(pH modifier, pretreatment chemo sensitizer/resistance reverser, ROS, increased survival in vivo)
Eur J Pharm Sci. 2011 Apr 18;42(5):439-44. Epub 2011 Feb 15.
Cimetidine: An anticancer drug?
Kubecova M,
Kolostova K,
Pinterova D,
Kacprzak G,
Bobek V.
Source
Department of Radiotherapy and Oncology, Charles University in Prague, Third Faculty of Medicine and Faculty Hospital Kralovske Vinohrady, Czech Republic.
LINK
Abstract
Cimetidine, H(2) receptor antagonists, is commonly prescribed for gastric and duodenal ulcer disease. Additionally, cimetidine has been shown to have anticancer effects. This review describes the mechanism of antitumor action of cimetidine including its
ability to interfere with tumor cell adhesion, angiogenesis and proliferation; its effect on the immune system; as well as inhibition of postoperative immunosuppression. Its anticancer effect is also compared to that of the other H(2) receptor antagonists as well as outcomes of cimetidine in clinical studies in cancer patients.
Copyright © 2011 Elsevier B.V. All rights reserved.
Expert Opin Pharmacother. 2005 Jun;6(7):1049-54.
Proton pump inhibitors may reduce tumour resistance.
De Milito A,
Fais S.
Resistance to cytotoxic agents is a major problem in treating cancer. The mechanisms underlying this phenomenon appear to take advantage of functions involved in the control of cell homeostasis.
A mechanism of resistance may be alteration of the tumour microenvironment via changes in the pH gradient between the extracellular environment and the cell cytoplasm. The extracellular pH of solid tumours is significantly more acidic than that of normal tissues, thus impairing the uptake of weakly basic chemotherapeutic drugs and reducing their effect on tumours. An option to revert multi-drug resistance is the use of agents that disrupt the pH gradient in tumours by inhibiting the function of pumps generating the pH gradient, such as vacuolar H(+)-ATPases (V-H(+)-ATPases). PPIs (including omeprazole, esomeprazole, lansoprazole, pantoprazole and rabeprazole) are protonable weak bases which selectively accumulate in acidic spaces. Recent findings from our group have shown that PPI pretreatment sensitised tumour cell lines to the effect of cisplatin, 5-fluoro-uracil and vinblastine V-H(+)-ATPases pump protons across the plasma membrane and across the membranes of various intracellular compartments. Some human tumour cells, particularly those selected for multi-drug resistance, exhibit enhanced V-H(+)-ATPase activity. A class of V-H(+)-ATPase inhibitors, called proton pump inhibitors (PPIs), have emerged as the drug class of choice for treating patients with peptic diseases. These drugs inhibit gastric acid secretion by targeting the gastric acid pump, but they also directly inhibit V-H(+)-ATPases..
PPI pretreatment was associated with the inhibition of V-H(+)-ATPase activity and an increase of both extracellular pH and the pH of lysosomal organelles, consistent with a cytoplasmic retention of the cytotoxic drugs and targeting to the nucleus in the case of doxorubicin. In vivo experiments showed that oral pretreatment with omeprazole induced a sensitivity of the human solid tumours to anticancer drugs.
PMID: 15957961 [PubMed - indexed for MEDLINE]
Int J Cancer. 2009 Oct 28. [Epub ahead of print]
pH-dependent antitumor activity of proton pump inhibitors against human melanoma is mediated by inhibition of tumor acidity.
De Milito A,
Canese R,
Marino ML,
Borghi M,
Iero M,
Villa A,
Venturi G,
Lozupone F,
Iessi E,
Logozzi M,
Mina PD,
Santinami M,
Rodolfo M,
Podo F,
Rivoltini L,
Fais S.
Department of Therapeutic Research and Medicines Evaluation, Unit of Antitumor Drugs, Istituto Superiore di SanitÃ*, Rome, Italy.
Metastatic melanoma is associated with poor prognosis and still limited therapeutic options. An innovative treatment approach for this disease is represented by targeting acidosis, a feature characterizing tumor microenvironment and playing an important role in cancer malignancy. Proton pump inhibitors (PPI), such as esomeprazole (ESOM) are prodrugs functionally activated by acidic environment, fostering pH neutralization by inhibiting proton extrusion. We used human melanoma cell lines and xeno-transplated SCID mice to provide preclinical evidence of ESOM antineoplastic activity. Human melanoma cell lines, characterized by different mutation and signaling profiles, were treated with ESOM in different pH conditions and evaluated for proliferation, viability and cell death. SCID mice engrafted with human melanoma were used to study ESOM administration effects on tumor growth and tumor pH by magnetic resonance spectroscopy (MRS). ESOM inhibited proliferation of melanoma cells in vitro and induced a cytotoxicity strongly boosted by low pH culture conditions. ESOM-induced tumor cell death occurred via rapid intracellular acidification and activation of several caspases. Inhibition of caspases activity by pan-caspase inhibitor z-vad-fmk completely abrogated the ESOM-induced cell death.
ESOM administration (2.5 mg kg(-1)) to SCID mice engrafted with human melanoma reduced tumor growth, consistent with decrease of proliferating cells and clear reduction of pH gradients in tumor tissue. Moreover, systemic ESOM administration dramatically increased survival of human melanoma-bearing animals, in absence of any relevant toxicity. These data show preclinical evidence supporting the use of PPI as novel therapeutic strategy for melanoma, providing the proof of concept that PPI target human melanoma modifying tumor pH gradients.
PMID: 19876915 [PubMed - as supplied by publisher]
J Natl Cancer Inst. 2004 Nov 17;96(22):1702-13.
Effect of proton pump inhibitor pretreatment on resistance of solid tumors to cytotoxic drugs.
Luciani F,
Spada M,
De Milito A,
Molinari A,
Rivoltini L,
Montinaro A,
Marra M,
Lugini L,
Logozzi M,
Lozupone F,
Federici C,
Iessi E,
Parmiani G,
Arancia G,
Belardelli F,
Fais S.
Department of Infectious, Parasitic and Immune-Mediated Diseases, Istituto Nazionale dei Tumori, Milan, Italy.
BACKGROUND: Resistance to antitumor agents is a major cause of treatment failure in patients with cancer.
Some mechanisms of tumor resistance to cytotoxic drugs may involve increased acidification of extracellular compartments. We investigated whether proton pump inhibitors (PPIs), currently used in the anti-acid treatment of peptic disease, could inhibit the acidification of the tumor microenvironment and increase the sensitivity of tumor cells to cytotoxic agents. METHODS: We pretreated cell lines derived from human melanomas, adenocarcinomas, and lymphomas with the PPIs omeprazole, esomeprazole, or pantoprazole and tested their response to cytotoxic drugs in cell death assays. We also evaluated extracellular and intracellular pH and vacuolar-H+-ATPase (V-H+-ATPase) expression, distribution, and activity in PPI-pretreated cells by using western blot analyses, immunocytochemistry, laser scanning confocal analysis, and bioluminescence assays. Finally, we evaluated human melanoma growth and cisplatin sensitivity with or without omeprazole pretreatment in xenografted SCID/SCID mice. RESULTS:
PPI pretreatment sensitized tumor cell lines to the effects of cisplatin, 5-fluorouracil, and vinblastine, with an IC50 value reduction up to 2 logs. PPI pretreatment was associated with the inhibition of V-H+-ATPase activity and increases in both extracellular pH and the pH of lysosomal organelles.
PPI pretreatment induced a marked increase in the cytoplasmic retention of the cytotoxic drugs, with clear targeting to the nucleus in the case of doxorubicin. In in vivo experiments, oral pretreatment with omeprazole was able to induce sensitivity of human solid tumors to cisplatin. CONCLUSION: Our results open new possibilities for the treatment of drug-resistant tumors through combination strategies based on the use of well-tolerated pH modulators such as PPIs.
PMID: 15547183 [PubMed - indexed for MEDLINE]
Cell Biol Int. 2009 Sep;33(9):1008-19. Epub 2009 Jun 6.
Effects and mechanisms of proton pump inhibitors as a novel chemosensitizer on human gastric adenocarcinoma (SGC7901) cells.
Chen M,
Zou X,
Luo H,
Cao J,
Zhang X,
Zhang B,
Liu W.
Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China.
Upregulation of proton extrusion is critical for tumor cell survival in an ischemic microenvironment with a lower extracellular pH (pHe). Lower pHe and higher intracellular pH (pHi) benefit cancer cells for invasion and growth. Vacuolar H(+)-ATPases (V-H(+)-ATPases) play a critical role in regulating the transmembrane pH gradient. Proton Pump Inhibitors (PPI), mainly treating acid-related diseases, could inhibit the expression of V-H(+)-ATPases. We have investigated whether PPI decreases the pHi of the human gastric adenocarcinoma cell line, SGC7901, by inhibiting V-H(+)-ATPases so as to enhance the cytotoxicity of anti-tumor drugs. We have assessed the optimal treatment time, pretreatment dosage of PPI and the possible mechanism of action.
PPI exceeding 10 microg/ml inhibited protein expression of V-H(+)-ATPases in a dose-dependent manner, decreased the pHi value and reversed the transmembrane pH gradient, whereas PPI at final concentration of 1 microg/ml could not. Changes of the pH gradient were positively correlated with PPI concentration. The inhibitory effects of PPI on V-H(+)-ATPases primarily occurs from 12h to 24h after PPI pretreatment (P<0.05). The pHi value of SGC7901 was lowest 24h after PPI pretreatment (P<0.05).
Administration of anti-tumor drugs 24h after PPI pretreatment produced the most cytotoxic effects on SGC7901 (P<0.05) and significantly improved the early and total apoptosis rates (P<0.01). PPI exceeding 20 microg/ml also significantly reduced the ADR-releasing index, thereby enhancing the intracellular ADR concentration (P<0.01). Therefore, PPI could enhance the cytotoxic effects of anti-tumor drugs on the SGC7901 cells.
PMID: 19501661 [PubMed - indexed for MEDLINE]
Am J Med. 2009 Oct;122(10):896-903.
Long-term safety concerns with proton pump inhibitors.
Ali T,
Roberts DN,
Tierney WM.
Department of Internal Medicine, University of Oklahoma, Oklahoma City, OK, USA.
tauseef-ali@ouhsc.edu
Proton pump inhibitors (PPIs) are among the most widely prescribed medications worldwide. Their use has resulted in dramatic improvements in treatment of peptic ulcer disease and gastroesophageal reflux disease. Despite an acceptable safety profile, mounting data demonstrate concerns about the long-term use of PPIs. To provide a comprehensive review regarding the concerns of long-term PPI use, a literature search was performed to identify pertinent original and review articles. Despite study shortcomings,
the collective body of information overwhelmingly suggests an increased risk of infectious complications and nutritional deficiencies. Data regarding any increased risk in gastric or colon malignancy are less convincing. PPIs have revolutionized the management and complications of acid-related disorders with a high margin of safety; however, with the data available, efforts to reduce the dosing of or discontinue the use of PPIs must be reassessed frequently.
PMID: 19786155 [PubMed - indexed for MEDLINE]
Am J Ther. 2008 Nov-Dec;15(6):536-42.
Is there a dark side to long-term proton pump inhibitor therapy?
Nealis TB,
Howden CW.
Divisions of Internal Medicine and Gastroenterology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Proton pump inhibitors (PPIs) are among the most widely used of prescription drugs. They have revolutionized the management of gastroesophageal reflux disease and other acid-related disorders. Although generally safe, concerns about possible adverse effects continue to arise. Some of these, such as gastric neoplasms, are of theoretical concern only and are related to suppression of gastric acid secretion and consequent hypergastrinemia; these have not been encountered in clinical practice despite millions of patient-years of use. Others are more idiosyncratic, unpredictable, and rare. In general, the therapeutic benefits of PPIs outweigh these potential risks. However, it is important that PPIs are only given for appropriate indications and that, whenever possible, they are used in the lowest effective dose. At present, there is no need for specific monitoring for adverse events during PPI therapy.
PMID: 19127138 [PubMed - indexed for MEDLINE]
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Novel approach overlooked
Cimetidine is the generic equivalent of the popular OTC drug better known by the brand name Tagamet. It is used primarily to relieve symptoms of esophageal reflux such as heartburn. Tagamet functions as a histamine (H2) receptor antagonist. What most doctors don't know is that T-lymphocyte suppressor cells have the H2 receptor. By blocking this receptor (using an H2 receptor antagonist such as Tagamet), the immune system can be temporarily turned up to help combat certain cancers and herpes viral infections.
Tagamet is manufactured by SmithKline Pharmaceuticals, headquartered in Philadelphia. When Life Extension asked about Tagamet's potential use in herpes treatment and quizzed about the lack of promotion for same, Carl Friedman from SmithKline's Research and Development Department said, “It [cimetidine] went off patent in 1994. We aren't vested in it anymore, so there's nothing to gain from it.” Echoing his sentiments, Deborah Frutos, from the pharmaceutical company's Corporate Finance and Administration Department said, “There's no incentive for us to promote our less expensive generic [cimetidine]. If we were to do any study for that, it would take lots of time and money. Even if it proved to be a good study, most physicians have other products they'd rather prescribe.” She added, “A grant guarantees that if we prove the drug is indicated for that [treating herpes], the generic would be manufactured and once the patent is protected, anyone can manufacture it. Let's just say we're not going to do it.”
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