Benzimidazole derivative, BMT-1, induces apoptosis in multiple myeloma cells via a mitochondrial-mediated pathway involving H+/K+-ATPase inhibition.
2-(1H-benzimidazol-2-yl)-4,5,6,7-tetrahydro-2H-indazol-3-ol (BMT-1), a bicyclic compound, belongs to the benzimidazole group and consists of the fusion of benzene and imidazole. The objective of the present study was to assess the effect of BMT-1 on the proliferation of multiple myeloma (MM) cells and identify whether BMT-1 induces apoptosis in MM cells. Our results showed a dose- and time-dependent decrease in the proliferation of MM cells treated with BMT-1. Further studies revealed that the antiproliferative effects of BMT-1 were caused by induction of apoptosis with activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase in MM cells. In addition, BMT-1 induced the loss of mitochondrial membrane potential resulting in the activation of caspase-8 and -9. Furthermore, the MM cells treated with BMT-1 showed a more acidic intracellular pH (pHi) as indicated by a lower FL1/FL2 ratio caused by inhibition of H+/K+-ATPase. Collectively, these findings demonstrated that a decrease in pHi, caused by H+/K+-ATPase inhibition induced by BMT-1, triggered the dysfunction of the mitochondria resulting in the apoptosis of MM cells. Therefore, BMT-1 may be used as a lead compound for the design and development of new agents with which to treat MM and other forms of cancer.
Department of Immunology, Chengdu Medical College, Chengdu, Sichuan 610083, P.R. China.
Tai
T
Yang
Department of Immunology, Chengdu Medical College, Chengdu, Sichuan 610083, P.R. China.
Min-Hui
MH
Li
Department of Immunology, Chengdu Medical College, Chengdu, Sichuan 610083, P.R. China.
Jin
J
Liu
Department of Immunology, Chengdu Medical College, Chengdu, Sichuan 610083, P.R. China.
Ning
N
Huang
Department of Immunology, Chengdu Medical College, Chengdu, Sichuan 610083, P.R. China.
Ning
N
Li
Department of Immunology, Chengdu Medical College, Chengdu, Sichuan 610083, P.R. China.
Si-Nian
SN
Liu
Department of Immunology, Chengdu Medical College, Chengdu, Sichuan 610083, P.R. China.
Yang
Y
Liu
Department of Oncology, Chengdu Military General Hospital, Chengdu, Sichuan 610083, P.R. China.
Tao
T
Zhang
Department of Immunology, Chengdu Medical College, Chengdu, Sichuan 610083, P.R. China.
Qiang
Q
Zou
Department of Oncology, Chengdu Military General Hospital, Chengdu, Sichuan 610083, P.R. China.
Hua
H
Li
D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D017506:H(+)-K(+)-Exchanging ATPase / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D054328:Proton Pump Inhibitors / Q000008:administration & dosage*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D001562:Benzimidazoles; D019253:Proto-Oncogene Proteins c-bcl-2; D054328:Proton Pump Inhibitors; D017382:Reactive Oxygen Species; C031000:benzimidazole; D017506:H(+)-K(+)-Exchanging ATPase