Indole Alkaloid Derivative B, a Novel Bifunctional Agent That Mitigates 5‑Fluorouracil-Induced Cardiotoxicity

Clinically approved therapeutics that mitigate chemotherapy-induced cardiotoxicity, a serious adverse effect of chemotherapy, are lacking. The aim of this study was to determine the putative protective capacity of a novel indole alkaloid derivative B (IADB) against 5-fluorouracil (5-FU)-induced cardiotoxicity. To assess the free-radical scavenging activities of IADB, the acetylcholine-induced relaxation assay in rat thoracic aorta was used. Further, IADB was tested in normal and cancer cell lines with assays gauging autophagy induction. We further examined whether IADB could attenuate cardiotoxicity in 5-FU-treated male ICR mice. We found that IADB could serve as a novel bifunctional agent (displaying both antioxidant and autophagy-modulating activities). Further, we demonstrated that IADB induced production of cytosolic autophagy-associated structures in both cancer and normal cell lines. We observed that IADB cytotoxicity was much lower in normal versus cancer cell lines, suggesting an enhanced potency toward cancer cells. The cardiotoxicity induced by 5-FU was significantly relieved in animals pretreated with IADB. Taken together, IADB treatment, in combination with chemotherapy, may lead to reduced cardiotoxicity, as well as the reduction of anticancer drug dosages that may further improve chemotherapeutic efficacy with decreased off-target effects. Our data suggest that the use of IADB may be therapeutically beneficial in minimizing cardiotoxicity associated with high-dose chemotherapy. On the basis of the redox status difference between normal and tumor cells, IADB selectively induces autophagic cell death, mediated by reactive oxygen species overproduction, in cancer cells. This novel mechanism could reveal novel therapeutic targets in chemotherapy-induced cardiotoxicity.