Entinostat reverses cisplatin resistance in esophageal squamous cell carcinoma via down-regulation of multidrug resistance gene 1

Entinostat reverses cisplatin resistance in esophageal squamous cell carcinoma via... Cisplatin resistance frequently occurs in esophageal squamous cell carcinoma (ESCC). The underlying mechanism for cisplatin resistance in ESCC remains largely obscure. Here we report that entinostat reversed cisplatin resistance in ESCC both in vitro and in vivo by induction of apoptosis and inhibition of cell proliferation, accompanied by a decrease of multidrug resistance gene 1 (MDR1), P-Src, Mcl-1, Cyclin D1 and an increase of cleaved PARP. MDR1 expression was associated with worsen survival of ESCC patients with cisplatin-based chemotherapy. Dasatinib potentiated entinostat to overcome cisplatin resistance. By inhibiting Src, dasatinib reduced the expression of MDR1 and Mcl-1. Furthermore, Obatoclax, an inhibitor of Mcl-1, obviously decreased the expression of MDR1, suggesting that entinostat might surmount cisplatin resistance in ESCC via a Src-Mcl-1-MDR1 pathway. Interestingly, cisplatin also enhanced the effect of entinostat both in vitro and in vivo. Our data disclose a molecular basis that entinostat reverses cisplatin resistance, and provide a promising strategy with combinatorial drugs to treat cisplatin resistant ESCC patients. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Cancer Letters Elsevier

Entinostat reverses cisplatin resistance in esophageal squamous cell carcinoma via down-regulation of multidrug resistance gene 1

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Publisher
Elsevier
Copyright
Copyright © 2017 Elsevier B.V.
ISSN
0304-3835
D.O.I.
10.1016/j.canlet.2017.10.023
Publisher site
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Abstract

Cisplatin resistance frequently occurs in esophageal squamous cell carcinoma (ESCC). The underlying mechanism for cisplatin resistance in ESCC remains largely obscure. Here we report that entinostat reversed cisplatin resistance in ESCC both in vitro and in vivo by induction of apoptosis and inhibition of cell proliferation, accompanied by a decrease of multidrug resistance gene 1 (MDR1), P-Src, Mcl-1, Cyclin D1 and an increase of cleaved PARP. MDR1 expression was associated with worsen survival of ESCC patients with cisplatin-based chemotherapy. Dasatinib potentiated entinostat to overcome cisplatin resistance. By inhibiting Src, dasatinib reduced the expression of MDR1 and Mcl-1. Furthermore, Obatoclax, an inhibitor of Mcl-1, obviously decreased the expression of MDR1, suggesting that entinostat might surmount cisplatin resistance in ESCC via a Src-Mcl-1-MDR1 pathway. Interestingly, cisplatin also enhanced the effect of entinostat both in vitro and in vivo. Our data disclose a molecular basis that entinostat reverses cisplatin resistance, and provide a promising strategy with combinatorial drugs to treat cisplatin resistant ESCC patients.

Journal

Cancer LettersElsevier

Published: Feb 1, 2018

References

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