Role of the Nrf2-antioxidant system in cytotoxicity mediated by anticancer cisplatin: implication to cancer cell resistance

Jeong-Min Cho; Sarala Manandhar; Hyang-Rim Lee; Hyun-Min Park; Mi-Kyoung Kwak

doi:10.1016/j.canlet.2007.10.022

Role of the Nrf2-antioxidant system in cytotoxicity mediated by anticancer cisplatin: implication to cancer cell resistance

Cancer Lett. 2008 Feb 18;260(1-2):96-108. doi: 10.1016/j.canlet.2007.10.022. Epub 2007 Nov 26.

Authors

Jeong-Min Cho¹, Sarala Manandhar, Hyang-Rim Lee, Hyun-Min Park, Mi-Kyoung Kwak

Affiliation

¹ College of Pharmacy, Yeungnam University, Gyeongsangbuk-do, South Korea.

PMID: 18036733
DOI: 10.1016/j.canlet.2007.10.022

Abstract

The treatment of alkylating cytotoxic drug cisplatin is often limited by high incidence rate of resistance. In the present study, the potential involvement of the transcription factor Nrf2 in determination of cisplatin cytotoxicity has been investigated. Nrf2-deficient murine embryonic fibroblasts showed increased cell death, cytotoxicity, and apoptosis in response to cisplatin treatment compared to wild-type cells. Cisplatin-resistant human ovarian cancer SK-OV cells, which are retaining 25-fold higher levels of GSH than murine fibroblasts, could be sensitized by inhibition of Nrf2. Transfection with Nrf2 siRNA into SK-OV cells resulted in severe degree of GSH depletion and exacerbated cytotoxicity following cisplatin treatment compared to scrambled RNA control. In conclusion, we propose that the Nrf2 pathway, which plays a protective role in normal cells, can be a potential target to control cancer cell resistance to oxidants, cytotoxic chemicals, and radiation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / pharmacology*
Antineoplastic Agents / therapeutic use
Antineoplastic Agents / toxicity
Antioxidants / metabolism*
Apoptosis / drug effects
Cell Line, Tumor
Cell Survival / drug effects
Cells, Cultured
Cisplatin / pharmacology*
Cisplatin / therapeutic use
Cisplatin / toxicity
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm* / genetics
Female
Fibroblasts / drug effects*
Fibroblasts / metabolism
Fibroblasts / pathology
Glutathione / metabolism
Humans
Mice
Mice, Knockout
NF-E2-Related Factor 2 / genetics
NF-E2-Related Factor 2 / metabolism*
Ovarian Neoplasms / drug therapy*
Ovarian Neoplasms / genetics
Ovarian Neoplasms / metabolism
Ovarian Neoplasms / pathology
RNA Interference
RNA, Small Interfering / metabolism
Transfection

Substances

Antineoplastic Agents
Antioxidants
NF-E2-Related Factor 2
NFE2L2 protein, human
Nfe2l2 protein, mouse
RNA, Small Interfering
Glutathione
Cisplatin