Abstract 5815: Aldose reductase inhibition prevents doxorubicin-induced inflammatory response in endothelial cells and macrophages

Abstract

Abstract Anthracycline class of chemotherapeutic drugs such as doxorubicin and daunorubicin has been known to be effective in the therapy of various types of cancer. However, in certain cancers such as colon cancer, the use of anthracyclines is restricted due to acquired drug resistance, which requires high amounts of drugs that cause severe toxic side effects. We have recently demonstrated that aldose reductase (AR) inhibitor, fidarestat, increases the sensitivity of doxorubicin towards colon cancer cells death in vitro and in vivo and decreases cardiotoxicity. However, the mechanisms through which AR inhibitor prevents doxorubicin-induced toxicity is not understood. We have examined how AR inhibition prevents doxorubicin-induced endothelial and cardiac toxicity along with inflammatory response in in vitro and in vivo models. Our results demonstrate that fidarestat prevents doxorubicin-induced oxidative stress, endothelial cell death, and monocyte adhesion. Further, fidarestat prevents the activation of NF-κB-dependent expression of endothelial cell markers ICAM-1 and VCAM-1 and expression of various inflammatory cytokines and chemokines in human vascular endothelial cells. In addition, fidarestat prevented the doxorubicin-induced decrease in eNOS and increase in iNOS expression. Similarly, AR inhibition prevented doxorubicin-induced endothelial dysfunction, cardiac hypertrophy, and cardiomyocyte injury in mice. Fidarestat also prevented doxorubicin-induced activation of monocytes and macrophages to proinflammatory phenotype in culture as well as in mouse models. Thus, our results suggest that by preventing doxorubicin-induced inflammatory as well as oxidative stress signals, fidarestat decreases cardiotoxic effects of doxorubicin. This is a novel adjuvant therapy of cancer using aldose reductase inhibitors with anthracyclines that would increase cancer therapeutic efficacy and decrease cardiotoxic side effects. Citation Format: Himangshu Sonowal, Ashish Saxena, Kota V. Ramana, Satish K. Srivastava. Aldose reductase inhibition prevents doxorubicin-induced inflammatory response in endothelial cells and macrophages [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5815.