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Molecular Pharmacology

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Research ArticleArticle

Chronic Oxidative Stress Increases Resistance to Doxorubicin-Induced Cytotoxicity in Renal Carcinoma Cells Potentially Through Epigenetic Mechanism

Logeswari Ponnusamy, Prathap Kumar S. Mahalingaiah and Kamaleshwar P. Singh
Molecular Pharmacology January 2016, 89 (1) 27-41; DOI: https://doi.org/10.1124/mol.115.100206
Logeswari Ponnusamy
Department of Environmental Toxicology, The Institute of Environmental and Human Health (TIEHH), Texas Tech University, Lubbock, Texas
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Prathap Kumar S. Mahalingaiah
Department of Environmental Toxicology, The Institute of Environmental and Human Health (TIEHH), Texas Tech University, Lubbock, Texas
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Kamaleshwar P. Singh
Department of Environmental Toxicology, The Institute of Environmental and Human Health (TIEHH), Texas Tech University, Lubbock, Texas
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Abstract

Renal cell carcinoma is the most common form of kidney cancer and is highly resistant to chemotherapy. Although the role of oxidative stress in kidney cancer is known, the chemotherapeutic response of cancer cells adapted to chronic oxidative stress is not clear. Hence, the effect of oxidative stress on sensitivity to doxorubicin-induced cytotoxicity was evaluated using an in vitro model of human kidney cancer cells adapted to chronic oxidative stress. Results of MTT- and anchorage-independent growth assays and cell cycle analysis revealed significant decrease in sensitivity to doxorubicin in Caki-1 cells adapted to oxidative stress. Changes in the expression of genes involved in drug transport, cell survival, and DNA repair–dependent apoptosis further confirmed increased resistance to doxorubicin-induced cytotoxicity in these cells. Decreased expression of mismatch repair (MMR) gene MSH2 in cells exposed to oxidative stress suggests that loss of MMR-dependent apoptosis could be a potential mechanism for increased resistance to doxorubicin-induced cytotoxicity. Additionally, downregulation of HDAC1, an increase in the level of histone H3 acetylation, and hypermethylation of MSH2 promoter were also observed in Caki-1 cells adapted to chronic oxidative stress. DNA-demethylating agent 5-Aza-2dC significantly restored the expression of MSH2 and doxorubicin-induced cytotoxicity in Caki-1 cells adapted to chronic oxidative stress, suggesting the role of DNA hypermethylation in inactivation of MSH2 expression and consequently MMR-dependent apoptosis in these cells. In summary, this study for the first time provides direct evidence for the role of oxidative stress in chemotherapeutic resistance in renal carcinoma cells potentially through epigenetic mechanism.

Footnotes

    • Received June 3, 2015.
    • Accepted October 29, 2015.
  • dx.doi.org/10.1124/mol.115.100206.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 89 (1)
Molecular Pharmacology
Vol. 89, Issue 1
1 Jan 2016
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Research ArticleArticle

Oxidative Stress–Induced Chemoresistance in Kidney Cancer

Logeswari Ponnusamy, Prathap Kumar S. Mahalingaiah and Kamaleshwar P. Singh
Molecular Pharmacology January 1, 2016, 89 (1) 27-41; DOI: https://doi.org/10.1124/mol.115.100206

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Research ArticleArticle

Oxidative Stress–Induced Chemoresistance in Kidney Cancer

Logeswari Ponnusamy, Prathap Kumar S. Mahalingaiah and Kamaleshwar P. Singh
Molecular Pharmacology January 1, 2016, 89 (1) 27-41; DOI: https://doi.org/10.1124/mol.115.100206
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