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Inhibition of CDK4 sensitizes multidrug resistant ovarian cancer cells to paclitaxel by increasing apoptosiss

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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.

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Acknowledgements

This work was supported in part by grants from the Gattegno and Wechsler funds. Dr. Duan is supported, in part, through a grant from the Sarcoma Foundation of America (SFA), a pilot grant from Sarcoma SPORE/NIH, and a grant from the National Cancer Institute (NCI)/National Institutes of Health (NIH), UO1, CA 151452.

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Authors and Affiliations

  1. Department of Clinical Laboratory Diagnostics, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China

    Yan Gao

  2. Sarcoma Biology Laboratory, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital and Harvard Medical School, 100 Blossom St, Jackson 1115, Boston, MA, 02114, USA

    Yan Gao, Jacson Shen, Edwin Choy, Henry Mankin, Francis Hornicek & Zhenfeng Duan

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  1. Yan Gao
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Gao, Y., Shen, J., Choy, E. et al. Inhibition of CDK4 sensitizes multidrug resistant ovarian cancer cells to paclitaxel by increasing apoptosiss. Cell Oncol. 40, 209–218 (2017). https://doi.org/10.1007/s13402-017-0316-x

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