PF-00477736 mediates checkpoint kinase 1 signaling pathway and potentiates docetaxel-induced efficacy in xenografts - PubMed (original) (raw)
. 2009 Jul 15;15(14):4630-40.
doi: 10.1158/1078-0432.CCR-08-3272. Epub 2009 Jul 7.
Zhengming Yan, Cory L Painter, Qin Zhang, Enhong Chen, Maria E Arango, Kyle Kuszpit, Kenneth Zasadny, Max Hallin, Jill Hallin, Anthony Wong, Dana Buckman, Guizhen Sun, Ming Qiu, Kenna Anderes, James G Christensen
Affiliations
- PMID: 19584159
- DOI: 10.1158/1078-0432.CCR-08-3272
PF-00477736 mediates checkpoint kinase 1 signaling pathway and potentiates docetaxel-induced efficacy in xenografts
Cathy Zhang et al. Clin Cancer Res. 2009.
Abstract
Purpose: Checkpoint kinase 1 (Chk1) plays a critical role in the activation of mitotic spindle checkpoint and DNA damage checkpoint. We examined the preclinical use of the Chk1 inhibitor PF-00477736 as a docetaxel-sensitizing agent. Specifically, we investigated the correlation between PF-00477736-mediated modulation of biomarkers and the sensitization of docetaxel efficacy.
Experimental design: In vitro and in vivo studies using COLO205 and other cell lines were done to assess PF-00477736-induced enhancement of docetaxel efficacy and effects on associated biomarkers.
Results: PF-00477736 significantly enhanced the docetaxel-induced efficacy in tumor cells and xenografts. Docetaxel induced dose- and time-dependent increase in the levels of phosphorylated Chk1 (Ser(345)), phosphorylated histone H3 (Ser(10)), and gammaH2AX foci and promoted the cytoplasmic localization of phosphorylated Cdc25C (Ser(216)). PF-00477736 cotreatment suppressed docetaxel-induced changes in phosphorylated histone H3 and cytoplasmic phosphorylated Cdc25C (Ser(216)) levels and concurrently sensitized the docetaxel-induced apoptosis. Docetaxel alone or in combination with PF-00477736 induced significant antiproliferative activity in xenografts, shown via [18F]FLT-PET imaging. However, changes in [18F]FLT uptake did not reflect the potentiation of docetaxel efficacy. In contrast, bioluminescence imaging showed that PF-00477736 sensitized docetaxel-induced suppression of tumor survival.
Conclusions: Docetaxel triggers mitotic spindle checkpoint activation at low concentrations and activates both the DNA damage checkpoint and the spindle checkpoint at high concentrations. In combination with docetaxel, PF-00477736 abrogates the mitotic checkpoint, as well as the DNA damage checkpoint, and results in sensitization to docetaxel. Chk1 inhibitor PF-00477736 offers a therapeutic potential for the enhancement of taxane therapy.
Similar articles
- Constitutive activation of the DNA damage response pathway as a novel therapeutic target in diffuse large B-cell lymphoma.
Derenzini E, Agostinelli C, Imbrogno E, Iacobucci I, Casadei B, Brighenti E, Righi S, Fuligni F, Ghelli Luserna Di Rorà A, Ferrari A, Martinelli G, Pileri S, Zinzani PL. Derenzini E, et al. Oncotarget. 2015 Mar 30;6(9):6553-69. doi: 10.18632/oncotarget.2720. Oncotarget. 2015. PMID: 25544753 Free PMC article. - Combined inhibition of Chk1 and Wee1 as a new therapeutic strategy for mantle cell lymphoma.
Chilà R, Basana A, Lupi M, Guffanti F, Gaudio E, Rinaldi A, Cascione L, Restelli V, Tarantelli C, Bertoni F, Damia G, Carrassa L. Chilà R, et al. Oncotarget. 2015 Feb 20;6(5):3394-408. doi: 10.18632/oncotarget.2583. Oncotarget. 2015. PMID: 25428911 Free PMC article. - In vitro and in vivo single-agent efficacy of checkpoint kinase inhibition in acute lymphoblastic leukemia.
Iacobucci I, Di Rorà AG, Falzacappa MV, Agostinelli C, Derenzini E, Ferrari A, Papayannidis C, Lonetti A, Righi S, Imbrogno E, Pomella S, Venturi C, Guadagnuolo V, Cattina F, Ottaviani E, Abbenante MC, Vitale A, Elia L, Russo D, Zinzani PL, Pileri S, Pelicci PG, Martinelli G. Iacobucci I, et al. J Hematol Oncol. 2015 Nov 5;8:125. doi: 10.1186/s13045-015-0206-5. J Hematol Oncol. 2015. PMID: 26542114 Free PMC article. - Keeping checkpoint kinases in line: new selective inhibitors in clinical trials.
Ashwell S, Janetka JW, Zabludoff S. Ashwell S, et al. Expert Opin Investig Drugs. 2008 Sep;17(9):1331-40. doi: 10.1517/13543784.17.9.1331. Expert Opin Investig Drugs. 2008. PMID: 18694366 Review. - Docetaxel-induced polyploidization may underlie chemoresistance and disease relapse.
Ogden A, Rida PC, Knudsen BS, Kucuk O, Aneja R. Ogden A, et al. Cancer Lett. 2015 Oct 28;367(2):89-92. doi: 10.1016/j.canlet.2015.06.025. Epub 2015 Jul 13. Cancer Lett. 2015. PMID: 26185000 Free PMC article. Review.
Cited by
- Perspective on the Use of DNA Repair Inhibitors as a Tool for Imaging and Radionuclide Therapy of Glioblastoma.
Everix L, Nair S, Driver CHS, Goethals I, Sathekge MM, Ebenhan T, Vandevoorde C, Bolcaen J. Everix L, et al. Cancers (Basel). 2022 Apr 3;14(7):1821. doi: 10.3390/cancers14071821. Cancers (Basel). 2022. PMID: 35406593 Free PMC article. Review. - Chk1 Inhibition Ameliorates Alzheimer's Disease Pathogenesis and Cognitive Dysfunction Through CIP2A/PP2A Signaling.
Hu W, Wang Z, Zhang H, Mahaman YAR, Huang F, Meng D, Zhou Y, Wang S, Jiang N, Xiong J, Westermarck J, Lu Y, Wang J, Wang X, Shentu Y, Liu R. Hu W, et al. Neurotherapeutics. 2022 Mar;19(2):570-591. doi: 10.1007/s13311-022-01204-z. Epub 2022 Mar 14. Neurotherapeutics. 2022. PMID: 35286657 Free PMC article. - Deficiency of NEIL3 Enhances the Chemotherapy Resistance of Prostate Cancer.
Wang Y, Xu L, Shi S, Wu S, Meng R, Chen H, Jiang Z. Wang Y, et al. Int J Mol Sci. 2021 Apr 15;22(8):4098. doi: 10.3390/ijms22084098. Int J Mol Sci. 2021. PMID: 33921035 Free PMC article. - Co-Inhibition of the DNA Damage Response and CHK1 Enhances Apoptosis of Neuroblastoma Cells.
Ando K, Nakamura Y, Nagase H, Nakagawara A, Koshinaga T, Wada S, Makishima M. Ando K, et al. Int J Mol Sci. 2019 Jul 29;20(15):3700. doi: 10.3390/ijms20153700. Int J Mol Sci. 2019. PMID: 31362335 Free PMC article. - Recent advances of therapeutic targets based on the molecular signature in breast cancer: genetic mutations and implications for current treatment paradigms.
Lima ZS, Ghadamzadeh M, Arashloo FT, Amjad G, Ebadi MR, Younesi L. Lima ZS, et al. J Hematol Oncol. 2019 Apr 11;12(1):38. doi: 10.1186/s13045-019-0725-6. J Hematol Oncol. 2019. PMID: 30975222 Free PMC article. Review.
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Research Materials
Miscellaneous