PMID- 21155627
OWN - NLM
STAT- MEDLINE
DCOM- 20110110
LR  - 20101215
IS  - 1089-5159 (Print)
IS  - 1089-5159 (Linking)
VI  - 15
IP  - 3
DP  - 2010 Sep
TI  - Manipulating tumor acidification as a cancer treatment strategy.
PG  - 264-72
AB  - Manipulation of the extracellular and/or intracellular pH of tumors may have 
      considerable potential in cancer therapy. The extracellular space of most tumors 
      is mildly acidic, owing to exuberant production of lactic acid. Aerobic 
      glycolysis - attributable largely to chronic activation of hypoxia-inducible 
      factor-1 (HIF-1) - as well as tumor hypoxia, are chiefly responsible for this 
      phenomenon. Tumor acidity tends to correlate with cancer aggressiveness; in part, 
      this reflects the ability of HIF-1 to promote invasiveness and angiogenesis. But 
      there is growing evidence that extracellular acidity per se boosts the 
      invasiveness and metastatic capacity of cancer cells; moreover, this acidity 
      renders cancer cells relatively resistant to the high proportion of 
      chemotherapeutic drugs that are mildly basic, and may impede immune rejection of 
      tumors. Thus, practical strategies for raising the extracellular pH of tumors may 
      have therapeutic utility. In rodents, oral administration of sodium bicarbonate 
      can raise the extracellular pH of tumors, an effect associated with inhibition of 
      metastasis and improved responsiveness to certain cytotoxic agents; clinical 
      application of this strategy appears feasible. As an alternative approach, drugs 
      that inhibit proton pumps in cancer cells may alleviate extracellular tumor 
      acidity while lowering the intracellular pH of cancer cells; reduction of 
      intracellular pH slows proliferation and promotes apoptosis in various cancer 
      cell lines. Well-tolerated doses of the proton pump inhibitor esomeprazole have 
      markedly impeded tumor growth and prolonged survival in nude mice implanted with 
      a human melanoma. Finally, it may prove feasible to exploit the aerobic 
      glycolysis of cancers in hyperacidification therapies; intense intracellular 
      acidification of cancer cells achieved by induced hyperglycemia, concurrent 
      administration of proton pump inhibitor drugs, and possibly dinitrophenol, may 
      have the potential to kill cancer cells directly, or to potentiate their 
      responsiveness to adjunctive measures. A similar strategy, but without proton 
      pump inhibition, could be employed to maximize extracellular tumor acidity, 
      enabling tumor-selective release of cytotoxic drugs encased in pH-sensitive 
      nanoparticles.
FAU - McCarty, Mark F
AU  - McCarty MF
AD  - Oasis of Hope Hospital and Whitaker Wellness Institute. markfmcarty@gmail.com
FAU - Whitaker, Julian
AU  - Whitaker J
LA  - eng
PT  - Journal Article
PT  - Review
PL  - United States
TA  - Altern Med Rev
JT  - Alternative medicine review : a journal of clinical therapeutic
JID - 9705340
RN  - 0 (Antineoplastic Agents, Alkylating)
RN  - 0 (Proton Pump Inhibitors)
MH  - Acid-Base Equilibrium/*drug effects
MH  - Animals
MH  - Antineoplastic Agents, Alkylating/*pharmacology/therapeutic use
MH  - Apoptosis/drug effects
MH  - Cell Proliferation/drug effects
MH  - Humans
MH  - Hydrogen-Ion Concentration/drug effects
MH  - Lymphoma/*drug therapy/metabolism
MH  - Melanoma/*drug therapy/metabolism
MH  - Mice
MH  - Proton Pump Inhibitors/*pharmacology/therapeutic use
EDAT- 2010/12/16 06:00
MHDA- 2011/01/11 06:00
CRDT- 2010/12/16 06:00
PHST- 2010/12/16 06:00 [entrez]
PHST- 2010/12/16 06:00 [pubmed]
PHST- 2011/01/11 06:00 [medline]
PST - ppublish
SO  - Altern Med Rev. 2010 Sep;15(3):264-72.