Cimetidine Shows Anticancer Efficacy That Warrants Further Investigation

Cimetidine has clinically important benefits in improving colon cancer survival and preclinical evidence shows that this benefit may extend to other types of cancer.

Researchers are searching for new uses of cimetidine, which was the first histamine-2 receptor antagonist (H2RA). The medication, which is known for its cytochrome 3A4 enzyme inhibition and its estrogenic effects, may help boost levels of other drugs, but may also have additional effects on the tumor microenvironment beyond its traditionally known characteristics.¹

Scientists hypothesize that cimetidine affects tumors beyond CYP3A4 inhibition, including an impact on histamine levels in the tumor microenvironment that may also affect the activity of regulatory T cells, dendritic cells, and natural killer cells. Additionally, cimetidine may affect cell adhesion mediated by endothelial expression of E-selectin and tumoral expression of sialyl Lewis antigens. Some evidence of an antiangiogenic effect of cimetidine has also been documented.¹

In a study published in a 2002 edition of the British Journal of Cancer, Matsumoto and colleagues studied the effects of cimetidine on patient survival in tumor recurrence in 64 patients with colorectal cancer who underwent surgical resection with the intent of cure. Cimetidine, which was administered starting 2 weeks after surgery at 800 mg daily, in combination with 200 mg of 5-fluorouracil daily over a 1-year period, significantly improved 10-year overall survival (OS) (84.6% with cimetidine vs 48.8% with placebo, P <.0001).²

This robust benefit was even stronger in a subgroup of patients with high tumoral levels of sialyl Lewis antigens. In this subgroup, nearly all of the patients treated with cimetidine for 1 year survived until year 10, versus just over one-third of those who did not receive cimetidine (95.5% OS vs 35.1% OS; P = .0001). Likewise, cimetidine had no effect on overall survival in patients with low levels of sialyl Lewis antigens, which strongly suggests an effect of cimetidine on cancer cell adhesion.²

Similar effects against cell adhesion have been documented in several other types of cancer, including breast cancer, salivary gland tumors, gastric cancer, and glioblastoma.¹ Animal study data indicates that the anticancer effects of cimetidine may not be limited to a subgroup of patients with colon cancer. For instance, cimetidine has been shown to enhance the antitumor effects of cyclophosphamide in male mice injected with leukemia cells, in addition to improving survival in those mice.³

It is important to note that use of cimetidine is not universally beneficial. Patients receiving cimetidine for a period of 2 years after resection of colon cancer or rectal cancer (n = 192) experienced no improvement in overall survival in an analysis limited to patients treated with the intent of curing the disease. However, in a subgroup of patients with more advanced disease (Dukes stage C), a trend toward an improvement in survival was observed (HR = 0.71; P = .11).⁴

In addition, a 442-patient study of patients with gastric cancer conducted in the United Kingdom did not show an improvement in survival with use of oral cimetidine.⁵

Beyond its potential therapeutic effects, cimetidine may also have some chemoprotective effects. For instance, in patients undergoing radiotherapy, cimetidine reduced the risk of adverse events in the para-aortic lymph nodes,⁶ and reduced the risk of vinorelbine-induced phlebitis.⁷

Additionally, because cimetidine inhibits a transporter in the kidneys (organic cation transporter 2), cimetidine may theoretically reduce the risk of cisplatin-mediated nephrotoxicity. Although the potential nephroprotective effect of cimetidine has not been confirmed in humans, murine studies show a protective effect and, encouragingly, do not show any reduction in the antitumor effects of cisplatin.⁸

According to lead author Pan Pantziarka, “Cimetidine is an interesting drug as it's very safe, very well known, and has clinical results in cancer that have been confirmed in a number of trials.” Pantizarka, who is a member of the Repurposing Drugs in Oncology project, is part of a group looking at the potential anticancer effects of already approved agents.⁹

According to Pantizarka, cimetidine is one of the most promising anticancer agents evaluated by the team to date. He noted that “Cimetidine is one of the most interesting examples of repurposed drugs in oncology a drug with an extensive history of preclinical and clinical evidence of efficacy in a range of different cancers and with multiple mechanisms of action at work.”⁹

References:

• Pantziarka P, Bouche G, Meheus L, Sukhatme V, Sukhatme VP. Repurposing drugs in oncology (ReDO)—cimetidine as an anti-cancer agent.eCancer Med Sci. 2014;8:485. http://ecancer.org/journal/8/485-repurposing-drugs-in-oncology-redo-cimetidine-as-an-anti-cancer-agent.php. Accessed December 2014.
• Matsumoto S, Imaeda Y, Umemoto S, Kobayashi K, Suzuki H, Okamoto T. Cimetidine increases survival of colorectal cancer patients with high levels of sialyl Lewis-X and sialyl Lewis-A epitope expression on tumour cells. Br J Cancer. 2002;86(2):161-167.
• Dorr RT, Alberts DS. Cimetidine enhancement of cyclophosphamide antitumour activity. Br J Cancer. 1982;45(1):35-43.
• Svendsen LB, Ross C, Knigge U, et al. Cimetidine as an adjuvant treatment in colorectal cancer. A double-blind, randomized pilot study. Dis Colon Rectum. 1995;38(5):514-518.
• Langman MJ, Dunn JA, Whiting JL, et al. Prospective, double-blind, placebo-controlled randomized trial of cimetidine in gastric cancer. British Stomach Cancer Group. Br J Cancer. 1999;81(8):1356-1362.
• Teshima T, Inoue T, Chatani M, et al. Radiation therapy of the para-aortic lymph nodes in carcinoma of the uterine cervix: the concurrent use of cimetidine to reduce acute and subacute side effects from radiation. Clin Ther. 1990;12(1):71-77.
• Vassilomanolakis M, Koumakis G, Barbounis V, Orphanos G, Efremidis A. Prevention of vinorelbine phlebitis with cimetidine. A two-step design study. Support Care Cancer. 2001;9(2):108-111.
• Sprowl JA, van Doorn L, Hu S, et al. Conjunctive therapy of cisplatin with the OCT2 inhibitor cimetidine: influence on antitumor efficacy and systemic clearance. Clin Pharmacol Ther. 2013;94(5):585-592.
• EurekAlert. How a common antacid could lead to cheaper anticancer drugs [press release]. http://www.eurekalert.org/pub_releases/2014-11/e-hac112414.php. Accessed December 2014.