Cimetidine: A Cancer Therapy with Mechanisms Targeting Cell Proliferation, Apoptosis, and Cell Adhesion

General Description

Cimetidine, a histamine antagonist, has shown potential in cancer treatment. It inhibits cell proliferation by suppressing histamine activity and inducing apoptosis. Additionally, cimetidine inhibits cell adhesion by targeting specific antigens and E-selectin, reducing metastasis risk. Clinical studies have demonstrated improved survival rates in gastric and colorectal cancer patients treated with cimetidine, as well as promising results in advanced renal cell carcinoma. However, further research is needed to optimize its use and understand its mechanisms fully. Overall, cimetidine's mechanisms of action make it a promising candidate for cancer therapy.

Figure 1. Tablets of cimetidine

Mechanisms of action

Cell proliferation and apoptosis

Cimetidine, a histamine antagonist, exhibits its mechanisms of action in cell proliferation and apoptosis through various pathways. Histamine, which is involved in physiological and pathophysiological processes, has been found to have high activity and rapid synthesis in certain types of tumors. In patients with solid malignant tumors, blood histamine concentration is significantly higher compared to healthy individuals. Histamine acts as a potential growth factor for breast cancer, melanoma cells, and colon cancer cell lines. One mechanism by which histamine affects cancer cell proliferation is through the activation of H1 or H2 receptors. Cimetidine, acting as a histamine antagonist at H2 receptors, suppresses tumor growth by inhibiting the action of histidine decarboxylase. In experimental studies using mice, cimetidine failed to suppress tumor growth in knockout mice lacking endogenous histamine but successfully suppressed tumor growth in wild-type mice. Cimetidine also induces apoptosis, or programmed cell death, in human colorectal cancer cells, salivary gland tumor cells, and gastric cancer cells. Daily administration of cimetidine in mouse models has been shown to significantly inhibit colon cancer growth by up-regulating the expression of tumor suppressive cytokines. Additionally, cimetidine has demonstrated the ability to retard the growth of human melanoma in mouse models and prolong survival in tumor-bearing mice. The antiproliferative effects of H2 receptor antagonists like cimetidine are likely multifactorial and may occur independently of H2 receptor activation. ¹

Cell adhesion

Cimetidine is a medication that has been found to inhibit cell adhesion, particularly in cancer cells. In various studies, it has been shown to effectively reduce the adhesion of breast cancer cells and human colon cancer cells to other cells. One of the mechanisms through which cimetidine exerts its action is by targeting specific antigens called sialyl LewisX and sialyl LewisA. These antigens are found on tumor cells and are associated with poor prognosis and metastasis. Cimetidine treatment has been found to be particularly effective in colorectal cancer patients with higher levels of these antigens. Additionally, cimetidine has been identified as an inhibitor of E-selectin, which is a vascular receptor involved in cell adhesion. Some anticancer drugs can increase the expression of E-selectin, but cimetidine has been shown to inhibit this increase at the protein level without affecting mRNA expression. This suggests that cimetidine's mechanism of action may involve inhibiting E-selectin-mediated interactions between tumor cells and platelets or endothelial cells, preventing cell extravasation from the bloodstream. Furthermore, cimetidine has been found to prolong the circulation period of cancer cells in the bloodstream, potentially making them more susceptible to the cytotoxic action of natural killer (NK) cells. Overall, cimetidine's mechanisms of action involve inhibiting cell adhesion, particularly through its effects on specific antigens and E-selectin, which could have implications for reducing metastasis and improving the efficacy of NK cell activity against cancer cells. ²

Clinical studies

Cimetidine, a drug commonly used to treat gastric disorders since the 1970s, has also shown potential in the treatment of cancer, as indicated by several clinical studies. In the late 1980s, the first studies suggesting the effectiveness of cimetidine against cancer were published. One study by Burtin et al found that gastric cancer patients treated with cimetidine or ranitidine combined with subcutaneous histamine had significantly improved survival compared to those receiving palliative treatment. Another study by Tonnesen et al showed that cimetidine, at normal therapeutic dosage, significantly prolonged the survival of gastric cancer patients, particularly in advanced stages of the disease. Furthermore, Adams and Morris reported that preoperative and short postoperative treatment with cimetidine reduced the immunosuppressive effect of surgery for colorectal carcinoma, resulting in improved survival rates. Matsumoto's study involving patients with colorectal cancer demonstrated that cimetidine treatment, in combination with 5-fluorouracil, significantly increased the 4-year survival rate compared to the control group. Cimetidine has also shown promise in the treatment of advanced renal cell carcinoma (RCC). Studies combining cimetidine with coumarin or interferon-demonstrated significant benefits, including complete and partial responses in metastatic RCC patients. While these studies provide encouraging evidence of cimetidine's potential therapeutic effects in cancer treatment, further research is needed to fully understand its mechanisms and optimize its use. ¹

Reference

1. Kubecova M, Kolostova K, Pinterova D, Kacprzak G, Bobek V. Cimetidine: an anticancer drug. Eur J Pharm Sci. 2011;42(5):439-444.

2. Zhang J, Takahashi HK, Liu K, et al. Histamine inhibits adhesion molecule expression in human monocytes, induced by advanced glycation end products, during the mixed lymphocyte reaction. Br J Pharmacol. 2010;160(6):1378-1386.

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