Chemotherapy-induced cardiotoxicity is a serious complication that limits the clinical use of chemotherapeutic agents. Currently, there is no clinically proven treatment available for chemotherapy-induced cardiotoxicity. Recently, we discovered an indole alkaloid derivative B (IADB) as a novel dual-functional agent (antioxidant and autophagy-modulating activity). We have demonstrated that IADB exhibiting potent free radical scavenging activities in the acetylcholine (Ach)-induced relaxation of the rat thoracic aorta assay. Moreover, we observed that treatment with IADB induced the appearance of autophagy-associated structures in the cytoplasm in both cancer and normal cell lines. Interestingly, the cytotoxicity of IADB was much lower in normal cell lines (i.e. H9C2 rat cardiomyocytes) than cancer cell lines (i.e. MDA-MB-231, HT-29, HeLa), suggesting that IADB was more potent in cancer cells. We further demonstrated the treatment of colon cancer HT-29 cells with the combination of IADB with 5-FU resulted in potentiation of the inhibitory effect on the proliferative activity and also an increase in the percentage of apoptotic cells. On the other hand, the histological results showed that of 5-FU alone treatment induced a degree of cardiotoxicity. The severity of the histological change was notably alleviated in sections from animals pretreated with IADB. At the subcellular level, 5-FU driven mitochondrial ROS correlated with the mitochondria dysfunction. However, a partial rescue of mitochondrial oxidative stress upon treatments with IADB + 5-FU was observed. The presently observed reversal of a number of the signs of toxicity associated with 5-FU by IADB are likely through its anti-oxidative properties and also maybe mediated in part via modulation of autophagy, and further exploratory <i>in vivo </i>studies is warranted.

Discovery of a novel dual functional compound (IADB) as chemo-sensitizing and cardio-protective agent

254th National Meeting (2017)

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