Benzimidazole derivative, BMT-1, induces apoptosis in multiple myeloma cells via a mitochondrial-mediated pathway involving H+/K+-ATPase inhibition

Yang,Tai; Li,Min-Hui; Liu,Jin; Huang,Ning; Li,Ning; Liu,Si‑Nian; Liu,Yang; Zhang,Tao; Zou,Qiang; Li,Hua

doi:10.3892/or.2014.3122

Benzimidazole derivative, BMT-1, induces apoptosis in multiple myeloma cells via a mitochondrial-mediated pathway involving H+/K+-ATPase inhibition

Authors:
- Tai Yang
- Min-Hui Li
- Jin Liu
- Ning Huang
- Ning Li
- Si‑Nian Liu
- Yang Liu
- Tao Zhang
- Qiang Zou
- Hua Li
View Affiliations

Affiliations: Department of Immunology, Chengdu Medical College, Chengdu, Sichuan 610083, P.R. China, Department of Oncology, Chengdu Military General Hospital, Chengdu, Sichuan 610083, P.R. China
Published online on: April 2, 2014 https://doi.org/10.3892/or.2014.3122
Pages: 2743-2750

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

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.

View Figures

View References

1	Kyle RA and Rajkumar SV: Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia. 23:3–9. 2009. View Article : Google Scholar : PubMed/NCBI
2	Mahindra A, Laubach J, Raje N, Munshi N, Richardson PG and Anderson K: Latest advances and current challenges in the treatment of multiple myeloma. Nat Rev Clin Oncol. 9:135–143. 2012. View Article : Google Scholar : PubMed/NCBI
3	Jáuregui I, García-Lirio E, Soriano AM, Gamboa PM and Antépara I: An overview of the novel H1-antihistamine bilastine in allergic rhinitis and urticaria. Expert Rev Clin Immunol. 8:33–41. 2012.PubMed/NCBI
4	Wexler RR, Greenlee WJ, Irvin JD, et al: Nonpeptide angiotensin II receptor antagonists: the next generation in antihypertensive therapy. J Med Chem. 39:625–656. 1996. View Article : Google Scholar : PubMed/NCBI
5	Navarrete-Vázquez G, Cedillo R, Hernández-Campos A, et al: Synthesis and antiparasitic activity of 2-(trifluoromethyl)-benzimidazole derivatives. Bioorg Med Chem Lett. 11:187–190. 2001.PubMed/NCBI
6	Sachs G, Shin JM, Vagin O, Lambrecht N, Yakubov I and Munson K: The gastric H,K ATPase as a drug target: past, present, and future. J Clin Gastroenterol. 41(Suppl 2): S226–S242. 2007. View Article : Google Scholar : PubMed/NCBI
7	Kim SK, Ahn CM, Choi SJ, Park YS, Cho HC and Koh CM: The growth inhibitiory effect of new pyrrolo[1,2-α]benzimidazole derivatives on human gastric cancer cells. Arch Pharm Res. 20:410–413. 1997.PubMed/NCBI
8	Grimaudo S, Tolomeo M, Chimirri A, Zappala M, Gancitano RA and D’Alessandro N: Selective induction of apoptosis in multidrug resistant HL60R cells by the thiazolobenzoimidazole derivative 1-(2,6-difluorophenyl)-1 H,3H-thiazolo [3,4-a] benzimidazole (TBZ). Eur J Cancer. 34:1756–1763. 1998. View Article : Google Scholar : PubMed/NCBI
9	Al-Douh MH, Sahib HB, Osman H, Abd Hamid S and Salhimi SM: Anti-proliferation effects of benzimidazole derivatives on HCT-116 colon cancer and MCF-7 breast cancer cell lines. Asian Pac J Cancer Prev. 13:4075–4079. 2012. View Article : Google Scholar : PubMed/NCBI
10	Youssef AM, Malki A, Badr MH, Elbayaa RY and Sultan AS: Synthesis and anticancer activity of novel benzimidazole and benzothiazole derivatives against HepG2 liver cancer cells. Med Chem. 8:151–162. 2012. View Article : Google Scholar : PubMed/NCBI
11	Lin ML, Chen SS, Lu YC, et al: Rhein induces apoptosis through induction of endoplasmic reticulum stress and Ca²⁺-dependent mitochondrial death pathway in human nasopharyngeal carcinoma cells. Anticancer Res. 27:3313–3322. 2007.PubMed/NCBI
12	Shin JM and Kim N: Pharmacokinetics and pharmacodynamics of the proton pump inhibitors. J Neurogastroenterol Motil. 19:25–35. 2013. View Article : Google Scholar : PubMed/NCBI
13	Webb BA, Chimenti M, Jacobson MP and Barber DL: Dysregulated pH: a perfect storm for cancer progression. Nat Rev Cancer. 11:671–677. 2011. View Article : Google Scholar : PubMed/NCBI
14	Chen M, Zou X, Luo H, et al: Effects and mechanisms of proton pump inhibitors as a novel chemosensitizer on human gastric adenocarcinoma (SGC7901) cells. Cell Biol Int. 33:1008–1019. 2009. View Article : Google Scholar : PubMed/NCBI
15	McCarty MF and Whitaker J: Manipulating tumor acidification as a cancer treatment strategy. Altern Med Rev. 15:264–272. 2010.PubMed/NCBI
16	Fais S: Proton pump inhibitor-induced tumour cell death by inhibition of a detoxification mechanism. J Intern Med. 267:515–525. 2010. View Article : Google Scholar : PubMed/NCBI
17	Monks A, Scudiero D, Skehan P, et al: Feasibility of a high-flux anticancer drug screen using a diverse panel of cultured human tumor cell lines. J Natl Cancer Inst. 83:757–766. 1991. View Article : Google Scholar : PubMed/NCBI
18	Karali N: Synthesis and primary cytotoxicity evaluation of new 5-nitroindole-2,3-dione derivatives. Eur J Med Chem. 37:909–918. 2002. View Article : Google Scholar : PubMed/NCBI
19	De Milito A, Iessi E, Logozzi M, et al: Proton pump inhibitors induce apoptosis of human B-cell tumors through a caspase-independent mechanism involving reactive oxygen species. Cancer Res. 67:5408–5417. 2007.PubMed/NCBI
20	Nilsson C, Kågedal K, Johansson U and Ollinger K: Analysis of cytosolic and lysosomal pH in apoptotic cells by flow cytometry. Methods Cell Sci. 25:185–194. 2003. View Article : Google Scholar : PubMed/NCBI
21	Cowling V and Downward J: Caspase-6 is the direct activator of caspase-8 in the cytochrome c-induced apoptosis pathway: absolute requirement for removal of caspase-6 prodomain. Cell Death Differ. 9:1046–1056. 2002. View Article : Google Scholar : PubMed/NCBI
22	Chen M, Guerrero AD, Huang L, et al: Caspase-9-induced mitochondrial disruption through cleavage of anti-apoptotic BCL-2 family members. J Biol Chem. 282:33888–33895. 2007. View Article : Google Scholar : PubMed/NCBI
23	Perry SW, Norman JP, Barbieri J, Brown EB and Gelbard HA: Mitochondrial membrane potential probes and the proton gradient: a practical usage guide. Biotechniques. 50:98–115. 2011. View Article : Google Scholar : PubMed/NCBI
24	Smolka AJ, Goldenring JR, Gupta S and Hammond CE: Inhibition of gastric H,K-ATPase activity and gastric epithelial cell IL-8 secretion by the pyrrolizine derivative ML 3000. BMC Gastroenterol. 4:42004. View Article : Google Scholar : PubMed/NCBI
25	Morii M, Takata H, Fujisaki H and Takeguchi N: The potency of substituted benzimidazoles such as E3810, omeprazole, Ro 18-5364 to inhibit gastric H⁺, K⁺-ATPase is correlated with the rate of acid-activation of the inhibitor. Biochem Pharmacol. 39:661–667. 1990. View Article : Google Scholar : PubMed/NCBI
26	Beil W and Sewing KF: Inhibition of partially purified K⁺/H⁺-ATPase from guinea-pig isolated and enriched parietal cells by substituted benzimidazoles. Br J Pharmacol. 82:651–657. 1984.PubMed/NCBI
27	Yeo M, Kim DK, Park HJ, Cho SW, Cheong JY and Lee KJ: Blockage of intracellular proton extrusion with proton extrusions with proton pump inhibitor induces apoptosis in gastric cancer. Cancer Sci. 99:1852008.
28	Pinto MC, Dias DF, Del Puerto HL, et al: Discovery of cytotoxic and pro-apoptotic compounds against leukemia cells: Tert-butyl-4-[(3-nitrophenoxy) methyl]-2,2-dimethyloxazolidine-3-carboxylate. Life Sci. 89:786–794. 2011.PubMed/NCBI
29	Chang WL, Chang CS, Chiang PC, et al: 2-Phenyl-5-(pyrrolidin-1-yl)-1-(3,4,5-trimethoxybenzyl)-1H-benzimidazole, a benzimidazole derivative, inhibits growth of human prostate cancer cells by affecting tubulin and c-Jun N-terminal kinase. Br J Pharmacol. 160:1677–1689. 2010.PubMed/NCBI
30	Liu JF, Huang YL, Yang WH, Chang CS and Tang CH: 1-Benzyl-2-phenylbenzimidazole (BPB), a benzimidazole derivative, induces cell apoptosis in human chondrosarcoma through intrinsic and extrinsic pathways. Int J Mol Sci. 13:16472–16488. 2012. View Article : Google Scholar : PubMed/NCBI
31	Vasaitis T, Belosay A, Schayowitz A, et al: Androgen receptor inactivation contributes to antitumor efficacy of 17α-hydroxylase/17,20-lyase inhibitor 3β-hydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene in prostate cancer. Mol Cancer Ther. 7:2348–2357. 2008.PubMed/NCBI
32	Liu JF, Chang CS, Fong YC, Kuo SC and Tang CH: FPipTB, a benzimidazole derivative, induces chondrosarcoma cell apoptosis via endoplasmic reticulum stress and apoptosis signal-regulating kinase 1. Mol Carcinog. May 18–2011.(Epub ahead of print).
33	Schultz BE and Chan SI: Structures and proton-pumping strategies of mitochondrial respiratory enzymes. Annu Rev Biophys Biomol Struct. 30:23–65. 2001. View Article : Google Scholar : PubMed/NCBI
34	Murakami T, Shibuya I, Ise T, et al: Elevated expression of vacuolar proton pump genes and cellular pH in cisplatin resistance. Int J Cancer. 93:869–874. 2001. View Article : Google Scholar : PubMed/NCBI
35	Streif D, Iglseder E, Hauser-Kronberger C, Fink KG, Jakab M and Ritter M: Expression of the non-gastric H⁺/K⁺ ATPase ATP12A in normal and pathological human prostate tissue. Cell Physiol Biochem. 28:1287–1294. 2011.PubMed/NCBI