Journal article
Chk1 signaling pathways that mediated G2M checkpoint in relation to the cellular resistance to the novel topoisomerase I poison BNP1350
Biochemical and biophysical research communications, Vol.295(2), pp.435-444
07/2002
DOI: 10.1016/S0006-291X(02)00683-6
Abstract
A novel karenitecin, BNP1350, is a topoisomerase I-targeting anticancer agent with significant antitumor activity in vitro and in vivo. A BNP1350-resistant human head and neck carcinoma A253 cell line, denoted A253/BNPR, was developed. The A253/BNPR cell line was approximately 9-fold resistant to BNP1350 and 4-fold cross-resistant to another topoisomerase I inhibitor SN-38, the active metabolite of irinotecan. After drug treatment with equimolar concentrations of BNP1350 (0.7 μM) for 2 h, activation of the DNA double-strand break repair protein complexes was similar in the two cell lines, suggesting that DNA dsb repair is not attributable to resistance to BNP1350 in the A253/BNPR cells. Cell cycle analysis indicates that the A253 cell line accumulated primarily in S phase, but G2 phase accumulation was observed in the A253/BNPR cell line at 48 h after drug removal. Elevated chk1 phosphorylation at Ser345 following DNA damage induced by BNP1350 was accompanied by G2 accumulation in the A253/BNPR cell line, while exposure to equimolar concentrations of BNP1350 (0.7 μM) induced S-phase arrest and no increased phosphorylation of chk1 at Ser345 in the A253 cell line. Under the same conditions, increased chk1 activity was observed in the A253/BNPR cell line, but not in the A253 cell line. Moreover, stimulated binding of 14-3-3 proteins to chk1 was observed in BNP1350-treated A253/BNPR cells. To confirm relationship between chk1 expression/phosphorylation and drug resistance to topo I poisons, we examined the effects of chk1 or chk2 antisense oligonucleotides on the cellular growth inhibition. Chk1 antisense oligonucleotide can sensitize the A253/BNPR cells to killing by topo I inhibitor BNP1350, but no significant sensitization of BNP1350-induced growth inhibition was observed in the drug-sensitive cell line. Chk2 antisense oligonucleotide has only a small sensitization effect on BNP1350-induced growth inhibition in both cell lines. The data indicate that the chk1 signaling pathways that mediate cell cycle checkpoint are associated with cellular resistance to BNP1350 in the A253/BNPR cell line. © 2002 Elsevier Science (USA). All rights reserved.
Details
- Title: Subtitle
- Chk1 signaling pathways that mediated G2M checkpoint in relation to the cellular resistance to the novel topoisomerase I poison BNP1350
- Creators
- Ming-biao Yin - Roswell Park Cancer InstituteGunnar Hapke - Roswell Park Cancer InstituteJiaxi Wu - Roswell Park Cancer InstituteRami G Azrak - Roswell Park Cancer InstituteCheryl Frank - Roswell Park Cancer InstituteCarol Wrzosek - Roswell Park Cancer InstituteYoucef M Rustum - Roswell Park Cancer Institute
- Resource Type
- Journal article
- Publication Details
- Biochemical and biophysical research communications, Vol.295(2), pp.435-444
- DOI
- 10.1016/S0006-291X(02)00683-6
- ISSN
- 0006-291X
- eISSN
- 1090-2104
- Language
- English
- Date published
- 07/2002
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984359800102771
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