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

Himangshu Sonowal, Pabitra B. Pal, Jian Jun Wen, Sanjay Awasthi, Kota Ramana, Satish Srivastava

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article number3182
JournalScientific Reports
Volume7
Issue number1
DOIs
StatePublished - Dec 1 2017

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Aldehyde Reductase
Doxorubicin
Colonic Neoplasms
Colorectal Neoplasms
Anthracyclines
HT29 Cells
Drug Costs
Daunorubicin
Troponin I
P-Glycoprotein
Heterografts
Nude Mice
Pharmaceutical Preparations
Cardiotoxicity
Biomarkers
fidarestat
Therapeutics
Growth
Neoplasms

ASJC Scopus subject areas

  • General

Cite this

Aldose reductase inhibitor increases doxorubicin-sensitivity of colon cancer cells and decreases cardiotoxicity. / Sonowal, Himangshu; Pal, Pabitra B.; Wen, Jian Jun; Awasthi, Sanjay; Ramana, Kota; Srivastava, Satish.

In: Scientific Reports, Vol. 7, No. 1, 3182, 01.12.2017.

Research output: Contribution to journalArticle

Sonowal, Himangshu ; Pal, Pabitra B. ; Wen, Jian Jun ; Awasthi, Sanjay ; Ramana, Kota ; Srivastava, Satish. / Aldose reductase inhibitor increases doxorubicin-sensitivity of colon cancer cells and decreases cardiotoxicity. In: Scientific Reports. 2017 ; Vol. 7, No. 1.
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