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.
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.
Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka, Japan.
Masanobu
M
Tsubaki
Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka, Japan.
Makiko
M
Komai
Department of Pathology, Kinki University School of Medicine, Osakasayama, Osaka, Japan.
Tatsuki
T
Itoh
Department of Surgery, Kinki University School of Medicine, Osakasayama, Osaka, Japan.
Motohiro
M
Imano
Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka, Japan.
Kotaro
K
Sakamoto
Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka, Japan.
Hirotaka
H
Shimaoka
Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka, Japan.
Tomoya
T
Takeda
Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka, Japan; Department of Pharmacy, Izumi Municipal Hospital, Izumi, Osaka, Japan.
Naoki
N
Ogawa
Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka, Japan; Department of Pharmacy, Japanese Red Cross Society Wakayama Medical Center, Wakayama, Japan.
Kenji
K
Mashimo
Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka, Japan; Department of Pharmacy, Japanese Red Cross Society Wakayama Medical Center, Wakayama, Japan.
Daiichiro
D
Fujiwara
Department of Pharmacy, Izumi Municipal Hospital, Izumi, Osaka, Japan.
Junji
J
Mukai
Department of Pharmacy, Japanese Red Cross Society Wakayama Medical Center, Wakayama, Japan.
Katsuhiko
K
Sakaguchi
Department of Pathology, Kinki University School of Medicine, Osakasayama, Osaka, Japan.
Takao
T
Satou
Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka, Japan. Electronic address: nishida@phar.kindai.ac.jp.
Shozo
S
Nishida
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000069439:Dasatinib; D003907:Dexamethasone / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D008558:Melphalan / Q000494:pharmacology; D008565:Membrane Proteins / Q000378:metabolism*; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology*; D000077022:Survivin; D013844:Thiazoles / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects; D014700:Verapamil / Q000494:pharmacology*; D019061:src-Family Kinases / Q000378:metabolism*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; C107489:BIRC5 protein, human; D000072224:Bcl-2-Like Protein 11; D051034:Inhibitor of Apoptosis Proteins; D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; D000077022:Survivin; D013844:Thiazoles; D003907:Dexamethasone; D004317:Doxorubicin; D014700:Verapamil; D019061:src-Family Kinases; D008558:Melphalan; D000069439:Dasatinib
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.