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Life Extension Magazine

LE Magazine May 2007
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Cimetidine


A Common Heartburn Remedy Complements Conventional Cancer Therapy
By Cynthia Haines, MD

Cimetidine Inhibits Tumor Growth

In addition to its effects in boosting immunity, cimetidine may help to slow or halt cancer by inhibiting the growth of several types of tumors.8

For example, in a cell-culture study of four colorectal tumor cell lines and four melanoma cell lines, histamine stimulated cell proliferation in a dose-dependent manner, while cimetidine reversed this effect.8,23 In another study, cimetidine inhibited the growth of human pancreatic cancer cells that had been grafted into immunodeficient mice.24 These findings suggest possible applications for cimetidine in colorectal, skin, and pancreatic cancers.

Scientists believe that cimetidine may prolong the survival of patients with various forms of cancer by inhibiting tumor-associated angiogenesis,25,26 the development of new blood vessels that tumors require to fuel their growth. In a 2005 report on cimetidine’s effects on angiogenesis and tumor growth, cimetidine markedly reduced the growth (and production of new blood vessels needed to sustain the growth) of a grafted tumor in an animal model of colon cancer. These findings suggest that cimetidine suppresses tumor growth by inhibiting tumor-associated angiogenesis.25

Cimetidine may also fight cancer by promoting apoptosis (programmed cell death) in cancer cells. In a Chinese study from 2006, cimetidine induced apoptosis and halted cell division in human gastric cancer cells, leading the researchers to propose that cimetidine may have applications in treating gastric cancer.26

By shutting down the growth-stimulating effect of histamine, inhibiting angiogenesis, and promoting apoptosis, cimetidine thus appears to work via several mechanisms to arrest the growth of deadly tumors.

Cimetidine Inhibits Cancer Cell Metastasis

Most cancer deaths are caused not by primary tumors, but instead by metastases, or the secondary tumors that form when cells from the primary tumor spread to another location in the body. Cimetidine may prolong cancer survival by blocking the ability of cancer cells to metastasize to other locales in the body.

Adhesion molecules play a crucial role in many biological processes, such as wound healing, immune response, and cancer metastasis. These adhesion molecules are expressed on the surface of endothelial cells that line the blood vessels, which facilitates their adherence to other cells.

Adhesion molecules are intimately involved in the spread of cancer cells through the bloodstream to other locations where they will form secondary tumors. For example, when epithelial tumor cells enter blood vessels leading to the liver, they trigger the expression of an adhesion molecule called E-selectin in the liver blood vessel endothelium.27 This helps cancer cells form a secondary tumor in the liver.

Several types of cancer cells use Lewis antigens—carbohydrate formations on cell surfaces that can activate an immune response—to bind with E-selectin in blood vessel walls. Cimetidine may help prevent cancer cells from migrating throughout the body and forming distant metastases by blocking the expression of E-selectin.

When given to immunosuppressed mice with liver cancer, cimetidine successfully blocked tumor metastasis. Cimetidine appears to be unique in its ability to block cancer metastasis—similar H2-blocking drugs such as famotidine (Pepcid®) and ranitidine (Zantac®) did not produce a similar effect.

Thus it appears that cimetidine’s ability to block cancer metastasis is independent of its ability to bind the H2 histamine receptor.28

Upon discovering cimetidine’s ability to block cancer metastasis, researchers re-visited a study in which colorectal cancer patients were treated with cimetidine immediately before and after cancer surgery. They found cimetidine was particularly effective in enhancing survival for colorectal cancer patients with tumors expressing higher levels of two Lewis antigens.3 When the tumors were analyzed for Lewis antigen expression, patients who had tumors expressing Lewis antigens and who received cimetidine had a remarkable 10-year survival rate of 91%, compared to 34% for those not treated with cimetidine.

In 2003, Japanese researchers published findings indicating that cimetidine blocked the adhesion of gastric, esophageal, and breast cancer cells (all of which expressed a specific Lewis antigen) to epithelial cells expressing E-selectin. They concluded that cimetidine may be effective in preventing metastasis of these cancers.29

Cimetidine thus holds great promise in protecting against metastasis, the process that paves the way for cancer’s often-fatal spread throughout the body.

Conclusion

Cimetidine’s beneficial effects in helping to manage various cancers are well documented. For more than 20 years, scientists have accumulated evidence that this low-cost, readily available heartburn remedy fights cancer via several mechanisms of action, including blocking the immunosuppressive action of histamine, modulating the body’s immune response, inhibiting angiogenesis, stimulating cancer cell death, and inhibiting cancer metastasis.

Cimetidine has not yet been approved by the FDA for use in treating cancer, and it remains unclear how its effects may enhance or synergize with other cancer treatments. However, cimetidine’s demonstrated effects suggest that it may markedly suppress the ability of certain cancers—particularly colorectal cancers—to grow and metastasize, even when used as a sole therapy. Further studies are needed to evaluate and document cimetidine’s efficacy both alone and in concert with other cancer-fighting regimens.

References

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2. Adams WJ, Morris DL. Short-course cimetidine and survival with colorectal cancer. Lancet. 1994 Dec 24;344(8939-8940):1768-9.

3. Matsumoto S, Imaeda Y, Umemoto S, et al. 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 Jan 21;86(2):161-7.

4. Yoshimatsu K, Ishibashi K, Yokomizo H, et al. Can the survival of patients with recurrent disease after curative resection of colorectal cancer be prolonged by the administration of cimetidine? Gan To Kagaku Ryoho. 2006 Nov;33(12):1730-2.

5. Lefranc F, Yeaton P, Brotchi J, Kiss R. Cimetidine, an unexpected anti-tumor agent, and its potential for the treatment of glioblastoma (review). Int J Oncol. 2006 May;28(5):1021-30.

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12. Nordlund JJ, Askenase PW. The effect of histamine, antihistamines, and a mast cell stabilizer on the growth of cloudman melanoma cells in DBA/2 mice. J Invest Dermatol. 1983 Jul;81(1):28-31.

13. Rocklin RE, Greineder DK, Melmon KL. Histamine-induced suppressor factor (HSF): further studies on the nature of the stimulus and the cell which produces it. Cell Immunol. 1979 May;44(2):404-15.

14. Griswold DE, Alessi S, Badger AM, Poste G, Hanna N. Differential sensitivity of T suppressor cell expression to inhibition by histamine type 2 receptor antagonists. J Immunol. 1986 Sep 15;137(6):1811-5.

15. Hansbrough JF, Zapata-Sirvent RL, Bender EM. Prevention of alterations in postoperative lymphocyte subpopulations by cimetidine and ibuprofen. Am J Surg. 1986 Feb;151(2):249-55.

16. Adams WJ, Lawson JA, Nicholson SE, Cook TA, Morris DL. The growth of carcinogen-induced colon cancer in rats is inhibited by cimetidine. Eur J Surg Oncol. 1993 Aug;19(4):332-5.

17. Harrison JC, Dean PJ, el-Zeky F, Vander ZR. From Dukes through Jass: pathological prognostic indicators in rectal cancer. Hum Pathol. 1994 May;25(5):498-505.

18. Morris DL, Adams WJ. Cimetidine and colorectal cancer—old drug, new use? Nat Med. 1995 Dec;1(12):1243-4.

19. Uchida A. Biological significance of autologous tumor-killing activity and its induction therapy. Cancer Immunol Immunother. 1993 Jul;37(2):75-83.

20. Adams WJ, Morris DL. Pilot study—cimetidine enhances lymphocyte infiltration of human colorectal carcinoma: results of a small randomized control trial. Cancer. 1997 Jul 1;80(1):15-21.

21. Li Y, Yang GL, Yuan HY, et al. Effects of perioperative cimetidine administration on peripheral blood lymphocytes and tumor infiltrating lymphocytes in patients with gastrointestinal cancer: results of a randomized controlled clinical trial. Hepatogastroenterology. 2005 Mar;52(62):504-8.

22. Asakage M, Tsuno NH, Kitayama J, et al. The effect of cimetidine mainly increases CD4+ cells of peripheral blood T lymphocytes. Gan To Kagaku Ryoho. 2005 Oct;32(11):1576-7.

23. Reynolds JL, Akhter J, Morris DL. In vitro effect of histamine and histamine H1 and H2RAs on cellular proliferation of human malignant melanoma cell lines. Melanoma Res. 1996 Apr;6(2):95-9.

24. Surucu O, Middeke M, Hoschele I, et al. Tumour growth inhibition of human pancreatic cancer xenografts in SCID mice by cimetidine. Inflamm Res. 2004 Mar;53 Suppl 1:S39-40.

25. Natori T, Sata M, Nagai R, Makuuchi M. Cimetidine inhibits angiogenesis and suppresses tumor growth. Biomed Pharmacother. 2005 Jan;59(1-2):56-60.

26. Jiang CG, Liu FR, Xu HM, Wu T, Gao J. Effects of cimetidine on the biological behaviors of human gastric cancer cells. Zhonghua Yi Xue Za Zhi. 2006 Jul 11;86(26):1813-6.

27. Khatib AM, Kontogiannea M, Fallavollita L, Jamison B, Meterissian S, Brodt P. Rapid induction of cytokine and E-selectin expression in the liver in response to metastatic tumor cells. Cancer Res. 1999 Mar 15;59(6):1356-61.

28. Kobayashi K, Matsumoto S, Morishima T, Kawabe T, Okamoto T. Cimetidine inhibits cancer cell adhesion to endothelial cells and prevents metastasis by blocking E-selectin expression. Cancer Res. 2000 Jul 15;60(14):3978-84.

29. Hayashi A, Kobayashi K, Imaeda Y, Matsumoto S. Cimetidine inhibits the adhesion of cancer cells with sialyl Lewis epitope onto the vascular endothelium. Gan To Kagaku Ryoho. 2003 Oct;30(11):1788-90.