New tricks for old drugs: the anticarcinogenic potential of DNA repair inhibitors

Abstract

Defective or abortive repair of DNA lesions has been associated with carcinogenesis. Therefore it is imperative for a cell to accurately repair its DNA after damage if it is to return to a normal cellular phenotype. In certain circumstances, if DNA damage cannot be repaired completely and with high fidelity, it is more advantageous for an organism to have some of its more severely damaged cells die rather than survive as neoplastic transformants. A number of DNA repair inhibitors have the potential to act as anticarcinogenic compounds. These drugs are capable of modulating DNA repair, thus promoting cell death rather than repair of potentially carcinogenic DNA damage mediated by error-prone DNA repair processes. In theory, exposure to a DNA repair inhibitor during, or immediately after, carcinogenic exposure should decrease or prevent tumorigenesis. However, the ability of DNA repair inhibitors to prevent cancer development is difficult to interpret depending upon the system used and the type of genotoxic stress. Inhibitors may act on multiple aspects of DNA repair as well as the cellular signaling pathways activated in response to the initial damage. In this review, we summarize basic DNA repair mechanisms and explore the effects of a number of DNA repair inhibitors that not only potentiate DNA-damaging agents but also decrease carcinogenicity. In particular, we focus on a novel anti-tumor agent, beta-lapachone, and its potential to block transformation by modulating poly(ADP-ribose) polymerase-1.

Harnessing the complexity of DNA-damage response pathways to improve cancer treatment outcomes

“…Specific inhibitors of DNA-dependent protein kinase (DNA-PK) or poly(ADP-ribose) polymerase (PARP) used to selectively reduce NHEJ and BER activity, respectively, have been shown to be effective as single-agent therapies in HR-defective tumors (O'Connor et al, 2007;Lieberman, 2008). Other reports describing inhibitors of BER, HR and mismatch repair pathways offer further prospects for targeted cancer therapies (Bentle et al, 2006;Kelley and Fishel, 2008;Lieberman, 2008). Platinum compounds are the key drugs for the treatment of cancers defective in FA-BRCA pathway; however, recent reports describe that hypersensitivity of FA-deficient cells to crosslinking agents can be suppressed by the inhibition of NHEJ, possibly owing to reactivation of HR (Adamo et al, 2010;Pace et al, 2010).…”

DNA damage-induced cell death: lessons from the central nervous system

“…An important biological strategy to guard against damaged and mutated cells is the activation of programmed cell death in response to DNA damage [1][2][3]. Furthermore, genotoxic agents such as ionizing radiation (IR) and chemotherapeutic drugs are the mainstay of cancer therapy because they can trigger programmed cell death [4,5]. Defects in DNA damage-induced cell death, therefore, not only increase the risk of cancer but also reduce the efficacy of cancer therapy.…”

The effects of resveratrol and selected metabolites on the radiation and antioxidant response

“…impose DNA damage and apoptosis, [43][44][45] inhibit DNA damage repair, 43,46 and inhibit tumor growth.…”