ArticleJournal of the National Cancer Institute2011
The role of p27(Kip1) in dasatinib-enhanced paclitaxel cytotoxicity in human ovarian cancer cells.
Article in Journal of the National Cancer Institute, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 26 citations in OpenAlex.
- Targeting the FAK-Src Complex in Desmoplastic Small Round Cell Tumors, Ewing Sarcoma, and Rhabdomyosarcoma.Sarcoma · 2022Article
- 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase-2 Regulates TP53-Dependent Paclitaxel Sensitivity in Ovarian and Breast Cancers.Clinical cancer research : an official journal of the American Association for Cancer Research · 2019Article
- Upregulation of P27International journal of clinical and experimental pathology · 2017Article
- Dasatinib enhances antitumor activity of paclitaxel in ovarian cancer through Src signaling.Molecular medicine reports · 2015Article
- Apoptosis of cholangiocytes modulated by thioredoxin of carcinogenic liver fluke.The international journal of biochemistry & cell biology · 2015Article
- Sparse expression bases in cancer reveal tumor drivers.Nucleic acids research · 2015Article
- Article
- Low-dose SN-38 with paclitaxel induces lethality in human uterine cervical adenocarcinoma cells by increasing caspase activity.Medical molecular morphology · 2014Article
- Dasatinib (BMS-35482) interacts synergistically with docetaxel, gemcitabine, topotecan, and doxorubicin in ovarian cancer cells with high SRC pathway activation and protein expression.International journal of gynecological cancer : official journal of the International Gynecological Cancer Society · 2014Article
- Combined SFK/MEK inhibition prevents metastatic outgrowth of dormant tumor cells.The Journal of clinical investigation · 2014Article
- Src Inhibition with saracatinib reverses fulvestrant resistance in ER-positive ovarian cancer models in vitro and in vivo.Clinical cancer research : an official journal of the American Association for Cancer Research · 2012Article
- Activation of abl family kinases in solid tumors.Genes & cancer · 2012Article
- Praziquantel synergistically enhances paclitaxel efficacy to inhibit cancer cell growth.PloS one · 2012Article
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Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
Abstract
backgroundLess than 50% of ovarian cancers respond to paclitaxel. Effective strategies are needed to enhance paclitaxel sensitivity.
methodsA library of silencing RNAs (siRNAs) was used to identify kinases that regulate paclitaxel sensitivity in human ovarian cancer SKOv3 cells. The effect of dasatinib, an inhibitor of Src and Abl kinases, on paclitaxel sensitivity was measured in ovarian cancer cells and HEY xenografts. The roles of p27(Kip1), Bcl-2, and Cdk1 in apoptosis induced by dasatinib and paclitaxel were assessed using a terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, siRNA knockdown of gene expression, transfection with Bcl-2 and Cdk1 expression vectors, and flow cytometry. All statistical tests were two-sided.
resultsSrc family and Abl kinases were identified as modulators of paclitaxel sensitivity in SKOv3 cells. The siRNA knockdown of Src, Fyn, or Abl1 enhanced paclitaxel-mediated growth inhibition in ovarian cancer cells compared with a control siRNA. HEY cells treated with dasatinib plus paclitaxel formed fewer colonies than did cells treated with either agent alone. Treatment of HEY xenograft-bearing mice with dasatinib plus paclitaxel inhibited tumor growth more than treatment with either agent alone (average tumor volume per mouse, dasatinib + paclitaxel vs paclitaxel: 0.28 vs. 0.81 cm3, difference = 0.53 cm3, 95% confidence interval [CI] = 0.44 to 0.62 cm3, P = .014); dasatinib + paclitaxel vs. dasatinib: 0.28 vs. 0.55 cm3, difference = 0.27 cm3, 95% CI = 0.21 to 0.33 cm3, P = .035). Combined treatment induced more TUNEL-positive apoptotic cells than did either agent alone. The siRNA knockdown of p27(Kip1) decreased dasatinib- and paclitaxel-induced apoptosis compared with a negative control siRNA (sub-G1 fraction, control siRNA vs. p27(Kip1) siRNA: 42.5% vs. 20.1%, difference = 22.4%, 95% CI = 20.1% to 24.7%, P = .017). Studies with forced expression and siRNA knockdown of Bcl-2 and Cdk1 suggest that dasatinib-mediated induction of p27(Kip1) enhanced paclitaxel-induced apoptosis by negatively regulating Bcl-2 and Cdk1 expression.
conclusionInhibition of Src family and Abl kinases with either siRNAs or dasatinib enhances paclitaxel sensitivity of ovarian cancer cells through p27(Kip1)-mediated suppression of Bcl-2 and Cdk1 expression.
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