Repurposing cimetidine for cholangiocarcinoma: Antitumor effects in vitro and in vivo

Dana,Paweena; Vaeteewoottacharn,Kulthida; Kariya,Ryusho; Matsuda,Kouki; Wongkham,Sopit; Okada,Seiji

doi:10.3892/ol.2017.5563

Repurposing cimetidine for cholangiocarcinoma: Antitumor effects in vitro and in vivo

Authors:
- Paweena Dana
- Kulthida Vaeteewoottacharn
- Ryusho Kariya
- Kouki Matsuda
- Sopit Wongkham
- Seiji Okada
View Affiliations

Affiliations: Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand, Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, Kumamoto 860‑0811, Japan
Published online on: January 2, 2017 https://doi.org/10.3892/ol.2017.5563
Pages: 1432-1436

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

Cimetidine is a histamine type-2 (H2) receptor antagonist that has been demonstrated to have antitumor effects on various types of malignancy. However, its effect on cholangiocarcinoma (CCA), a chemotherapy‑resistant bile duct tumor, has yet to be investigated. In the present study, the antitumor activity of cimetidine in vitro and in vivo was evaluated. A methylthiotetrazole assay revealed that the proliferation of certain CCA cell lines was inhibited by cimetidine, which induced the caspase‑dependent apoptosis of CCA cells via suppression of the protein kinase B signaling pathway. Suppression of Akt phosphorylation, caspase‑3, ‑8 and ‑9 activation, phosphotidylserine exposure determined by Annexin V binding assay and the presence of a sub‑G1 population were demonstrated by western blotting and flow cytometry analysis. In a CCA xenograft mouse model cimetidine inhibited the growth of CCA cells without observable adverse effects. These results suggest that cimetidine has the potential to be an effective antitumor agent for the treatment of CCA.

View Figures

View References

1	Vatanasapt V, Sriamporn S and Vatanasapt P: Cancer control in Thailand. Jpn J Clin Oncol. 32:(Suppl). S82–S91. 2002. View Article : Google Scholar : PubMed/NCBI
2	Endo I, Gonen M, Yopp AC, Dalal KM, Zhou Q, Klimstra D, D'Angelica M, DeMatteo RP, Fong Y, Schwartz L, et al: Intrahepatic cholangiocarcinoma: Rising frequency, improved survival, and determinants of outcome after resection. Ann Surg. 248:84–96. 2008. View Article : Google Scholar : PubMed/NCBI
3	Sripa B and Pairojkul C: Cholangiocarcinoma: Lessons from Thailand. Curr Opin Gastroenterol. 24:349–356. 2008. View Article : Google Scholar : PubMed/NCBI
4	Wongkham S and Silsirivanit A: State of serum markers for detection of cholangiocarcinoma. Asian Pac J Cancer Prev. 13:(Suppl). S17–S27. 2012.
5	Anderson CD, Pinson CW, Berlin J and Chari RS: Diagnosis and treatment of cholangiocarcinoma. Oncologist. 9:43–57. 2004. View Article : Google Scholar : PubMed/NCBI
6	Adams WJ and Morris DL: Short-course cimetidine and survival with colorectal cancer. Lancet. 344:1768–1769. 1994. View Article : Google Scholar : PubMed/NCBI
7	Freston JW: Cimetidine: II. Adverse reactions and patterns of use. Ann Intern Med. 97:728–734. 1982. View Article : Google Scholar : PubMed/NCBI
8	Tønnesen H, Knigge U, Bülow S, Damm P, Fischerman K, Hesselfeldt P, Hjortrup A, Pedersen IK, Pedersen VM and Siemssen OJ: Effect of cimetidine on survival after gastric cancer. Lancet. 2:990–992. 1988. View Article : Google Scholar : PubMed/NCBI
9	Adams W and Morris D: Cimetidine and colorectal cancer. Dis Colon Rectum. 39:111–112. 1996. View Article : Google Scholar : PubMed/NCBI
10	Kelly MD, King J, Cherian M, Dwerryhouse SJ, Finlay IG, Adams WJ, King DW, Lubowski DZ and Morris DL: Randomized trial of preoperative cimetidine in patients with colorectal carcinoma with quantitative assessment of tumor-associated lymphocytes. Cancer. 85:1658–1663. 1999. View Article : Google Scholar : PubMed/NCBI
11	Dexeus FH, Logothetis CJ, Sella A, Fitz K, Amato R, Reuben JM and Dozier N: Phase II study of coumarin and cimetidine in patients with metastatic renal cell carcinoma. J Clin Oncol. 8:325–329. 1990.PubMed/NCBI
12	Morton RF, Creagan ET, Cullinan SA, Mailliard JA, Ebbert L, Veeder MH and Chang M: Phase II studies of single-agent cimetidine and the combination N-phosphonacetyl-L-aspartate (NSC-224131) plus L-alanosine (NSC-153353) in advanced malignant melanoma. J Clin Oncol. 5:1078–1082. 1987.PubMed/NCBI
13	Lefranc F, Yeaton P, Brotchi J and Kiss R: Cimetidine, an unexpected anti-tumor agent, and its potential for the treatment of glioblastoma (review). Int J Oncol. 28:1021–1030. 2006.PubMed/NCBI
14	Adams WJ, Lawson JA and Morris DL: Cimetidine inhibits in vivo growth of human colon cancer and reverses histamine stimulated in vitro and in vivo growth. Gut. 35:1632–1636. 1994. View Article : Google Scholar : PubMed/NCBI
15	Natori T, Sata M, Nagai R and Makuuchi M: Cimetidine inhibits angiogenesis and suppresses tumor growth. Biomed Pharmacother. 59:56–60. 2005. View Article : Google Scholar : PubMed/NCBI
16	Sahasrabudhe DM, McCune CS, O'Donnell RW and Henshaw EC: Inhibition of suppressor T lymphocytes (Ts) by cimetidine. J Immunol. 138:2760–2763. 1987.PubMed/NCBI
17	Kobayashi K, Matsumoto S, Morishima T, Kawabe T and Okamoto T: Cimetidine inhibits cancer cell adhesion to endothelial cells and prevents metastasis by blocking E-selectin expression. Cancer Res. 60:3978–3984. 2000.PubMed/NCBI
18	Seubwai W, Vaeteewoottacharn K, Hiyoshi M, Suzu S, Puapairoj A, Wongkham C, Okada S and Wongkham S: Cepharanthine exerts antitumor activity on cholangiocarcinoma by inhibiting NF-kappaB. Cancer Sci. 101:1590–1595. 2010. View Article : Google Scholar : PubMed/NCBI
19	Ono A, Hattori S, Kariya R, Iwanaga S, Taura M, Harada H, Suzu S and Okada S: Comparative study of human hematopoietic cell engraftment into BALB/c and C57BL/6 strain of rag-2/jak3 double-deficient mice. J Biomed Biotechnol. 2011:5397482011. View Article : Google Scholar : PubMed/NCBI
20	Kubecova M, Kolostova K, Pinterova D, Kacprzak G and Bobek V: Cimetidine: An anticancer drug? Eur J Pharm Sci. 42:439–444. 2011. View Article : Google Scholar : PubMed/NCBI
21	Morris DL and Adams WJ: Cimetidine and colorectal cancer-old drug, new use? Nat Med. 1:1243–1244. 1995. View Article : Google Scholar : PubMed/NCBI
22	Vaeteewoottacharn K, Seubwai W, Bhudhisawasdi V, Okada S and Wongkham S: Potential targeted therapy for liver fluke associated cholangiocarcinoma. J Hepatobiliary Pancreat Sci. 21:362–370. 2014. View Article : Google Scholar : PubMed/NCBI
23	Maemura K, Natsugoe S and Takao S: Molecular mechanism of cholangiocarcinoma carcinogenesis. J Hepatobiliary Pancreat Sci. 21:754–760. 2014. View Article : Google Scholar : PubMed/NCBI
24	Datta SR, Brunet A and Greenberg ME: Cellular survival: A play in three Akts. Genes Dev. 13:2905–2927. 1999. View Article : Google Scholar : PubMed/NCBI
25	Schmitz KJ, Lang H, Wohlschlaeger J, Sotiropoulos GC, Reis H, Schmid KW and Baba HA: AKT and ERK1/2 signaling in intrahepatic cholangiocarcinoma. World J Gastroenterol. 13:6470–6477. 2007. View Article : Google Scholar : PubMed/NCBI
26	Adams WJ, Morris DL, Ross WB, Lubowski DZ, King DW and Peters L: Cimetidine preserves non-specific immune function after colonic resection for cancer. Aust N Z J Surg. 64:847–852. 1994. View Article : Google Scholar : PubMed/NCBI
27	Zheng Y, Xu M, Li X, Jia J, Fan K and Lai G: Cimetidine suppresses lung tumor growth in mice through proapoptosis of myeloid-derived suppressor cells. Mol Immunol. 54:74–83. 2013. View Article : Google Scholar : PubMed/NCBI