Chemotherapy is one of the most common option for colorectal cancer (CRC), specifically at the advanced stages and after surgical resection of the tumor. Anthracycline drugs such as doxorubicin, daunorubicin are the most commonly used for the therapy of leukemia, lymphoma and breast cancer. However, doxorubicin is not a very effective drug to kill CRC cells since a high amount of doxorubicin is required for colon cancer therapy, which leads to unwanted side effects like cardiac toxicity and cardiomyopathy. Therefore, better adjuvant therapies are required to increase sensitivity of CRC to doxorubicin as well as to decrease the associated cardiomyopathy. Our recent studies indicate that aldose reductase (AR; AKR1B1) inhibitors such as fidarestat prevent CRC growth as well as metastasis in nude mice xenograft models. We now examined our hypothesis that AR inhibition increases the sensitivity of CRC to doxorubicin and decreases its cardiotoxicity by modulating oxidative stress-mediated signaling pathways. We have investigated the effect of co-administration of doxorubicin along with AR inhibitor fidarestat in in vitro and in vivo CRC cells growth and toxicity. Our results suggest that treatment of CRC cells with fidarestat increases the efficacy of doxorubicin-induced death of HT-29 and SW-480 colon cancer cells. Flow cytometric analysis indicates that in fidarestat + doxorubicin -treated CRC cells, the intracellular accumulation of doxorubicin is increased as compared to doxorubicin alone-treated cells. Further, AR inhibition prevents doxorubicin-induced increase in the expression of drug transporter proteins such as MRP-1 and ABCG-2 in CRC cells. In addition, combination of fidarestat with doxorubicin significantly prevented the growth of CRC cells in nude mice xenografts as compared to doxorubicin alone. Fidarestat also prevented the doxorubicin-induced cardiac toxicity as measured by serum troponin-I levels and inflammatory cytokines and chemokines in the serum and heart of doxorubicin-treated mice in combination with fidarestat. Most importantly, fidarestat protects the cardiac damage and dysfunction in doxorubicin-treated mice. Thus, our results suggest that fidarestat could be used as a novel adjuvant therapy in enhancing doxorubicin sensitivity of CRC cells and to reduce the doxorubicin-associated cardiotoxicity.

Citation Format: Himangshu Sonowal, Pabitra B. Pal, Satish K. Srivastava, Kota V. Ramana. Aldose reductase inhibitor increases doxorubicin-sensitivity of colon cancer cells and decreases cardiomyopathy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1052. doi:10.1158/1538-7445.AM2017-1052