Abstract
Chemoprevention presents a major strategy for the medical management of colorectal cancer. Most drugs used for colorectal cancer therapy induce DNA-alkylation damage, which is primarily repaired by the base excision repair (BER) pathway. Thus, blockade of BER pathway is an attractive option to inhibit the spread of colorectal cancer. Using an in silico approach, we performed a structure-based screen by docking small-molecules onto DNA polymerase β (Pol-β) and identified a potent anti-Pol-β compound, NSC-124854. Our goal was to examine whether NSC-124854 could enhance the therapeutic efficacy of DNA-alkylating agent, Temozolomide (TMZ), by blocking BER. First, we determined the specificity of NSC-124854 for Pol-β by examining in vitro activities of APE1, Fen1, DNA ligase I, and Pol-β-directed single nucleotide (SN)- and long-patch (LP)-BER. Second, we investigated the effect of NSC-124854 on the efficacy of TMZ to inhibit the growth of mismatch repair (MMR)-deficient and MMR-proficient colon cancer cell lines using in vitro clonogenic assays. Third, we explored the effect of NSC-124854 on TMZ-induced in vivo tumor growth inhibition of MMR-deficient and MMR-proficient colonic xenografts implanted in female homozygous SCID mice. Our data showed that NSC-124854 has high specificity to Pol-β and blocked Pol-β-directed SN- and LP-BER activities in in vitro reconstituted system. Furthermore, NSC-124854 effectively induced the sensitivity of TMZ to MMR-deficient and MMR-proficient colon cancer cells both in vitro cell culture and in vivo xenograft models. Our findings suggest a potential novel strategy for the development of highly specific structure-based inhibitor for the prevention of colonic tumor progression.
Highlights
Colorectal cancer is the third most common cancer and the second most common cause of cancer related deaths worldwide [1]
To identify a potent anti-polymerase b (Pol-b) compound, we used an in silico high-throughput structure-based molecular docking approach and screened approximately 140,000 small molecule compounds for their ability to interact with the adenomatous polyposis coli (APC)-binding site of Pol-b (Fig. 1A) [48]
The 22 highest scoring small molecular compounds were requested from the Developmental Therapeutics Program (DTP) of National Cancer Institute (NCI) for functional evaluation
Summary
Colorectal cancer is the third most common cancer and the second most common cause of cancer related deaths worldwide [1]. The first choice of chemotherapeutic drug for colorectal cancer has been 5-Fluorouracil (5-FU) It is mostly used as neoadjuvant therapy with radiation and in combination with several other chemotherapeutic drugs, such as mitomycin, cisplatin, oxaliplatin, camptosar, eloxatin, avastin, erbitux, and vectibix for the treatment of colorectal cancer that becomes metastasized [2]. These drugs give best results at higher doses, but cause serious side effects, including the killing of healthy cells of lining of mouth, the lining of the gastrointestinal tract, the hair follicles, the bone marrow and cause liver injury and hypertension [3]
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