By inhibiting Src, verapamil and dasatinib overcome multidrug resistance via increased expression of Bim and decreased expressions of MDR1 and survivin in human multidrug-resistant myeloma cells

Masanobu Tsubaki; Makiko Komai; Tatsuki Itoh; Motohiro Imano; Kotaro Sakamoto; Hirotaka Shimaoka; Tomoya Takeda; Naoki Ogawa; Kenji Mashimo; Daiichiro Fujiwara; Junji Mukai; Katsuhiko Sakaguchi; Takao Satou; Shozo Nishida

doi:10.1016/j.leukres.2013.10.017

By inhibiting Src, verapamil and dasatinib overcome multidrug resistance via increased expression of Bim and decreased expressions of MDR1 and survivin in human multidrug-resistant myeloma cells

Leuk Res. 2014 Jan;38(1):121-30. doi: 10.1016/j.leukres.2013.10.017. Epub 2013 Oct 28.

Authors

Affiliations

¹ Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka, Japan.
² Department of Pathology, Kinki University School of Medicine, Osakasayama, Osaka, Japan.
³ Department of Surgery, Kinki University School of Medicine, Osakasayama, Osaka, Japan.
⁴ Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka, Japan; Department of Pharmacy, Izumi Municipal Hospital, Izumi, Osaka, Japan.
⁵ Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka, Japan; Department of Pharmacy, Japanese Red Cross Society Wakayama Medical Center, Wakayama, Japan.
⁶ Department of Pharmacy, Izumi Municipal Hospital, Izumi, Osaka, Japan.
⁷ Department of Pharmacy, Japanese Red Cross Society Wakayama Medical Center, Wakayama, Japan.
⁸ Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka, Japan. Electronic address: nishida@phar.kindai.ac.jp.

PMID: 24239173
DOI: 10.1016/j.leukres.2013.10.017

Abstract

The calcium channel blocker verapamil inhibits the transport function of multidrug resistance protein 1 (MDR1). Although verapamil acts to reverse MDR in cancer cells, the underlying mechanism remains unclear. In the present study, we investigated the mechanism of reversing MDR by verapamil in anti-cancer drug-resistant multiple myeloma (MM) cell lines. We found that verapamil suppresses MDR1 and survivin expressions and increases Bim expression via suppression of Src activation. Furthermore, dasatinib reversed the drug-resistance of the drug-resistant cell lines. These findings suggest that Src inhibitors are potentially useful as an anti-MDR agent for the treatment of malignant tumor cells.

Keywords: ATP; Bim; Dasatinib; Drug resistance; MDR; MDR1; MM; Multiple myeloma; PBS; Src; Survivin; Verapamil; adenosine triphosphate; multi-drug resistance; multidrug resistance protein 1; multiple myeloma; phosphate buffer saline..

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
Animals
Antineoplastic Agents / pharmacology
Apoptosis Regulatory Proteins / metabolism*
Bcl-2-Like Protein 11
Blotting, Western
Cell Line
Cell Line, Tumor
Cell Survival / drug effects
Dasatinib
Dexamethasone / pharmacology
Down-Regulation / drug effects
Doxorubicin / pharmacology
Drug Resistance, Multiple / drug effects
Drug Resistance, Neoplasm / drug effects
Drug Synergism
Enzyme Activation / drug effects
Humans
Inhibitor of Apoptosis Proteins / metabolism*
Melphalan / pharmacology
Membrane Proteins / metabolism*
Multiple Myeloma / metabolism
Multiple Myeloma / pathology
Protein Kinase Inhibitors / pharmacology
Proto-Oncogene Proteins / metabolism*
Pyrimidines / pharmacology*
Survivin
Thiazoles / pharmacology*
Up-Regulation / drug effects
Verapamil / pharmacology*
src-Family Kinases / metabolism*

Substances

ATP Binding Cassette Transporter, Subfamily B, Member 1
Antineoplastic Agents
Apoptosis Regulatory Proteins
BCL2L11 protein, human
BIRC5 protein, human
Bcl-2-Like Protein 11
Inhibitor of Apoptosis Proteins
Membrane Proteins
Protein Kinase Inhibitors
Proto-Oncogene Proteins
Pyrimidines
Survivin
Thiazoles
Dexamethasone
Doxorubicin
Verapamil
src-Family Kinases
Melphalan
Dasatinib