American Journal of Pharmacology and Toxicology

Retinoids Chemosensitize Ovarian Cancer Cell Lines to Cisplatin Independent of Nuclear Receptors and p53

Suresh Guruswamy and Doris M. Benbrook

DOI : 10.3844/ajptsp.2006.87.93

American Journal of Pharmacology and Toxicology

Volume 1, Issue 4

Pages 87-93

Abstract

Treatment of ovarian cancer with cisplatin-based chemotherapy is highly toxic and is often followed by cancer recurrence. Repeated treatments with cisplatin frequently result in the development of resistance to this drug. Drugs with low toxicity that could enhance the tumor cell killing effects of cisplatin could potentially reduce the toxicity and enhance the efficacy of cisplatin. The mechanism of cell kill by cisplatin is partially due to induction of apoptosis through the p53 pathway. Retinoids can regulate apoptosis through nuclear retinoic acid receptors, but the role of p53 in the mechanism varies with the individual retinoid and cell type. The objective of this study was to evaluate the potential of receptor-active and –independent retinoids as chemosensitization of ovarian cancer cell lines with different p53 status. The growth of two ovarian cancer cell lines, OVCAR-3 that has wild type p53 and Caov-3 that has mutant type, was evaluated in the presence and absence of various combinations of cisplatin, a series of retinoids and a chemical inhibitor of p53 transactivation activity (pifithrinα). Both receptor active and receptor independent retinoids chemosensitized the two cell lines to cisplatin. PFTα partially attenuated growth inhibition by cisplatin, slightly enhanced the growth inhibition of retinoids and did not affect growth inhibition when retinoids were used in combination with cisplatin. RNase protection demonstrated that PFTα did not alter retinoid effects on p53 regulated genes. In conclusion, retinoids chemosensitize both sensitive and resistant ovarian cancer cells to cisplatin through mechanisms independent of nuclear retinoid receptors and p53.

Copyright

© 2006 Suresh Guruswamy and Doris M. Benbrook. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.