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Tumor Biology
Published in: Tumor Biology 7/2015

01-07-2015 | Research Article

Zoledronate can promote apoptosis and inhibit the proliferation of colorectal cancer cells

Authors: Xiang Gao, Bo Jiang, Shitao Zou, Ting Zhang, Xiaowei Qi, Linfang Jin, Xiaosong Ge, Shou-Ching Tang, Dong Hua, Weichang Chen

Published in: Tumor Biology | Issue 7/2015

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Abstract

Zoledronate (ZOL) is a third-generation bisphosphonate (BP), clinically used to treat lytic bone lesions caused by malignancies or bone resorption disorders. Mechanistically, ZOL was recently shown to have direct pro-apoptotic effects on tumor cells and to inhibit cancer cell invasion, adhesion, proliferation, and angiogenesis. The molecular mechanism of ZOL-induced apoptosis remains unknown. In this study, we observed that ZOL induced apoptosis in colorectal cancer cells HCT116 and Caco-2. After HCT116 and Caco-2 cells were treated with ZOL, decreased fluorescence of JC-1 aggregates (590 nm) was seen in mitochondria. Western blotting analysis showed that cytochrome c was decreased in the mitochondria and increased in the cytosol, respectively. The effects were dependent on the concentration and treatment time by ZOL. In vivo experiments showed that ZOL inhibited the growth of xenograft tumor in mice. Hematoxylin and eosin (H&E) staining of tissue samples showed a significantly increased apoptosis body in the ZOL-treated xenografts compared to control. Taken together, our data demonstrated that ZOL inhibits growth of HCT116 cells both in vitro and in vivo and induce apoptosis through the mitochondria pathway.
Literature
1.
Metzger B, Chambeau L, Begon DY, Faber C, Kayser J, Berchem G, et al. The human epidermal growth factor receptor (egfr) gene in European patients with advanced colorectal cancer harbors infrequent mutations in its tyrosine kinase domain. BMC Med Genet. 2011;12:144.CrossRefPubMedPubMedCentral
2.
Bihl MP, Hoeller S, Andreozzi MC, Foerster A, Rufle A, Tornillo L, et al. Kras mutation testing in colorectal cancer: comparison of the results obtained using 3 different methods for the analysis of codons g12 and g13. Diagn Mol Pathol. 2012;21:14–23.CrossRefPubMed
3.
Rojas AM, Fuentes G, Rausell A, Valencia A. The ras protein superfamily: evolutionary tree and role of conserved amino acids. J Cell Biol. 2012;196:189–201.CrossRefPubMedPubMedCentral
4.
Pines G, Kostler WJ, Yarden Y. Oncogenic mutant forms of egfr: lessons in signal transduction and targets for cancer therapy. FEBS Lett. 2010;584:2699–706.CrossRefPubMedPubMedCentral
5.
Doggrell SA. Clinical efficacy and safety of zoledronic acid in prostate and breast cancer. Expert Rev Anticancer Ther. 2009;9:1211–8.CrossRefPubMed
6.
Ottewell PD, Wang N, Brown HK, Reeves KJ, Fowles CA, Croucher PI, et al. Zoledronic acid has differential antitumor activity in the pre- and postmenopausal bone microenvironment in vivo. Clin Cancer Res. 2014;20:2922–32.CrossRefPubMedPubMedCentral
7.
Merrell MA, Wakchoure S, Lehenkari PP, Harris KW, Selander KS. Inhibition of the mevalonate pathway and activation of p38 map kinase are independently regulated by nitrogen-containing bisphosphonates in breast cancer cells. Eur J Pharmacol. 2007;570:27–37.CrossRefPubMed
8.
Oades GM, Senaratne SG, Clarke IA, Kirby RS, Colston KW. Nitrogen containing bisphosphonates induce apoptosis and inhibit the mevalonate pathway, impairing ras membrane localization in prostate cancer cells. J Urol. 2003;170:246–52.CrossRefPubMed
9.
Raikkonen J, Monkkonen H, Auriola S, Monkkonen J. Mevalonate pathway intermediates downregulate zoledronic acid-induced isopentenyl pyrophosphate and atp analog formation in human breast cancer cells. Biochem Pharmacol. 2010;79:777–83.CrossRefPubMed
10.
Mitrofan LM, Pelkonen J, Monkkonen J. The level of atp analog and isopentenyl pyrophosphate correlates with zoledronic acid-induced apoptosis in cancer cells in vitro. Bone. 2009;45:1153–60.CrossRefPubMed
11.
Ahn SG, Kim SH, Lee HM, Lee SA, Jeong J. Survival benefit of zoledronic acid in postmenopausal breast cancer patients receiving aromatase inhibitors. J Breast Cancer. 2014;17:350–5.CrossRefPubMedPubMedCentral
12.
Lluch A, Cueva J, Ruiz-Borrego M, Ponce J, Perez-Fidalgo JA. Zoledronic acid in the treatment of metastatic breast cancer. Anti-Cancer Drugs. 2014;25:1–7.CrossRefPubMed
13.
Riebeling C, Forsea AM, Raisova M, Orfanos CE, Geilen CC. The bisphosphonate pamidronate induces apoptosis in human melanoma cells in vitro. Br J Cancer. 2002;87:366–71.CrossRefPubMedPubMedCentral
14.
Iguchi T, Miyakawa Y, Yamamoto K, Kizaki M, Ikeda Y. Nitrogen-containing bisphosphonates induce s-phase cell cycle arrest and apoptosis of myeloma cells by activating mapk pathway and inhibiting mevalonate pathway. Cell Signal. 2003;15:719–27.CrossRefPubMed
15.
Liu SS, Wang XP, Li XB, Liang JY, Liu LL, Lu Y, et al. Zoledronic acid exerts antitumor effects in nb4 acute promyelocytic leukemia cells by inducing apoptosis and s phase arrest. Biomed Pharmacother: Biomed Pharmacother. 2014;68:1031–6.CrossRefPubMed
16.
Oades GM, Coxon J, Colston KW. The potential role of bisphosphonates in prostate cancer. Prostate Cancer Prostatic Dis. 2002;5:264–72.CrossRefPubMed
17.
Caraglia M, D’Alessandro AM, Marra M, Giuberti G, Vitale G, Viscomi C, et al. The farnesyl transferase inhibitor r115777 (zarnestra) synergistically enhances growth inhibition and apoptosis induced on epidermoid cancer cells by zoledronic acid (zometa) and pamidronate. Oncogene. 2004;23:6900–13.CrossRefPubMed
18.
Horie N, Murata H, Nishigaki Y, Matsui T, Segawa H, Nogawa M, et al. The third-generation bisphosphonates inhibit proliferation of murine osteosarcoma cells with induction of apoptosis. Cancer Lett. 2006;238:111–8.CrossRefPubMed
19.
Ullen A, Schwarz S, Lennartsson L, Kalkner KM, Sandstrom P, Costa F, et al. Zoledronic acid induces caspase-dependent apoptosis in renal cancer cell lines. Scand J Urol Nephrol. 2009;43:98–103.CrossRefPubMed
20.
Hirsh V, Major PP, Lipton A, Cook RJ, Langer CJ, Smith MR, et al. Zoledronic acid and survival in patients with metastatic bone disease from lung cancer and elevated markers of osteoclast activity. J Thorac Oncol: Off Publ Int Assoc Study Lung Cancer. 2008;3:228–36.CrossRef
21.
Liu CY, Yang PS, Cheng SP, Huang YC, Lee JJ, Ko CC, et al. Zoledronic acid, an aminobisphosphonate, prolongs survival of skin allografts. Clin Invest Med. 2012;35:E165–72.PubMed
22.
23.
Monkkonen H, Kuokkanen J, Holen I, Evans A, Lefley DV, Jauhiainen M, et al. Bisphosphonate-induced atp analog formation and its effect on inhibition of cancer cell growth. Anti-Cancer Drugs. 2008;19:391–9.CrossRefPubMed
24.
Monkkonen H, Auriola S, Lehenkari P, Kellinsalmi M, Hassinen IE, Vepsalainen J, et al. 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. 2006;147:437–45.CrossRefPubMedPubMedCentral
25.
Karabulut B, Erten C, Gul MK, Cengiz E, Karaca B, Kucukzeybek Y, et al. Docetaxel/zoledronic acid combination triggers apoptosis synergistically through downregulating antiapoptotic bcl-2 protein level in hormone-refractory prostate cancer cells. Cell Biol Int. 2009;33:239–46.CrossRefPubMed
26.
Nakajima H, Magae J, Tsuruga M, Sakaguchi K, Fujiwara I, Mizuta M, et al. Induction of mitochondria-dependent apoptosis through the inhibition of mevalonate pathway in human breast cancer cells by ym529, a new third generation bisphosphonate. Cancer Lett. 2007;253:89–96.CrossRefPubMed
27.
Sewing L, Steinberg F, Schmidt H, Goke R. The bisphosphonate zoledronic acid inhibits the growth of hct-116 colon carcinoma cells and induces tumor cell apoptosis. Apoptosis. 2008;13:782–9.CrossRefPubMed
Metadata
Title
Zoledronate can promote apoptosis and inhibit the proliferation of colorectal cancer cells
Authors
Xiang Gao
Bo Jiang
Shitao Zou
Ting Zhang
Xiaowei Qi
Linfang Jin
Xiaosong Ge
Shou-Ching Tang
Dong Hua
Weichang Chen
Publication date
01-07-2015
Publisher
Springer Netherlands
Published in
Tumor Biology / Issue 7/2015
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-015-3192-x

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