Balance Cell Apoptosis and Pyroptosis of Caspase-3-Activating Chemotherapy for Better Antitumor Therapy

SIMPLE SUMMARY: Chemotherapy has been widely used in clinic to treat various types of tumors, although severe side effects have been the most critical limitation of this treatment modality. For a long time, it has been believed that toxicity derives from the apoptosis of normal cells induced by the use of chemotherapeutic drugs due to their off-target biodistribution. In 2017, a breakthrough finding by Shao Feng’s group showed that the side effects were related to pyroptosis caused by chemotherapeutic-drug-induced GSDME activation, and, interestingly, pyroptosis shares the same upstream signaling molecule with apoptosis, i.e., the caspase-3 activation. From then on, great research attention has been paid to chemotherapy-induced pyroptosis. In reality, pyroptosis is a “double-edged sword”, causing side effects in normal tissue, but also being able to promote antitumor effects, owing to its regulation of antitumor immunity. Therefore, rationally balancing the cell apoptosis and pyroptosis of caspase-3-activating chemotherapy is critically important for better antitumor therapy. This critical review aims to summarize recent progress in the field, focusing on how to balance cell apoptosis and pyroptosis for better tumor chemotherapy. ABSTRACT: Chemotherapy is a standard treatment modality in clinic that exerts an antitumor effect via the activation of the caspase-3 pathway, inducing cell death. While a number of chemotherapeutic drugs have been developed to combat various types of tumors, severe side effects have been their common limitation, due to the nonspecific drug biodistribution, bringing significant pain to cancer patients. Recently, scientists found that, besides apoptosis, chemotherapy could also cause cell pyroptosis, both of which have great influence on the therapeutic index. For example, cell apoptosis is, generally, regarded as the main mechanism of killing tumor cells, while cell pyroptosis in tumors promotes treatment efficacy, but in normal tissue results in toxicity. Therefore, significant research efforts have been paid to exploring the rational modulation mode of cell death induced by chemotherapy. This critical review aims to summarize recent progress in the field, focusing on how to balance cell apoptosis and pyroptosis for better tumor chemotherapy. We first reviewed the mechanisms of chemotherapy-induced cell apoptosis and pyroptosis, in which the activated caspase-3 is the key signaling molecule for regulating both types of cell deaths. Then, we systematically discussed the rationale and methods of switching apoptosis to pyroptosis for enhanced antitumor efficacy, as well as the blockage of pyroptosis to decrease side effects. To balance cell pyroptosis in tumor and normal tissues, the level of GSDME expression and tumor-targeting drug delivery are two important factors. Finally, we proposed potential future research directions, which may provide guidance for researchers in the field.