Aldose reductase inhibitor increases doxorubicin-sensitivity of colon cancer cells and decreases cardiotoxicity

• Published in: Scientific reports 2017-06, Vol.7 (1), p.3182-14, Article 3182
• Main Authors: Sonowal, Himangshu, Pal, Pabitra B., Wen, Jian-Jun, Awasthi, Sanjay, Ramana, Kota V., Srivastava, Satish K.
• Format: Article
• Language: English
• Subjects: 13/106; 13/2; 631/67/2195; 64/60; 692/4028/67/1059/99; 82/29; 96/95; Aldehyde reductase; Aldehyde Reductase - antagonists & inhibitors; Aldehyde Reductase - genetics; Animals; Anthracycline; ATP Binding Cassette Transporter, Subfamily B, Member 1 - genetics; ATP Binding Cassette Transporter, Subfamily G, Member 2 - genetics; Calcium-binding protein; Cancer therapies; Cardiotoxicity; Cardiotoxicity - drug therapy; Cell Proliferation; Colon cancer; Colonic Neoplasms - drug therapy; Colonic Neoplasms - genetics; Colonic Neoplasms - pathology; Colorectal cancer; Colorectal carcinoma; Daunorubicin; Doxorubicin; Doxorubicin - administration & dosage; Doxorubicin - adverse effects; Drug Resistance, Neoplasm - genetics; Gene Expression Regulation, Neoplastic - drug effects; Heart; Heart diseases; HT29 Cells; Humanities and Social Sciences; Humans; Imidazolidines - administration & dosage; Inflammation; MDR1 protein; Mice; multidisciplinary; Multidrug Resistance-Associated Proteins - genetics; Neoplasm Proteins - genetics; Science; Science (multidisciplinary); Troponin; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-03284-w

Anthracycline drugs such as doxorubicin (DOX) and daunorubicin remain some of the most active wide-spectrum and cost-effective drugs in cancer therapy. However, colorectal cancer (CRC) cells are inherently resistant to anthracyclines which at higher doses cause cardiotoxicity. Our recent studies indicate that aldose reductase (AR) inhibitors such as fidarestat inhibit CRC growth in vitro and in vivo . Here, we show that treatment of CRC cells with fidarestat increases the efficacy of DOX-induced death in HT-29 and SW480 cells and in nude mice xenografts. AR inhibition also results in higher intracellular accumulation of DOX and decreases the expression of drug transporter proteins MDR1, MRP1, and ABCG2. Further, fidarestat also inhibits DOX–induced increase in troponin-I and various inflammatory markers in the serum and heart and restores cardiac function in mice. These results suggest that fidarestat could be used as adjuvant therapy to enhance DOX sensitivity of CRC cells and to reduce DOX-associated cardiotoxicity.