rather than testing a specific proprietary candidate, it represents discovery-stage insight that remains at an early distance from clinical implementation.
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For decades, common chemotherapeutic drugs have been established to trigger apoptosis, the preferred immunologically "silent" form of cell death. The primary objective of this review was to show that various FDA-approved chemotherapeutic drugs, including cisplatin, cyclosporine, doxorubicin, etoposide, 5-fluorouracil, gemcitabine, paclitaxel, or vinblastine can trigger necroptosis and pyroptosis. We aimed to provide the advantages and disadvantages of the induction of the given type of cell death by chemotherapeutical agents. Moreover, we give a short overview of the molecular mechanism of each type of cell death and indicate the existing crosstalks between cell death types. Finally, we provide a comparison of cell death types to facilitate the exploration of cell death types induced by other chemotherapeutical agents. Understanding the cell death pathway induced by a drug can lessen side effects and assist the discovery of new combinations with synergistic effects and low systemic toxicity.
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DOI: 10.1016/j.bbcan.2023.189024
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