Gemcitabine resistance mediated by ribonucleotide reductase M2 in lung squamous cell carcinoma is reversed by GW8510 through autophagy induction

Clinical Science
Ping ChenJian Li

Abstract

Although chemotherapeutic regimen containing gemcitabine is the first-line therapy for advanced lung squamous cell carcinoma (LSCC), gemcitabine resistance remains an important clinical problem. Some studies suggest that overexpressions of ribonucleotide reductase (RNR) subunit M2 (RRM2) may be involved in gemcitabine resistance. We used a novel RRM2 inhibitor, GW8510, as a gemcitabine sensitization agent to investigate the therapeutic utility in reversing gemcitabine resistance in LSCC. Results showed that the expressions of RRM2 were increased in gemcitabine intrinsic resistant LSCC cells upon gemcitabine treatment. GW8510 not only suppressed LSCC cell survival, but also sensitized gemcitabine-resistant cells to gemcitabine through autophagy induction mediated by RRM2 down-regulation along with decrease in dNTP levels. The combination of GW8510 and gemcitabine produced a synergistic effect on killing LSCC cells. The synergism of the two agents was impeded by addition of autophagy inhibitors chloroquine (CQ) or bafilomycin A1 (Baf A1), or knockdown of the autophagy gene, Bcl-2-interacting protein 1 (BECN1). Moreover, GW8510-caused LSCC cell sensitization to gemcitabine through autophagy induction was parallel with impairment o...Continue Reading

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Citations

Jun 15, 2019·Journal of Experimental & Clinical Cancer Research : CR·Ping ChenJian Li
Jan 2, 2021·Frontiers in Cell and Developmental Biology·Zhengdong DengJianming Wang
Nov 24, 2020·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Yaqiong ZhanYunqing Qiu
Feb 21, 2021·Archives of Pharmacal Research·Hye-Young Min, Ho-Young Lee
Mar 15, 2021·Biochemical and Biophysical Research Communications·Jie HuXiu-Ping Wei
May 16, 2021·Archives of Biochemistry and Biophysics·Maria Luiza Caldas NogueiraVictor L Davidson

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