NSC666715 and Its Analogs Inhibit Strand-Displacement Activity of DNA Polymerase β and Potentiate Temozolomide-Induced DNA Damage, Senescence and Apoptosis in Colorectal Cancer Cells.
Recently approved chemotherapeutic agents to treat colorectal cancer (CRC) have made some impact; however, there is an urgent need for newer targeted agents and strategies to circumvent CRC growth and metastasis. CRC frequently exhibits natural resistance to chemotherapy and those who do respond initially later acquire drug resistance. A mechanism to potentially sensitize CRC cells is by blocking the DNA polymerase β (Pol-β) activity. Temozolomide (TMZ), an alkylating agent, and other DNA-interacting agents exert DNA damage primarily repaired by a Pol-β-directed base excision repair (BER) pathway. In previous studies, we used structure-based molecular docking of Pol-β and identified a potent small molecule inhibitor (NSC666715). In the present study, we have determined the mechanism by which NSC666715 and its analogs block Fen1-induced strand-displacement activity of Pol-β-directed LP-BER, cause apurinic/apyrimidinic (AP) site accumulation and induce S-phase cell cycle arrest. Induction of S-phase cell cycle arrest leads to senescence and apoptosis of CRC cells through the p53/p21 pathway. Our initial findings also show a 10-fold reduction of the IC50 of TMZ when combined with NSC666715. These results provide a guide for the development of a target-defined strategy for CRC chemotherapy that will be based on the mechanisms of action of NSC666715 and TMZ. This combination strategy can be used as a framework to further reduce the TMZ dosages and resistance in CRC patients.
Division of Hematology and Oncology, Department of Medicine, University of Florida, Gainesville, Florida, 32610, United States of America.
Aruna S
AS
Jaiswal
Department of Anatomy and Cell Biology, University of Florida, Gainesville, Florida, 32610, United States of America.
Harekrushna
H
Panda
Department of Pharmacology and Experimental Therapeutics, University of Florida, Gainesville, Florida, 32610, United States of America.
Brian K
BK
Law
Celprogen Inc., Torrance, California, 90503, United States of America.
Jay
J
Sharma
Celprogen Inc., Torrance, California, 90503, United States of America.
Jitesh
J
Jani
Division of Hematology and Oncology, Department of Medicine, University of Florida, Gainesville, Florida, 32610, United States of America.
Robert
R
Hromas
Department of Anatomy and Cell Biology, University of Florida, Gainesville, Florida, 32610, United States of America.
Satya
S
Narayan
D017209:Apoptosis / Q000187:drug effects*; D052160:Benzothiazoles / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects*; D015179:Colorectal Neoplasms / Q000473:pathology*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004249:DNA Damage; D019951:DNA Polymerase beta / Q000378:metabolism*; D004260:DNA Repair / Q000187:drug effects; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D045325:HCT116 Cells; D006801:Humans; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D013438:Sulfhydryl Compounds / Q000737:chemistry / Q000494:pharmacology*; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*; D000077204:Temozolomide; D014050:Toluene / Q000031:analogs & derivatives / Q000494:pharmacology; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D000096926:Benzenesulfonamides
D052160:Benzothiazoles; D050759:Cyclin-Dependent Kinase Inhibitor p21; D019951:DNA Polymerase beta; D003606:Dacarbazine; D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D013438:Sulfhydryl Compounds; D013449:Sulfonamides; D000077204:Temozolomide; D014050:Toluene; D014230:Triazoles; D016159:Tumor Suppressor Protein p53; C000604551:NSC666715; D000096926:Benzenesulfonamides; C121565:pifithrin