Inhibition of CDK4 Sensitizes Multidrug Resistant Ovarian Cancer Cells to Paclitaxel by Increasing Apoptosiss

Overview

Journal Cell Oncol (Dordr)

Publisher Springer

Date 2017 Mar 1

PMID 28243976

Citations 15

Authors

Yan Gao

Jacson Shen

Edwin Choy

Henry Mankin

Francis Hornicek

Zhenfeng Duan

Affiliations

Soon will be listed here.

Abstract

Purpose: Overexpression of cyclin-dependent kinase (CDK) 4 has been observed in a variety of cancers and has been found to contribute to tumor cell growth and proliferation. However, the effect of inhibition of CDK4 in ovarian cancer is unknown. We investigated the therapeutic effect of the CDK4 inhibitor palbociclib in combination with paclitaxel in ovarian cancer cells.

Methods: Cell viabilities were determined by MTT assay after exposure to different dosages of palbociclib and/or paclitaxel. Western blot, immunofluorescence, and Calcein AM assays were conducted to determine the mechanisms underlying the cytotoxic effects of palbociclib in combination with paclitaxel. CDK4 siRNA was used to validate the outcome of targeting CDK4 by palbociclib in ovarian cancer cells.

Results: We found that combinations of palbociclib and paclitaxel significantly enhanced drug sensitivity in both Rb-positive (SKOV3TR) and Rb-negative (OVCAR8TR) ovarian cancer-derived cells. When combined with paclitaxel, palbociclib induced apoptosis in both SKOV3TR and OVCAR8TR cells. We also found that palbociclib inhibited the activity of P-glycoprotein (Pgp), and that siRNA-mediated CDK4 knockdown sensitized multidrug resistant (MDR) SKOV3TR and OVCAR8TR cells to paclitaxel.

Conclusions: Inhibition of CDK4 by palbociclib can enhance paclitaxel sensitivity in both Rb-positive and Rb-negative MDR ovarian cancer cells by increasing apoptosis. CDK4 may serve as a promising target in the treatment of ovarian cancer.

Citing Articles

Palbociclib inhibits the progression of head and neck cancer and improves the Cetuximab response under specific condition in vitro and in vivo.

Li R, Wang Q, Zhao Y, Zhu Y, Wang X Mol Biol Rep. 2024; 51(1):455.

PMID: 38536540 DOI: 10.1007/s11033-024-09423-7.

The Evolving Pathways of the Efficacy of and Resistance to CDK4/6 Inhibitors in Breast Cancer.

Gomes I, Abreu C, Costa L, Casimiro S Cancers (Basel). 2023; 15(19).

PMID: 37835528 PMC: 10571967. DOI: 10.3390/cancers15194835.

The Resistance of Cancer Cells to Palbociclib, a Cyclin-Dependent Kinase 4/6 Inhibitor, is Mediated by the ABCB1 Transporter.

Fu H, Wu Z, Lei Z, Teng Q, Yang Y, Ashby C Front Pharmacol. 2022; 13:861642.

PMID: 35350768 PMC: 8957877. DOI: 10.3389/fphar.2022.861642.

Clinical Utility of CDK4/6 Inhibitors in Sarcoma: Successes and Future Challenges.

Hsu J, Seligson N, Hays J, Miles W, Chen J JCO Precis Oncol. 2022; 6:e2100211.

PMID: 35108033 PMC: 8820917. DOI: 10.1200/PO.21.00211.

CDK4 and CDK6 kinases: From basic science to cancer therapy.

Fassl A, Geng Y, Sicinski P Science. 2022; 375(6577):eabc1495.

PMID: 35025636 PMC: 9048628. DOI: 10.1126/science.abc1495.

References

Szakacs G, Paterson J, Ludwig J, Booth-Genthe C, Gottesman M . Targeting multidrug resistance in cancer. Nat Rev Drug Discov. 2006; 5(3):219-34. DOI: 10.1038/nrd1984. View

Altieri D . The case for survivin as a regulator of microtubule dynamics and cell-death decisions. Curr Opin Cell Biol. 2006; 18(6):609-15. DOI: 10.1016/j.ceb.2006.08.015. View

Yang X, Iyer A, Singh A, Milane L, Choy E, Hornicek F . Cluster of Differentiation 44 Targeted Hyaluronic Acid Based Nanoparticles for MDR1 siRNA Delivery to Overcome Drug Resistance in Ovarian Cancer. Pharm Res. 2014; 32(6):2097-109. PMC: 4425596. DOI: 10.1007/s11095-014-1602-1. View

Sellers W, Kaelin Jr W . Role of the retinoblastoma protein in the pathogenesis of human cancer. J Clin Oncol. 1997; 15(11):3301-12. DOI: 10.1200/JCO.1997.15.11.3301. View

Taylor-Harding B, Aspuria P, Agadjanian H, Cheon D, Mizuno T, Greenberg D . Cyclin E1 and RTK/RAS signaling drive CDK inhibitor resistance via activation of E2F and ETS. Oncotarget. 2015; 6(2):696-714. PMC: 4359249. DOI: 10.18632/oncotarget.2673. View

Leonard J, LaCasce A, Smith M, Noy A, Chirieac L, Rodig S . Selective CDK4/6 inhibition with tumor responses by PD0332991 in patients with mantle cell lymphoma. Blood. 2012; 119(20):4597-607. DOI: 10.1182/blood-2011-10-388298. View

Goetze K, Fabian C, Siebers A, Binz L, Faber D, Indraccolo S . Manipulation of tumor metabolism for therapeutic approaches: ovarian cancer-derived cell lines as a model system. Cell Oncol (Dordr). 2015; 38(5):377-85. DOI: 10.1007/s13402-015-0237-5. View

Duan Z, Brakora K, Seiden M . Inhibition of ABCB1 (MDR1) and ABCB4 (MDR3) expression by small interfering RNA and reversal of paclitaxel resistance in human ovarian cancer cells. Mol Cancer Ther. 2004; 3(7):833-8. View

Barbie T, Barbie D, MacLaughlin D, Maheswaran S, Donahoe P . Mullerian Inhibiting Substance inhibits cervical cancer cell growth via a pathway involving p130 and p107. Proc Natl Acad Sci U S A. 2003; 100(26):15601-6. PMC: 307614. DOI: 10.1073/pnas.2636900100. View

10.

Strauss M, Lukas J, Bartek J . Unrestricted cell cycling and cancer. Nat Med. 1995; 1(12):1245-6. DOI: 10.1038/nm1295-1245. View

11.

Karlan B, Oza A, Richardson G, Provencher D, Hansen V, Buck M . Randomized, double-blind, placebo-controlled phase II study of AMG 386 combined with weekly paclitaxel in patients with recurrent ovarian cancer. J Clin Oncol. 2011; 30(4):362-71. DOI: 10.1200/JCO.2010.34.3178. View

12.

Zhang T, Nanney L, Luongo C, Lamps L, Heppner K, DuBois R . Concurrent overexpression of cyclin D1 and cyclin-dependent kinase 4 (Cdk4) in intestinal adenomas from multiple intestinal neoplasia (Min) mice and human familial adenomatous polyposis patients. Cancer Res. 1997; 57(1):169-75. View

13.

Kolomeichuk S, Terrano D, Lyle C, Sabapathy K, Chambers T . Distinct signaling pathways of microtubule inhibitors--vinblastine and Taxol induce JNK-dependent cell death but through AP-1-dependent and AP-1-independent mechanisms, respectively. FEBS J. 2008; 275(8):1889-99. DOI: 10.1111/j.1742-4658.2008.06349.x. View

14.

Ingemarsdotter C, Tookman L, Browne A, Pirlo K, Cutts R, Chelela C . Paclitaxel resistance increases oncolytic adenovirus efficacy via upregulated CAR expression and dysfunctional cell cycle control. Mol Oncol. 2015; 9(4):791-805. PMC: 5528770. DOI: 10.1016/j.molonc.2014.12.007. View

15.

Yang X, Shen J, Gao Y, Feng Y, Guan Y, Zhang Z . Nsc23925 prevents the development of paclitaxel resistance by inhibiting the introduction of P-glycoprotein and enhancing apoptosis. Int J Cancer. 2015; 137(8):2029-39. PMC: 4529776. DOI: 10.1002/ijc.29574. View

16.

Wang X, Fu L . Interaction of tyrosine kinase inhibitors with the MDR- related ABC transporter proteins. Curr Drug Metab. 2010; 11(7):618-28. DOI: 10.2174/138920010792927316. View

17.

Musgrove E, Caldon C, Barraclough J, Stone A, Sutherland R . Cyclin D as a therapeutic target in cancer. Nat Rev Cancer. 2011; 11(8):558-72. DOI: 10.1038/nrc3090. View

18.

Wang Z, Chen Y, Liang H, Bender A, Glen R, Yan A . P-glycoprotein substrate models using support vector machines based on a comprehensive data set. J Chem Inf Model. 2011; 51(6):1447-56. DOI: 10.1021/ci2001583. View

19.

Shinozaki H, Ozawa S, Ando N, Tsuruta H, Terada M, Ueda M . Cyclin D1 amplification as a new predictive classification for squamous cell carcinoma of the esophagus, adding gene information. Clin Cancer Res. 1996; 2(7):1155-61. View

20.

Ha T, Segev D, Barbie D, Masiakos P, Tran T, Dombkowski D . Mullerian inhibiting substance inhibits ovarian cell growth through an Rb-independent mechanism. J Biol Chem. 2000; 275(47):37101-9. DOI: 10.1074/jbc.M005701200. View