Overexpression of cMOAT (MRP2/ABCC2) is associated with decreased formation of platinum-DNA adducts and decreased G2-arrest in melanoma cells resistant to cisplatin.

Abstract

Resistance to various anti-neoplastic agents is a common observation in clinical management of melanoma. The biologic mechanisms conferring these different drug-resistant phenotypes, including resistance against the commonly used anti-cancer drug cisplatin, are unclear. In order to elucidate the role of the membrane adenosine triphosphate binding cassette-transporter cMOAT (canalicular multispecific anion transporter) (MRP2/ABCC2) in cisplatin resistance of melanoma, the expression of this protein was analyzed in the platinum drug-resistant cell line MeWo CIS 1. Cisplatin-resistant melanoma cells showed a distinct overexpression of cMOAT on mRNA and protein level. This observation was accompanied by a reduced formation of platinum-induced intrastrand cross-links in the nuclear DNA measured by an immunocytologic assay. This decrease in DNA platination was accompanied by an accelerated re-entry into the cell cycle after the typical cisplatin-induced G2 arrest, and a resistance to undergo apoptosis. Kinetics of formation and elimination of platinum-DNA adducts suggest that the DNA repair capacity for Pt-d(GpG) adducts was not elevated in platinum drug-resistant melanoma cells. The decrease in platinum-DNA adduct formation in cisplatin-resistant melanoma cells was rather a reflection of the protecting activity of the transporter cMOAT. In conclusion, the functional inhibition of cMOAT might be a promising strategy in the reversal of resistance to platinum-based anti-cancer drugs in human melanoma.

• Authors: Bernd Liedert, Verena Materna, Dirk Schadendorf, Jürgen Thomale, Hermann Lage
• Journal: The Journal of investigative dermatology (J Invest Dermatol) Vol. 121 Issue 1 Pg. 172-6 (Jul 2003) ISSN: 0022-202X [Print] United States
• PMID: 12839578 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ABCC2 protein, human
• Antineoplastic Agents
• DNA Adducts
• Membrane Transport Proteins
• Multidrug Resistance-Associated Protein 2
• Multidrug Resistance-Associated Proteins
• Platinum
• Cisplatin

Topics

• Antineoplastic Agents (metabolism, pharmacology)
• Cisplatin (metabolism, pharmacology)
• DNA Adducts (metabolism)
• Drug Resistance, Neoplasm
• G2 Phase (drug effects, genetics)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Melanoma
• Membrane Transport Proteins
• Multidrug Resistance-Associated Protein 2
• Multidrug Resistance-Associated Proteins (genetics)
• Phenotype
• Platinum (metabolism, pharmacology)
• Skin Neoplasms
• Transfection
• Tumor Cells, Cultured (cytology, drug effects)