Reversal of efflux of an anticancer drug in human drug-resistant breast cancer cells by inhibition of protein kinase Cα (PKCα) activity.
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.
Department of Applied Chemistry, Faculty of Engineering, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan.|Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD, 20892, USA.
Chan Woo
CW
Kim
Department of Microbiology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki, 216-8511, Japan.
Daisuke
D
Asai
Division of Biopharmaceutics and Pharmacokinetics, National Cerebral and Cardiovascular Center Research Institute, 5-7-1 Fujishiro-dai, Suita, Osaka, 565-8565, Japan.
Jeong-Hun
JH
Kang
Department of Applied Chemistry, Faculty of Engineering, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan.|Graduate School of Systems Life Sciences, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan.|Center for Future Chemistry, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan.
Akihiro
A
Kishimura
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.|Graduate School of Systems Life Sciences, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan. mori.takeshi.880@m.kyushu-u.ac.jp.|Center for Future Chemistry, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan. mori.takeshi.880@m.kyushu-u.ac.jp.
Takeshi
T
Mori
Department of Applied Chemistry, Faculty of Engineering, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan. ykatatcm@mail.cstm.kyushu-u.ac.jp.|Graduate School of Systems Life Sciences, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan. ykatatcm@mail.cstm.kyushu-u.ac.jp.|Center for Future Chemistry, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan. ykatatcm@mail.cstm.kyushu-u.ac.jp.|International Research Center for Molecular Systems, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan. ykatatcm@mail.cstm.kyushu-u.ac.jp.|Center for Advanced Medical Innovation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. ykatatcm@mail.cstm.kyushu-u.ac.jp.|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.
Yoshiki
Y
Katayama
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D061986:MCF-7 Cells; D008301:Maleimides / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D051571:Protein Kinase C-alpha / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D007211:Indoles; D008301:Maleimides; D004317:Doxorubicin; C496628:PRKCA protein, human; D051571:Protein Kinase C-alpha; C064755:Ro 31-7549
Anticancer drug; Drug resistance; P-glycoprotein; Protein kinase C α; Protein kinase inhibitor