Cimetidine, an unexpected anti-tumor agent, and its potential for the treatment of glioblastoma (review)

Abstract

Abstract. Cimetidine (CIM), the prototypical histamine H2 receptor antagonist (H2RA), was brought to market based on its ability to accelerate healing of gastrointestinal ulcers through the inhibition of gastric acid secretion. Cimetidine, the most studied H2RA, has been demonstrated to possess anti-tumor activity against colon, gastric and kidney cancers, and melanomas. This activity involves a number of different mechanisms of action: a) CIM antagonizes tumor cellmediated interleukin-1-induced activation of selectins in liver sinusoids, inhibiting tumor cell binding on liver sinusoids, thereby reducing the development of liver metastasis; b) histamine acts as a growth factor in various tumor cell types via the activation of H2 receptors; CIM therefore may antagonize this effect; c) CIM acts as an immunomodulator by enhancing the host's immune response to tumor cells. With respect to malignant gliomas, CIM added to temozolomide was superior in vivo when compared to temozolomide alone in extending survival of nude mice with human glioblastoma cells orthotopically xenografted into their brain. We review the various mechanisms of action potentially associated with the therapeutic effects of CIM in the case of experimental glioblastomas, observations we hope will encourage clinical investigation of CIM in the management of highly malignant gliomas.

The Pivotal Roles of GSK3β in Glioma Biology

“…Cimetidine has been demonstrated to possess anti-tumor activity against colon, gastric, and kidney cancers and melanomas. This activity involves a number of different mechanisms of action, including blocking the cell growth-promoting activity of histamine (Lefranc et al, 2006). With respect to GBM, cimetidine combined with temozolomide was superior to temozolomide alone in extending the survival of nude mice with human GBM cells orthotopically xenografted into their brain (Lefranc et al, 2005).…”

Anti-tumor effects of cimetidine on hepatocellular carcinomas in diethylnitrosamine-treated rats

“…Since that time, several studies have reported survival advantages with cimetidine treatment, mainly in patients with gastrointestinal cancer (11)(12)(13)(14). Further, positive effects have also been demonstrated in non-gastrointestinal cancer patients, such as those with renal cell carcinoma (15), malignant melanoma (16) and glioblastoma (17).…”

Phase‐II trial of combination treatment of interferon‐α, cimetidine, cyclooxygenase‐2 inhibitor and renin‐angiotensin‐system inhibitor (I‐CCA therapy) for advanced renal cell carcinoma

“…( [15][16][17][18][19][20][21] Of note is the fact that all three drugs have shown anti-angiogenic activity. We have recently reported three cases in which favorable responses to a combination treatment comprising cimetidine, COX-2 inhibitor and RAS inhibitor in mRCC were observed with a relatively long duration of the effects, at least 1 year of time to progression.…”

“…Recently, two phase-III trials (13,14) have shown improved PFS and increased objective response rate (ORR) with bevacizumab plus IFN-a, when compared with IFN-a alone, as first-line treatment. The combination of IFN-a plus bevacizumab has now become one of the standard first-line treatments for favorable-to intermediate-risk mRCC patients.The antitumor effects of cimetidine, cyclooxygenase-2 (COX-2) inhibitor and renin-angiotensin-system (RAS) inhibitor (angiotensin-converting-enzyme [ACE] inhibitor or angiotensin-II type-1 receptor [AT1R] antagonist) have been recognized in previous studies.( [15][16][17][18][19][20][21] Of note is the fact that all three drugs have shown anti-angiogenic activity. We have recently reported three cases in which favorable responses to a combination treatment comprising cimetidine, COX-2 inhibitor and RAS inhibitor in mRCC were observed with a relatively long duration of the effects, at least 1 year of time to progression.…”