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Novel Poly(ADP-ribose) Polymerase-1 Inhibitor, AG14361, Restores Sensitivity to Temozolomide in Mismatch Repair-Deficient Cells

Lookup NU author(s): Professor Nicola Curtin, Lan Wang, Suzanne Kyle, Dr Christine Arris, Emeritus Professor Barbara Durkacz, Professor Alan Calvert, Professor Herbie Newell

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Abstract

Purpose: Mismatch repair (MMR) deficiency confers resistance to temozolomide, a clinically active DNA-methylating agent. The purpose of the current study was to investigate the reversal mechanism of temozolomide resistance by the potent novel poly(ADP-ribose) polymerase (PARP)-1 inhibitor, AG14361, in MMR-proficient and -deficient cells. Experimental Design: The effects of AG14361, in comparison with the methylguanine DNA methyltransferase inhibitor, benzylguanine, on temozolomide-induced growth inhibition were investigated in matched pairs of MMR-proficient (HCT-Ch3, A2780, and CP70-ch3) and -deficient (HCT116, CP70, and CP70-ch2) cells. Results: AG14361 enhanced temozolomide activity in all MMR-proficient cells (1.5-3.3-fold) but was more effective in MMR-deficient cells (3.7-5.2-fold potentiation), overcoming temozolomide resistance. In contrast, benzylguanine only increased the efficacy of temozolomide in MMR-proficient cells but was ineffective in MMR-deficient cells. The differential effect of AG14361 in MMR-deficient cells was not attributable to differences in PARP-1 activity or differences in its inhibition by AG14361, nor was it attributable to differences in DNA strand breaks induced by temozolomide plus AG14361. MMR-deficient cells are resistant to cisplatin, but AG14361 did not sensitize any cells to cisplatin. PARP-1 inhibitors potentiate topotecan-induced growth inhibition, but AG14361 did not potentiate topotecan in MMR-deficient cells more than in MMR-proficient cells. Conclusions: MMR defects are relatively common in sporadic tumors and cancer syndromes. PARP-1 inhibition represents a novel way of selectively targeting such tumors. The underlying mechanism is probably a shift of the cytotoxic locus of temozolomide to N7-methylguanine and N3-methyladenine, which are repaired by the base excision repair pathway in which PARP-1 actively participates.


Publication metadata

Author(s): Curtin NJ, Wang L, Yiakouvaki A, Kyle S, Arris C, Canan-Koch S, Webber S, Durkacz BW, Calvert AH, Hostomsky Z, Newell DR

Publication type: Article

Publication status: Published

Journal: Clinical Cancer Research

Year: 2004

Volume: 10

Issue: 3

Pages: 881-889

ISSN (print): 1078-0432

ISSN (electronic): 1557-3265

Publisher: American Association for Cancer Research

URL: http://dx.doi.org/10.1158/1078-0432.CCR-1144-3

DOI: 10.1158/1078-0432.CCR-1144-3

PubMed id: 14871963


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