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

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 st...

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Autores principales:	Himangshu Sonowal, Pabitra B. Pal, Jian-Jun Wen, Sanjay Awasthi, Kota V. Ramana, Satish K. Srivastava
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/6f2463b6cece423cb821de61b7c4f45e
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spelling	oai:doaj.org-article:6f2463b6cece423cb821de61b7c4f45e2021-12-02T16:05:58ZAldose reductase inhibitor increases doxorubicin-sensitivity of colon cancer cells and decreases cardiotoxicity10.1038/s41598-017-03284-w2045-2322https://doaj.org/article/6f2463b6cece423cb821de61b7c4f45e2017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-03284-whttps://doaj.org/toc/2045-2322Abstract 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.Himangshu SonowalPabitra B. PalJian-Jun WenSanjay AwasthiKota V. RamanaSatish K. SrivastavaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-14 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Himangshu Sonowal Pabitra B. Pal Jian-Jun Wen Sanjay Awasthi Kota V. Ramana Satish K. Srivastava Aldose reductase inhibitor increases doxorubicin-sensitivity of colon cancer cells and decreases cardiotoxicity
description	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.
format	article
author	Himangshu Sonowal Pabitra B. Pal Jian-Jun Wen Sanjay Awasthi Kota V. Ramana Satish K. Srivastava
author_facet	Himangshu Sonowal Pabitra B. Pal Jian-Jun Wen Sanjay Awasthi Kota V. Ramana Satish K. Srivastava
author_sort	Himangshu Sonowal
title	Aldose reductase inhibitor increases doxorubicin-sensitivity of colon cancer cells and decreases cardiotoxicity
title_short	Aldose reductase inhibitor increases doxorubicin-sensitivity of colon cancer cells and decreases cardiotoxicity
title_full	Aldose reductase inhibitor increases doxorubicin-sensitivity of colon cancer cells and decreases cardiotoxicity
title_fullStr	Aldose reductase inhibitor increases doxorubicin-sensitivity of colon cancer cells and decreases cardiotoxicity
title_full_unstemmed	Aldose reductase inhibitor increases doxorubicin-sensitivity of colon cancer cells and decreases cardiotoxicity
title_sort	aldose reductase inhibitor increases doxorubicin-sensitivity of colon cancer cells and decreases cardiotoxicity
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/6f2463b6cece423cb821de61b7c4f45e
work_keys_str_mv	AT himangshusonowal aldosereductaseinhibitorincreasesdoxorubicinsensitivityofcoloncancercellsanddecreasescardiotoxicity AT pabitrabpal aldosereductaseinhibitorincreasesdoxorubicinsensitivityofcoloncancercellsanddecreasescardiotoxicity AT jianjunwen aldosereductaseinhibitorincreasesdoxorubicinsensitivityofcoloncancercellsanddecreasescardiotoxicity AT sanjayawasthi aldosereductaseinhibitorincreasesdoxorubicinsensitivityofcoloncancercellsanddecreasescardiotoxicity AT kotavramana aldosereductaseinhibitorincreasesdoxorubicinsensitivityofcoloncancercellsanddecreasescardiotoxicity AT satishksrivastava aldosereductaseinhibitorincreasesdoxorubicinsensitivityofcoloncancercellsanddecreasescardiotoxicity
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Aldose reductase inhibitor increases doxorubicin-sensitivity of colon cancer cells and decreases cardiotoxicity

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