Reversal of efflux of an anticancer drug in human drug-resistant breast cancer cells by inhibition of protein kinase Cα (PKCα) activity

Chan Woo Kim; Daisuke Asai; Jeong-Hun Kang; Akihiro Kishimura; Takeshi Mori; Yoshiki Katayama

doi:10.1007/s13277-015-3963-4

Reversal of efflux of an anticancer drug in human drug-resistant breast cancer cells by inhibition of protein kinase Cα (PKCα) activity

Tumour Biol. 2016 Feb;37(2):1901-8. doi: 10.1007/s13277-015-3963-4. Epub 2015 Sep 2.

Authors

Chan Woo Kim^{1

2}, Daisuke Asai³, Jeong-Hun Kang⁴, Akihiro Kishimura^{1

5

6}, Takeshi Mori^{7

8

9}, Yoshiki Katayama^{10

11

12

13

14

15}

Affiliations

¹ Department of Applied Chemistry, Faculty of Engineering, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan.
² Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD, 20892, USA.
³ Department of Microbiology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki, 216-8511, Japan.
⁴ Division of Biopharmaceutics and Pharmacokinetics, National Cerebral and Cardiovascular Center Research Institute, 5-7-1 Fujishiro-dai, Suita, Osaka, 565-8565, Japan.
⁵ Graduate School of Systems Life Sciences, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan.
⁶ Center for Future Chemistry, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan.
⁷ Department of Applied Chemistry, Faculty of Engineering, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan. mori.takeshi.880@m.kyushu-u.ac.jp.
⁸ Graduate School of Systems Life Sciences, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan. mori.takeshi.880@m.kyushu-u.ac.jp.
⁹ Center for Future Chemistry, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan. mori.takeshi.880@m.kyushu-u.ac.jp.
¹⁰ Department of Applied Chemistry, Faculty of Engineering, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan. ykatatcm@mail.cstm.kyushu-u.ac.jp.
¹¹ Graduate School of Systems Life Sciences, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan. ykatatcm@mail.cstm.kyushu-u.ac.jp.
¹² Center for Future Chemistry, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan. ykatatcm@mail.cstm.kyushu-u.ac.jp.
¹³ International Research Center for Molecular Systems, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan. ykatatcm@mail.cstm.kyushu-u.ac.jp.
¹⁴ Center for Advanced Medical Innovation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. ykatatcm@mail.cstm.kyushu-u.ac.jp.
¹⁵ Innovation Center for Medical Redox Navigation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. ykatatcm@mail.cstm.kyushu-u.ac.jp.

PMID: 26323260
DOI: 10.1007/s13277-015-3963-4

Abstract

P-glycoprotein (Pgp) is a 170-kDa transmembrane protein that mediates the efflux of anticancer drugs from cells. Pgp overexpression has a distinct role in cells exhibiting multidrug resistance (MDR). We examined reversal of drug resistance in human MDR breast cancer cells by inhibition of protein kinase Cα (PKCα) activity, which is associated with Pgp-mediated efflux of anticancer drugs. PKCα activity was confirmed by measurement of phosphorylation levels of a PKCα-specific peptide substrate (FKKQGSFAKKK-NH2), showing relatively higher basal activity in drug-resistant MCF-7/ADR cells (84 %) than that in drug-sensitive MCF-7 cells (63 %). PKCα activity was effectively suppressed by the PKC inhibitor, Ro-31-7549, and reversal of intracellular accumulation of doxorubicin was observed by inhibition of PKCα activity in MCF-7/ADR cells compared with their intrinsic drug resistance. Importantly, increased accumulation of doxorubicin could enhance the therapeutic efficacy of doxorubicin in MDR cells significantly. These results suggest a potential for overcoming MDR via inhibition of PKCα activity with conventional anticancer drugs.

Keywords: Anticancer drug; Drug resistance; P-glycoprotein; Protein kinase C α; Protein kinase inhibitor.

MeSH terms

ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
Antineoplastic Agents / pharmacology*
Breast Neoplasms / drug therapy*
Breast Neoplasms / metabolism
Doxorubicin / pharmacology
Drug Resistance, Multiple / drug effects
Drug Resistance, Neoplasm / drug effects*
Female
Humans
Indoles / pharmacology
MCF-7 Cells
Maleimides / pharmacology
Phosphorylation / drug effects
Protein Kinase C-alpha / antagonists & inhibitors*
Tumor Cells, Cultured

Substances

ATP Binding Cassette Transporter, Subfamily B, Member 1
Antineoplastic Agents
Indoles
Maleimides
Doxorubicin
PRKCA protein, human
Protein Kinase C-alpha
Ro 31-7549