Drugs classified as poly (ADP-ribose) polymerase (PARP) inhibitors have been shown to be promising anticancer agents for breast and ovarian cancers deficient in either BRCA1 or BRCA2. Now, according to data from a preclinical study published in the April 1, 2013 issue of Cancer Research, a journal of the American Association for Cancer Research, PARP inhibitors may offer a novel treatment strategy for patients with cancer that has become resistant to the commonly used antineoplastic agent cis-diammineplatinum(II) dichloride / cisplatin (CDDP;Platinol?/Platinol?-AQ; Bristol-Myers Squibb Company/BMS)

While cisplatin, a platinum-based drug with positive evidence of risk in pregnancy (category D), generally seen as the cornerstone of treatment of many cancers (including testicular, ovarian, bladder, head and neck, esophageal, small and non-small cell lung, breast, cervical, stomach and prostate cancers) with a high initial platinum responsiveness, the majority of cancer patients will eventually relapse with cisplatin-resistant disease. Furthermore, despite poor response rates and limited response duration in the treatment of non-small cell lung cancer (NSCLC), platinum-based compounds such as cisplatin, are still the foundation of many chemotherapy regimens.

Commenting on this phenomenon, Guido Kroemer, M.D., Ph.D., professor at University Paris Descartes in Paris, France, noted: ?Cisplatin is one of the most widely used conventional, anticancer chemotherapy drugs. Unfortunately, most patients respond only transiently to cisplatin therapy because their cancer cells develop ways to resist the effects of the drug.?

Kroemer and colleagues set out to identify the biochemical changes that arise as cancer cells become resistant to cisplatin in the hope that the information could provide clues to potential new therapies. They focused their study on non-small cell lung cancer (NSCLC) cells because NSCLC is the leading cause of cancer-related morbidity and mortality worldwide and patients with NSCLC are frequently treated with cisplatin, Kroemer said.

PARP1 and PAR
The researchers found that most NSCLC cell lines resistant to cisplatin had high levels of the protein poly (ADP-ribose) polymerase 1 (PARP1) and elevated amounts of poly (ADP-ribosyl) (PAR). In addition, they found that the PARP1 was hyperactivated. They observed similar results for cisplatin-resistant mesothelioma, ovarian cancer and cervical cancer cell lines.

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When cisplatin-resistant NSCLC cell lines with high levels of hyperactivated PARP1 and PAR were exposed to each of two distinct PARP inhibitors, the cell lines initiated a cellular process that resulted in their death. Levels of PAR were more predictive of response to PARP inhibitors than were levels of PARP1 itself, suggesting that PAR may be an effective biomarker of response to cisplatin, Kroemer explained.

Biochemical changes
The researchers further examined whether treatment with a PARP inhibitor affected the growth of tumors in mice xenografted with human NSCLC cell lines. They found that treatment significantly slowed tumor growth. ?Our data show that in most cases, cisplatin resistance is linked to stereotyped biochemical changes in cancer cells that render them vulnerable to PARP inhibitors,? Kroemer said. ?This has clear implications for new treatment regimens and for developing biomarkers of response to cisplatin. We are following up these exciting clinical possibilities in our laboratory.?

Other studies
In an unrelated study, Yu-Ru Lee from the Graduate Institute of Life Science, National Defense Medical Center, Taipei, Taiwan, evaluated anticancer activities of anthraquinone-derived tricyclic and tetracyclic small molecules and their structure-activity relationships with PARP-1 inhibition in non-small cell lung cancer (NSCLC) and NSCLC-overexpressing Oct4 and Nanog clone, which show high-expression of PARP-1 and more resistance to anticancer drug. These researchers concluded that telomere maintenance should be taken into consideration in efforts not only to overcome drug resistance, but also to optimize the use of telomere-based therapeutics. Lee and his colleagues believe that their findings will be of great value to facilitate structure-based design of selective PARP inhibitors, in general, and telomerase inhibitors, in particular.

For more information:
– Michels J, Vitale I, Galluzzi L, Adam J, Olaussen KA, Kepp, Senovilla L, Talhaoui I, et al. Cisplatin Resistance Associated with PARP Hyperactivation. Cancer Res April 1, 2013 73; 2271 doi: 10.1158/0008-5472.CAN-12-3000
– Cheng H, Zhang Z, Borczuk A, Powell CA, Balajee AS, Lieberman HB, Halmos B.PARP inhibition selectively increases sensitivity to cisplatin in ERCC1-low non-small cell lung cancer cells. Carcinogenesis. 2013 Jan 18. [Epub ahead of print]
– Lee YR, Yu DS, Liang YC, Huang KF, Chou SJ, Chen TC, Lee CC, Chen CL, Chiou SH, Huang HS. New Approaches of PARP-1 Inhibitors in Human Lung Cancer Cells and Cancer Stem-Like Cells by Some Selected Anthraquinone-Derived Small Molecules.PLoS One. 2013;8(2):e56284. doi: 10.1371/journal.pone.0056284. Epub 2013 Feb 25 [Abstract][Full Article]

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