The aldose reductase (AR) inhibitor fidarestat is found as an adjuvant therapy to enhance doxorubicin sensitivity of colorectal cancer cells and to reduce doxorubicin-associated cardiotoxicity, according to researchers at The University of Texas Medical Branch at Galveston and Texas Tech University Health Sciences Center. Results of their study, published in the Journal Scientific Reports Nature, demonstrated that fidarestat inhibits colorectal cancer cell growth in vitro and in vivo.
Doxorubicin is highly effective in fighting cancer and is widely used. However, it can be toxic to the heart at higher doses. The researchers report that cardiotoxicity was significantly reduced when combining doxorubicin with fidarestat.
Doxorubicin has completed phase 2 clinical trials in the United States and phase 3 trials in Japan for the prevention of diabetic neuropathy, and no major side effects were reported. The agent is commonly used to treat several types of cancers, including breast and lung cancers. Doxorubicin is very cost effective compared with other cancer drugs. However, colon cancers become resistant to this agent so a higher dosage must be used for it to be effective, creating a conundrum because higher doses have greater cardiotoxicity.
In this study, the researchers demonstrated that treatment of colorectal cancer cells with fidarestat increases the efficacy of doxorubicin-induced death in HT-29 and SW480 cells and in nude mice xenografts. This approach also resulted in higher intracellular accumulation of doxorubicin and decreased the expression of drug transporter proteins MDR1, MRP1, and ABCG2. The researchers report that fidarestat also inhibited doxorubicin-induced increase in troponin-I and various inflammatory markers in the serum and heart in the mouse models.
1. Sonowal H, Pal PB, Wen J, et al. Aldose reductase inhibitor increases doxorubicin-sensitivity of colon cancer cells and decreases cardiotoxicity [published online June 9, 2017].
Scientific Reports. doi: 10.1038/s41598-017-03284-w