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Chk1 Inhibition as a novel therapeutic strategy for treating triple-negative breast and ovarian cancers

التفاصيل البيبلوغرافية
العنوان: Chk1 Inhibition as a novel therapeutic strategy for treating triple-negative breast and ovarian cancers
المؤلفون: Andrew J Massey, Rebecca Rawlinson, Christopher J. Bryant
المصدر: BMC Cancer
بيانات النشر: Springer Science and Business Media LLC, 2014.
سنة النشر: 2014
مصطلحات موضوعية: Oncology, Cancer Research, Indoles, Triple Negative Breast Neoplasms, Deoxycytidine, Breast cancer, Urea, Ovarian Neoplasms, Benzodiazepinones, Drug Synergism, Combination chemotherapy, Cell cycle, Gene Expression Regulation, Neoplastic, MCF-7 Cells, Female, biological phenomena, cell phenomena, and immunity, HT29 Cells, Research Article, medicine.drug, medicine.medical_specialty, Pyridones, DNA repair, DNA damage, Chk1, Thiophenes, Ovarian cancer, Cell Line, Tumor, Internal medicine, Biomarkers, Tumor, Genetics, medicine, Humans, CHEK1, Protein Kinase Inhibitors, Cisplatin, V158411, business.industry, medicine.disease, Gemcitabine, Checkpoint Kinase 1, Triple-negative, Cancer research, Pyrazoles, business, Protein Kinases
الوصف: Background Chk1 inhibitors are currently in clinical trials as putative potentiators of cytotoxic chemotherapy drugs. Chk1 inhibitors may exhibit single agent anti-tumor activity in cancers with underlying DNA repair, DNA damage response or DNA replication defects. Methods Here we describe the cellular effects of the pharmacological inhibition of the checkpoint kinase Chk1 by the novel inhibitor V158411 in triple-negative breast cancer and ovarian cancer. Cytotoxicity, the effect on DNA damage response and cell cycle along with the ability to potentiate gemcitabine and cisplatin cytotoxicity in cultured cells was investigated. Western blotting of proteins involved in DNA repair, checkpoint activation, cell cycle and apoptosis was used to identify potential predictive biomarkers of Chk1 inhibitor sensitivity. Results The Chk1 inhibitors V158411, PF-477736 and AZD7762 potently inhibited the proliferation of triple-negative breast cancer cells as well as ovarian cancer cells, and these cell lines were sensitive compared to ER positive breast and other solid cancer cells lines. Inhibition of Chk1 in these sensitive cell lines induced DNA damage and caspase-3/7 dependent apoptosis. Western blot profiling identified pChk1 (S296) as a predictive biomarker of Chk1 inhibitor sensitivity in ovarian and triple-negative breast cancer and pH2AX (S139) in luminal breast cancer. Conclusions This finding suggests that Chk1 inhibitors either as single agents or in combination chemotherapy represents a viable therapeutic option for the treatment of triple-negative breast cancer. pChk1 (S296) tumor expression levels could serve as a useful biomarker to stratify patients who might benefit from Chk1 inhibitor therapy.
تدمد: 1471-2407
DOI: 10.1186/1471-2407-14-570
URL الوصول: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3037298c5b020da31b5b9abbb6be872c
https://doi.org/10.1186/1471-2407-14-570
Rights: OPEN
رقم الانضمام: edsair.doi.dedup.....3037298c5b020da31b5b9abbb6be872c
قاعدة البيانات: OpenAIRE
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