title: Induction of apoptosis in colon cancer cells by a novel topoisomerase I inhibitor TopIn.
abstract: The tumor suppressor p53 plays an important role in cellular emergency mechanisms through regulating the genes involved in cell cycle arrest and apoptosis. To identify small molecules that can activate p53-responsive transcription, we performed chemical screening using genetically engineered HCT116 reporter cells. We found that TopIn (7-phenyl-6H-[1,2,5]oxadiazolo[3,4-e]indole 3-oxide) efficiently activated p53-mediated transcriptional activity and induced phosphorylation of p53 at Ser15, thereby stabilizing the p53 protein. Furthermore, TopIn upregulated the expression of p21(WAF1/CIP1), a downstream target of p53, and suppressed cellular proliferation in various colon cancer cells. Additionally, TopIn induced DNA fragmentation, caspase-3/7 activation and poly ADP ribose polymerase cleavage, typical biochemical markers of apoptosis, in p53 wild-type and mutated colon cancer cells. Finally, we found that TopIn inhibited topoisomerase I activity, but not topoisomerase II, in vitro and induced the formation of the topoisomerase I-DNA complex in HCT116 colon cancer cells. Unlike camptothecin (CPT) and its derivative SN38, TopIn did not affect the activity of the ATP-binding cassette transporter breast cancer resistance protein (BCRP) or multidrug-resistant protein-1 (MDR-1). These results suggest that TopIn may present a promising new topoisomerase I-targeting anti-tumor therapeutics.
authors.affiliation: College of Pharmacy, The Catholic University of Korea, Bucheon, Republic of Korea.
authors.forename: Soo Kyung
authors.initials: SK
authors.lastname: Bae
authors.forename: Jungsug
authors.initials: J
authors.lastname: Gwak
authors.forename: Im-Sook
authors.initials: IS
authors.lastname: Song
authors.forename: Hyung-Soon
authors.initials: HS
authors.lastname: Park
authors.forename: Sangtaek
authors.initials: S
authors.lastname: Oh
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000201:enzymology*; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D004285:Dogs; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000378:metabolism; D010069:Oxadiazoles / Q000737:chemistry / Q000494:pharmacology*; D059004:Topoisomerase I Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000819:agonists
chemical_list: C559941:7-phenyl-6H-(1,2,5)oxadiazolo(3,4-e)indole 3-oxide; C116614:ABCG2 protein, human; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D007211:Indoles; D009363:Neoplasm Proteins; D010069:Oxadiazoles; D059004:Topoisomerase I Inhibitors; D016159:Tumor Suppressor Protein p53; D004264:DNA Topoisomerases, Type I