Document Detail


Proton pump inhibitor-induced tumour cell death by inhibition of a detoxification mechanism.
MedLine Citation:
PMID:  20433578     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
This review presents a possible new approach against cancer, as represented by inhibition of proton pumps, a mechanism used by tumour cells to avoid intracellular accumulation of toxic substances. Proton pump inhibitors (PPIs) belong to a family of pro-drugs that are currently used in the treatment of peptic diseases needing acidity to be activated. PPIs target the acidic tumour mass, where they are metabolized, thus blocking proton traffic. Proton pump inhibition triggers a rapid cell death as a result of intracellular acidification, caspase activation and early accumulation of reactive oxygen species into tumour cells. As a whole, the devastating effect of PPIs on tumour cells suggest the triggering of a fatal cell toxification. Many human tumours, including melanoma, osteosarcoma, lymphomas and various adenocarcinomas are responsive to PPIs. This appears highly conceivable, in as much as almost all human tumours are acidic and express high levels of proton pumps. Paradoxically, metastatic tumours appear to be more responsive to PPIs being more acidic than the majority of primary tumours. However, two clinical trials test the effectiveness of PPIs in chemosensitizing melanoma and osteosarcoma patients. Indeed, tumour acidity represents a very potent mechanism of chemoresistance. A majority of cytotoxic agents, being weak bases, are quickly protonated outside and do not enter the cells, thus preventing drugs to reach specific cellular targets. Clinical data will provide the proof of concept on the use of PPIs as a new class of antitumour agent with a very low level of systemic toxicity as compared with standard chemotherapeutic agents.
Authors:
S Fais
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Review    
Journal Detail:
Title:  Journal of internal medicine     Volume:  267     ISSN:  1365-2796     ISO Abbreviation:  J. Intern. Med.     Publication Date:  2010 May 
Date Detail:
Created Date:  2010-05-03     Completed Date:  2010-06-14     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8904841     Medline TA:  J Intern Med     Country:  England    
Other Details:
Languages:  eng     Pagination:  515-25     Citation Subset:  IM    
Affiliation:
Anti-Tumour Drugs Section, Department of Therapeutic Research and Medicines Evaluation, Istituo Superiore di Sanit? (National Institute of Health), Rome, Italy. stefano.fais@iss.it
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / pharmacology*,  therapeutic use
Apoptosis / drug effects*,  physiology
Extracellular Space / chemistry
Humans
Hydrogen-Ion Concentration
Intracellular Space / chemistry
Neoplasm Metastasis
Neoplasms / drug therapy*
Proton Pump Inhibitors / pharmacology*,  therapeutic use
Proton Pumps / chemistry
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Proton Pump Inhibitors; 0/Proton Pumps

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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