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Schedule-Dependent Cytotoxicity of Etoposide and Cyclophosphamide in P-Glycoprotein-Expressing Human Leukemic K-562 Cells

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Title: Schedule-Dependent Cytotoxicity of Etoposide and Cyclophosphamide in P-Glycoprotein-Expressing Human Leukemic K-562 Cells
Authors: Tazawa, Yuki Browse this author
Usukubo, Ippei Browse this author
Takada, Kazuki Browse this author
Takekuma, Yoh Browse this author →KAKEN DB
Shibayama, Yoshihiro Browse this author
Sugawara, Mitsuru Browse this author →KAKEN DB
Keywords: etoposide
cell cycle
Issue Date: Aug-2014
Publisher: Pharmaceutical Society of Japan
Journal Title: Biological & Pharmaceutical Bulletin
Volume: 37
Issue: 8
Start Page: 1323
End Page: 1329
Publisher DOI: 10.1248/bpb.b14-00207
Abstract: Combination chemotherapy is often used to treat cancer. Many studies have shown schedule-dependent effects between anticancer drugs. Our previous studies showed that K-562 cells pretreated with non-cytotoxic concentrations of 4-hydroperoxycyclophosphamide (4-HPC), which is a preactivated analog of cyclophosphamide (CY), enhanced the cytotoxicity of etoposide (VP-16). The appearance of cellular resistance to anticancer drugs is a major problem in cancer chemotherapy. P-Glycoprotein (P-gp) plays an important role in drug resistance, and VP-16 is a substrate for this efflux pump. In the present study, we demonstrated schedule-dependent cytotoxicity of VP-16 and CY in P-gp-overexpressed K-562/P-gp cells. Cytotoxicity of VP-16 was enhanced in K-562/P-gp cells that were pretreated with a non-cytotoxic concentration of 4-HPC compared to that of cells not treated with 4-HPC. 4-HPC arrested the cell cycle at S phase. Cells in S phase are most sensitive to VP-16. The results suggest that cell cycle arrest by 4-HPC pretreatment may be responsible for the enhanced cytotoxicity of VP-16. The findings in this study should lead to improvements in clinical combination chemotherapy.
Type: article
Appears in Collections:薬学研究院 (Faculty of Pharmaceutical Sciences) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 菅原 満

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