Induction of apoptosis in colon cancer cells by a novel topoisomerase I inhibitor TopIn

Journal Article · Fri May 27 00:00:00 EDT 2011 · Biochemical and Biophysical Research Communications

DOI:https://doi.org/10.1016/J.BBRC.2011.04.108· OSTI ID:22204929

Bae, Soo Kyung ^[1]; Gwak, Jungsug ^[2]; Song, Im-Sook ^[3]; Park, Hyung-Soon ^[4]; Oh, Sangtaek ^[2]

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1. College of Pharmacy, The Catholic University of Korea, Bucheon 420-743 (Korea, Republic of)
2. Department of Advanced Fermentation Fusion Science and Technology, Kookmin University, Seoul 136-702 (Korea, Republic of)
3. PharmcoGenomics Research Center, Inje University College of Medicine, Busan 614-735 (Korea, Republic of)
4. Probiond Co., Ltd., Seoul 143-834 (Korea, Republic of)

Highlights: {yields} TopIn activates p53-dependent transcription in colon cancer cells. {yields} TopIn induces apoptosis in colon cancer cells. {yields} TopIn selectively inhibits topoisomerase I activity. {yields} TopIn does not affect the activity of BCRP and MDR-1. -- 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{sup 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.

• OSTI ID: 22204929
• Journal Information: Biochemical and Biophysical Research Communications, Journal Name: Biochemical and Biophysical Research Communications Journal Issue: 1 Vol. 409; ISSN 0006-291X; ISSN BBRCA9
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ADP
APOPTOSIS
ATP
CELL CYCLE
CELL PROLIFERATION
DNA
IN VITRO
INDOLES
LARGE INTESTINE
MAMMARY GLANDS
MONOCLINIC LATTICES
NEOPLASMS
OXIDES
PHOSPHORYLATION
PROTEINS
RIBOSE
TRANSCRIPTION