Hydrogel-mediated delivery of celastrol and doxorubicin induces a synergistic effect on tumor regression via upregulation of ceramides

The release of anticancer drugs in systemic circulation and their associated toxicity are responsible for the poor efficacy of chemotherapy. Therefore, the identification of new chemotherapeutic combinations designed to be released near the tumor site in a sustained manner has the potential to enhance the efficacy and reduce the toxicity associated with chemotherapy. Here, we present the identification of a combination of doxorubicin, a DNA-binding topoisomerase inhibitor, with a naturally occurring triterpenoid, celastrol, that induces a synergistic effect on the apoptosis of colon cancer cells. Hydrogel-mediated sustained release of a combination of doxorubicin and celastrol in a murine tumor model abrogates tumor proliferation, and increases the median survival with enhanced apoptosis and concurrent reduction in proliferation. Sphingolipid profiling (LC-MS/MS) of treated tumors showed that the combination of celastrol and doxorubicin induces global changes in the expression of sphingolipids with an increase in levels of ceramides. We further demonstrate that this dual drug combination induces a significant increase in the expression of ceramide synthase 1, 4, and 6, thereby increasing the level of ceramides that contribute to the synergistic apoptotic effect. Therefore, hydrogel-mediated localized delivery of a combination of celastrol and doxorubicin provides a new therapeutic combination that induces a sphingolipid-mediated synergistic effect against colon cancer.