Therapy-induced senescence is a major cellular response to
chemotherapy in solid
tumors. Senescent
tumor cells acquire a secretory phenotype, or SASP, and produce pro-inflammatory factors, whose expression is largely under NF-κB transcriptional control. Secreted factors play a positive role in driving antitumor immunity, but also exert negative influences on the microenvironment, and promote
tumor growth and
metastasis. Moreover, subsets of
cancer cells can escape the senescence arrest, driving
tumor recurrence
after treatments. Hence, removal the senescent
tumor cells, or reprogramming of the senescent secretome, have become attractive therapeutic options. The marine drug
trabectedin was shown to inhibit the production of pro-inflammatory mediators by
tumor-infiltrating immune cells and by
myxoid liposarcoma cells. Here, we demonstrate that
trabectedin inhibits the SASP, thus limiting the pro-tumoral activities of senescent
tumor cells in vitro. We show that
trabectedin modulates NF-κB transcriptional activity in senescent
tumor cells. This results in disruption of the balance between antiapoptotic and proapoptotic signals, and sensitization of cells to Fas-mediated apoptosis. Further, we found that
trabectedin inhibits escape from
therapy-induced senescence, at concentrations that do not affect the viability of bulk
tumor population. Overall, our data demonstrate that
trabectedin has the potential to inhibit multiple detrimental effects of
therapy-induced senescence.