Chemo-Senolytic Therapeutic Potential against Angiosarcoma

Abstract

Angiosarcoma is an aggressive soft-tissue sarcoma with a poor prognosis. Chemotherapy for this cancer typically employs paclitaxel, a taxane (genotoxic drug), although it has a limited effect owing to chemoresistance to prolonged treatment. Here, we examine an alternative angiosarcoma treatment approach that combines chemotherapeutic and senolytic agents. We find that the chemotherapeutic drugs cisplatin and paclitaxel efficiently induce senescence in angiosarcoma cells. Subsequent treatment with the senolytic agent ABT-263 eliminates senescent cells by activating the apoptotic pathway. In addition, expression analysis indicates that senescence-associated secretory phenotype (SASP) genes are activated in senescent angiosarcoma cells and that ABT-263 treatment down-regulates type I interferon (IFN-I) pathway genes in senescent cells. Moreover, we show that cisplatin treatment alone requires high doses to remove angiosarcoma cells. In contrast, lower doses of cisplatin are sufficient to induce senescence, followed by the elimination of senescent cells by the senolytic treatment. This study sheds light on a potential therapeutic strategy against angiosarcoma by combining a relatively low dose of cisplatin with the ABT-263 senolytic agent, which can help ease the deleterious side effects of chemotherapy.