Abstract
Enhanced DNA damage repair is one mechanism involved in colon cancer drug resistance. Thus, targeting molecular components of repair pathways with specific small molecule inhibitors may improve the efficacy of chemotherapy. ABT-888 and VE-821, inhibitors of poly-ADP-ribose-polymerase (PARP) and the serine/threonine-kinase Ataxia telangiectasia related (ATR), respectively, were used to treat colon cancer cell lines in combination with the topoisomerase-I inhibitor irinotecan (SN38). Our findings show that each of these DNA repair inhibitors utilized alone at nontoxic single agent concentrations resulted in sensitization to SN38 producing a 1.4–3 fold reduction in the 50% inhibitory concentration (IC50) of SN38 in three colon cancer cell lines. When combined together, nontoxic concentrations of ABT-888 and VE-821 produced a 4.5–27 fold reduction in the IC50 of SN38 with the HCT-116 colon cancer cells demonstrating the highest sensitization as compared to LoVo and HT-29 colon cancer cells. Furthermore, the combination of all three agents was associated with maximal G2 −M arrest and enhanced DNA-damage (γH2AX) in all three colon cancer cell lines. The mechanism of this enhanced sensitization was associated with: (a) maximal suppression of SN38 induced PARP activity in the presence of both inhibitors and (b) ABT-888 producing partial abrogation of the VE-821 enhancement of SN38 induced DNA-PK phosphorylation, resulting in more unrepaired DNA damage; these alterations were only present in the HCT-116 cells which have reduced levels of ATM. This novel combination of DNA repair inhibitors may be useful to enhance the activity of DNA damaging chemotherapies such as irinotecan and help produce sensitization to this drug in colon cancer.
Highlights
DNA-interacting chemotherapy drugs remain the mainstay therapy for most advanced cancers, including metastatic colon cancer
Irinotecan sensitized by Ataxia telangiectasia related (ATR)/PARP inhibition support to the development of inhibitors of key enzymes involved in the DNA damage response (DDR) with promising preclinical results (Panasci et al, 2001; Aloyz et al, 2004; Willmore et al, 2004; Amrein et al, 2011; Siddiqui-Jain et al, 2012; Davidson et al, 2012a)
Based on the IC50 values obtained for ABT-888 and VE-821 non-toxic concentrations of these compounds were selected for combination drug treatments with SN38
Summary
DNA-interacting chemotherapy drugs remain the mainstay therapy for most advanced cancers, including metastatic colon cancer. Irinotecan sensitized by ATR/PARP inhibition support to the development of inhibitors of key enzymes involved in the DNA damage response (DDR) with promising preclinical results (Panasci et al, 2001; Aloyz et al, 2004; Willmore et al, 2004; Amrein et al, 2011; Siddiqui-Jain et al, 2012; Davidson et al, 2012a). Inhibitors of DNA-PK or PARP individually can sensitize cancer cells to DNA-damaging agents (Willmore et al, 2004; Donawho et al, 2007; Penning et al, 2009; Amrein et al, 2011; Siddiqui-Jain et al, 2012; Davidson et al, 2012b). We have previously demonstrated increased sensitization of primary chronic lymphocytic leukemia cells to chlorambucil by the use of two DNA repair inhibitors employed together targeting HRR and/or DNA-PK (Amrein et al, 2011)
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