Antiproliferative and antimigratory activities of bisphosphonates in human breast cancer cell line MCF‑7

Buranrat,Benjaporn; Bootha,Supavadee

doi:10.3892/ol.2019.10438

Antiproliferative and antimigratory activities of bisphosphonates in human breast cancer cell line MCF‑7

Authors:
- Benjaporn Buranrat
- Supavadee Bootha
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Affiliations: Faculty of Medicine, Mahasarakham University, Maha Sarakham 44000, Thailand, School of Pharmaceutical Sciences, University of Phayao, Phayao 56000, Thailand
Published online on: June 5, 2019 https://doi.org/10.3892/ol.2019.10438
Pages: 1246-1258
Copyright: © Buranrat et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Bisphosphonates (BPs) are antiresorptive drugs that act as effective inhibitors of cancer cell proliferation. However, not all bisphosphonates are equally effective against breast cancer cells in vitro. The present study investigated the extent to which three BPs decrease the viability of MCF‑7 human breast cancer cells, stimulate cell apoptosis and inhibit cell migration by modulating proteins in the mevalonate pathway. The three BPs exerted direct anticancer effects against MCF‑7 cells in a dose‑ and time‑dependent manner, with pamidronate demonstrating the highest efficacy. In addition, the BPs inhibited colony formation ability. The activity of BPs against MCF‑7 cells was inhibited by the mevalonate product geranylgeranyl pyrophosphate, which was potentiated by doxorubicin. It was also identified that BPs modulated Ras‑related C3 botulinum toxin substrate 1, Ras homolog gene family member A and cell division control protein 42 homolog gene expression. Consistent with the observed growth inhibitory effects, BPs also inhibited the cell cycle by promoting G1 phase arrest and the downregulation of cyclin D1 and upregulation of p21. Additionally, BPs were revealed to induce reactive oxygen species expression, caspase‑3 activity and increase the mitochondrial transmembrane potential, which was associated with apoptosis. BP‑induced cancer cell apoptosis was detected by acridine orange/ethidium bromide staining and flow cytometry analysis, and was identified to be associated with the induction of caspase‑3 and cytochrome c protein expression. Furthermore, BPs significantly decreased cancer cell migration in a dose‑dependent manner and reduced matrix metallopeptidase‑9 protein expression. In summary, the current study demonstrated that BPs exhibited a direct anticancer effect and an antimigratory effect on MCF‑7 cells. These findings suggest that BPs may be developed as a therapeutic option for breast cancer and may serve as sensitizing chemotherapeutic agents.

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1	Gnant M and Clézardin P: Direct and indirect anticancer activity of bisphosphonates: A brief review of published literature. Cancer Treat Rev. 38:407–415. 2012. View Article : Google Scholar : PubMed/NCBI
2	Labropoulou VT, Theocharis AD, Symeonidis A, Skandalis SS, Karamanos NK and Kalofonos HP: Pathophysiology and pharmacological targeting of tumor-induced bone disease: Current status and emerging therapeutic interventions. Curr Med Chem. 18:1584–1598. 2011. View Article : Google Scholar : PubMed/NCBI
3	Fleisch H: Development of bisphosphonates. Breast Cancer Res. 4:30–34. 2002. View Article : Google Scholar : PubMed/NCBI
4	Rogers MJ, Gordon S, Benford HL, Coxon FP, Luckman SP, Monkkonen J and Frith JC: Cellular and molecular mechanisms of action of bisphosphonates. Cancer. 88:2961–2978. 2000. View Article : Google Scholar : PubMed/NCBI
5	Clezardin P: Potential anticancer properties of bisphosphonates: Insights from preclinical studies. Anticancer Agents Med Chem. 12:102–113. 2012. View Article : Google Scholar : PubMed/NCBI
6	Jagdev SP, Coleman RE, Shipman CM, Rostami HA and Croucher PI: The bisphosphonate, zoledronic acid, induces apoptosis of breast cancer cells: Evidence for synergy with paclitaxel. Br J Cancer. 84:1126–1134. 2001. View Article : Google Scholar : PubMed/NCBI
7	Goffinet M, Thoulouzan M, Pradines A, Lajoie-Mazenc I, Weinbaum C, Faye JC and Séronie-Vivien S: Zoledronic acid treatment impairs protein geranyl-geranylation for biological effects in prostatic cells. BMC Cancer. 6:602006. View Article : Google Scholar : PubMed/NCBI
8	Koshimune R, Aoe M, Toyooka S, Hara F, Ouchida M, Tokumo M, Sano Y, Date H and Shimizu N: Anti-tumor effect of bisphosphonate (YM529) on non-small cell lung cancer cell lines. BMC Cancer. 7:82007. View Article : Google Scholar : PubMed/NCBI
9	Ou YJ, Chiu HF, Wong YH and Yang YH: Bisphosphonate use and the risk of endometrial cancer: A meta-analysis of observational studies. Pharmacoepidemiol Drug Saf. 25:1107–1115. 2016. View Article : Google Scholar : PubMed/NCBI
10	Passarelli MN, Newcomb PA, LaCroix AZ, Lane DS, Ho GY and Chlebowski RT: Oral bisphosphonate use and colorectal cancer incidence in the Women's Health Initiative. J Bone Miner Res. 28:2043–2048. 2013. View Article : Google Scholar : PubMed/NCBI
11	Guo RT, Cao R, Liang PH, Ko TP, Chang TH, Hudock MP, Jeng WY, Chen CK, Zhang Y, Song Y, et al: Bisphosphonates target multiple sites in both cis- and trans-prenyltransferases. Proc Natl Acad Sci USA. 104:10022–10027. 2007. View Article : Google Scholar : PubMed/NCBI
12	Mönkkönen H, Auriola S, Lehenkari P, Kellinsalmi M, Hassinen IE, Vepsäläinen J and Mönkkönen J: A new endogenous ATP analog (ApppI) inhibits the mitochondrial adenine nucleotide translocase (ANT) and is responsible for the apoptosis induced by nitrogen-containing bisphosphonates. Br J Pharmacol. 147:437–445. 2006. View Article : Google Scholar : PubMed/NCBI
13	Luckman SP, Hughes DE, Coxon FP, Graham R, Russell G and Rogers MJ: Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent post-translational prenylation of GTP-binding proteins, including Ras. J Bone Miner Res. 13:581–589. 1998. View Article : Google Scholar : PubMed/NCBI
14	Wada A, Fukui K, Sawai Y, Imanaka K, Kiso S, Tamura S, Shimomura I and Hayashi N: Pamidronate induced anti-proliferative, apoptotic, and anti-migratory effects in hepatocellular carcinoma. J Hepatol. 44:142–150. 2006. View Article : Google Scholar : PubMed/NCBI
15	Coxon JP, Oades GM, Kirby RS and Colston KW: Zoledronic acid induces apoptosis and inhibits adhesion to mineralized matrix in prostate cancer cells via inhibition of protein prenylation. BJU Int. 94:164–170. 2004. View Article : Google Scholar : PubMed/NCBI
16	Wakchoure S, Merrell MA, Aldrich W, Millender-Swain T, Harris KW, Triozzi P and Selander KS: Bisphosphonates inhibit the growth of mesothelioma cells in vitro and in vivo. Clin Cancer Res. 12:2862–2868. 2006. View Article : Google Scholar : PubMed/NCBI
17	Denoyelle C, Hong L, Vannier JP, Soria J and Soria C: New insights into the actions of bisphosphonate zoledronic acid in breast cancer cells by dual RhoA-dependent and -independent effects. Br J Cancer. 88:1631–1640. 2003. View Article : Google Scholar : PubMed/NCBI
18	Qie S and Diehl JA: Cyclin D1, cancer progression, and opportunities in cancer treatment. J Mol Med (Berl). 94:1313–1326. 2016. View Article : Google Scholar : PubMed/NCBI
19	Vega FM and Ridley AJ: Rho GTPases in cancer cell biology. FEBS Lett. 582:2093–2101. 2008. View Article : Google Scholar : PubMed/NCBI
20	Yoshida T, Zhang Y, Rivera Rosado LA, Chen J, Khan T, Moon SY and Zhang B: Blockade of Rac1 activity induces G1 cell cycle arrest or apoptosis in breast cancer cells through downregulation of cyclin D1, survivin, and X-linked inhibitor of apoptosis protein. Mol Cancer Ther. 9:1657–1668. 2010. View Article : Google Scholar : PubMed/NCBI
21	Rachner TD, Singh SK, Schoppet M, Benad P, Bornhäuser M, Ellenrieder V, Ebert R, Jakob F and Hofbauer LC: Zoledronic acid induces apoptosis and changes the TRAIL/OPG ratio in breast cancer cells. Cancer Lett. 287:109–116. 2010. View Article : Google Scholar : PubMed/NCBI
22	Buranrat B, Senggunprai L, Prawan A and Kukongviriyapan V: Simvastatin and atorvastatin as inhibitors of proliferation and inducers of apoptosis in human cholangiocarcinoma cells. Life Sci. 153:41–49. 2016. View Article : Google Scholar : PubMed/NCBI
23	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
24	Porter AP, Papaioannou A and Malliri A: Deregulation of Rho GTPases in cancer. Small GTPases. 7:123–138. 2016. View Article : Google Scholar : PubMed/NCBI
25	Orgaz JL, Herraiz C and Sanz-Moreno V: Rho GTPases modulate malignant transformation of tumor cells. Small GTPases. 5:e290192014. View Article : Google Scholar : PubMed/NCBI
26	Mahtani R and Jahanzeb M: Bisphosphonates as anticancer therapy for early breast cancer. Clin Breast Cancer. 10:359–366. 2010. View Article : Google Scholar : PubMed/NCBI
27	Sahai E and Marshall CJ: RHO-GTPases and cancer. Nat Rev Cancer. 2:133–142. 2002. View Article : Google Scholar : PubMed/NCBI
28	Cayrol C, Knibiehler M and Ducommun B: p21 binding to PCNA causes G1 and G2 cell cycle arrest in p53-deficient cells. Oncogene. 16:311–320. 1998. View Article : Google Scholar : PubMed/NCBI
29	Brugarolas J, Chandrasekaran C, Gordon JI, Beach D, Jacks T and Hannon GJ: Radiation-induced cell cycle arrest compromised by p21 deficiency. Nature. 377:552–557. 1995. View Article : Google Scholar : PubMed/NCBI
30	Niculescu AB III, Chen X, Smeets M, Hengst L, Prives C and Reed SI: Effects of p21(Cip1/Waf1) at both the G1/S and the G2/M cell cycle transitions: pRb is a critical determinant in blocking DNA replication and in preventing endoreduplication. Mol Cell Biol. 18:629–643. 1998. View Article : Google Scholar : PubMed/NCBI
31	Lung JC, Chu JS, Yu JC, Yue CT, Lo YL, Shen CY and Wu CW: Aberrant expression of cell-cycle regulator cyclin D1 in breast cancer is related to chromosomal genomic instability. Genes Chromosomes Cancer. 34:276–284. 2002. View Article : Google Scholar : PubMed/NCBI
32	Nelsen CJ, Kuriyama R, Hirsch B, Negron VC, Lingle WL, Goggin MM, Stanley MW and Albrecht JH: Short term cyclin D1 overexpression induces centrosome amplification, mitotic spindle abnormalities, and aneuploidy. J Biol Chem. 280:768–776. 2005. View Article : Google Scholar : PubMed/NCBI
33	Sandor V, Senderowicz A, Mertins S, Sackett D, Sausville E, Blagosklonny MV and Bates SE: P21-dependent g(1)arrest with downregulation of cyclin D1 and upregulation of cyclin E by the histone deacetylase inhibitor FR901228. Br J Cancer. 83:817–825. 2000. View Article : Google Scholar : PubMed/NCBI
34	Ghavami S, Hashemi M, Ande SR, Yeganeh B, Xiao W, Eshraghi M, Bus CJ, Kadkhoda K, Wiechec E, Halayko AJ and Los M: Apoptosis and cancer: Mutations within caspase genes. J Med Genet. 46:497–510. 2009. View Article : Google Scholar : PubMed/NCBI
35	Senaratne SG, Pirianov G, Mansi JL, Arnett TR and Colston KW: Bisphosphonates induce apoptosis in human breast cancer cell lines. Br J Cancer. 82:1459–1468. 2000. View Article : Google Scholar : PubMed/NCBI
36	Ebert R, Meissner-Weigl J, Zeck S, Määttä J, Auriola S, Coimbra de Sousa S, Mentrup B, Graser S, Rachner TD, Hofbauer LC and Jakob F: Probenecid as a sensitizer of bisphosphonate-mediated effects in breast cancer cells. Mol Cancer. 13:2652014. View Article : Google Scholar : PubMed/NCBI
37	Morrissey MA, Hagedorn EJ and Sherwood DR: Cell invasion through basement membrane: The netrin receptor DCC guides the way. Worm. 2:e261692013. View Article : Google Scholar : PubMed/NCBI
38	Green JR: Antitumor effects of bisphosphonates. Cancer. 97:840–847. 2003. View Article : Google Scholar : PubMed/NCBI
39	Boissier S, Ferreras M, Peyruchaud O, Magnetto S, Ebetino FH, Colombel M, Delmas P, Delaissé JM and Clézardin P: Bisphosphonates inhibit breast and prostate carcinoma cell invasion, an early event in the formation of bone metastases. Cancer Res. 60:2949–2954. 2000.PubMed/NCBI
40	Teronen O, Heikkilä P, Konttinen YT, Laitinen M, Salo T, Hanemaaijer R, Teronen A, Maisi P and Sorsa T: MMP inhibition and downregulation by bisphosphonates. Ann N Y Acad Sci. 878:453–465. 1999. View Article : Google Scholar : PubMed/NCBI
41	Stearns ME and Wang M: Alendronate blocks metalloproteinase secretion and bone collagen I release by PC-3 ML cells in SCID mice. Clin Exp Metastasis. 16:693–702. 1998. View Article : Google Scholar : PubMed/NCBI
42	Raftopoulou M and Hall A: Cell migration: Rho GTPases lead the way. Dev Biol. 265:23–32. 2004. View Article : Google Scholar : PubMed/NCBI
43	Idris AI, Rojas J, Greig IR, Van't Hof RJ and Ralston SH: Aminobisphosphonates cause osteoblast apoptosis and inhibit bone nodule formation in vitro. Calcif Tissue Int. 82:191–201. 2008. View Article : Google Scholar : PubMed/NCBI
44	Shmeeda H, Amitay Y, Gorin J, Tzemach D, Mak L, Ogorka J, Kumar S, Zhang JA and Gabizon A: Delivery of zoledronic acid encapsulated in folate-targeted liposome results in potent in vitro cytotoxic activity on tumor cells. J Control Release. 146:76–83. 2010. View Article : Google Scholar : PubMed/NCBI