Targeting SASP with FDA-approved agents: minoxidil and diazoxide as potential senomorphic agents in cancer therapy

Objectives: Chemotherapy-induced senescent cells are recognized to lead to cancer progression and resistance to treatment by releasing factors associated with the senescence-associated secretory phenotype (SASP). Therefore, targeting SASP via senomorphic agents is an emerging therapeutic strategy. In this study, we evaluated the potential of L-type Ca2+ channel blockers, nifedipine and verapamil, and K-ATP(+) channel openers, minoxidil and diazoxide, to influence senescence development and SASP-related secretory activity. Methods: Senescence development was evaluated by beta-galactosidase activity and senescent cell morphology. Senomorphic activity was evaluated by measuring the secretion levels of total protein and IL-6, which are considered indicators of the SASP. Additionally, the effects of SASP were tested for cancer cell proliferation using the transwell system and cell migration using wound healing methods. Results: Our findings indicate that neither L-type Ca2+ channel blockers, nifedipine and verapamil, nor K-ATP(+) channel openers, minoxidil and diazoxide, influence the induction of senescence by doxorubicin or alter senescent cell morphology. The K-ATP(+) channel openers minoxidil and diazoxide notably inhibit the secretion of the proinflammatory cytokine IL-6 and VEGF-A in senescent HeLa cells, implying potential senomorphic properties. Moreover, although minoxidil and diazoxide did not reduce the proliferative effects of SASP on cancer cells, these drugs modulated the secretory phenotype of senescent cells to reduce HeLa cell migration significantly. Conclusions: We suggest that minoxidil and diazoxide may have potential as senomorphic adjuvants in cancer therapy. If confirmed by invivo and clinical studies, these drugs may be repurposed to attenuate SASP-induced tumor progression. Moreover, K-ATP(+) channels represent potential targets for senotherapy.