PMID- 26972280
OWN - NLM
STAT- MEDLINE
DCOM- 20170216
LR  - 20170216
IS  - 1475-6374 (Electronic)
IS  - 1475-6366 (Linking)
VI  - 31
IP  - 6
DP  - 2016 Dec
TI  - A nonmainstream approach against cancer.
PG  - 882-9
LID - 10.3109/14756366.2016.1156105 [doi]
AB  - The discovery of antibiotics as specific and effective drugs against infectious 
      agents has generated the belief that the famous Paul Erlich theory on magic 
      bullet should be applied to cancer as well. However, after around 60 years of 
      failures in finding a magic bullet against cancer, a question appears mandatory: 
      does the magic bullet against cancer really exist? In trying to understand more 
      on the issue, we propose three discoveries are coming from a nonmainstream 
      approach against cancer. Tumor is acidic, and tumor acidity impairs drugs 
      entering within tumor cells and isolates tumors from the rest of the body. Proton 
      pumps are key in allowing tumor cells to live in the acidic microenvironment. A 
      class of antiacidic drugs, proton pump inhibitors (PPIs), were shown to have a 
      potent anti-tumor effect, through inhibition of proton pumps in tumor cells. PPIs 
      are indeed prodrugs needing acidity to be activated into the active molecule. So 
      they use protonation by H+ as an activating mechanism, while the vast majority of 
      drugs are totally neutralized by protonation. An anti-tumor therapy based on PPI 
      showed to be effective both in vitro and in vivo. Differently from normal cells, 
      cancer cells meet their energy needs in great part by fermentation, and it 
      appears conceivable that hypoxia and low nutrient transform tumor cells into 
      fermenting anaerobes. This suggests that cancer cells are more similar to 
      unicellular organisms, aimed at surviving in a continuous fighting, rather than 
      cooperating, with other cells, as it occurs in the normal homeostasis of our 
      body. We have shown that cancer cells take their fuel by "cannibalizing" other 
      cells, either dead or alive, especially when starved and in acidic condition. 
      This finding led to the discovery of a new oncogene TM9SF4 that human malignant 
      cell shares with amoebas. The evidence is accumulating that almost all the cells 
      release extracellular vehicles (EVs), from micro- to nanosize, which shuttle a 
      variety of molecules. Tumor cells, particularly when stressed in their hostile 
      microenvironment, release high levels of EVs, able to interact with target cells 
      in various ways, within an organ or at a distance. They may represent both 
      valuable tumor biomarker and shuttles for drugs with anti-tumor properties. This 
      article wants to burst a real change in future anti-cancer strategies, based on 
      the idea that tumors are much more common features than specific molecular 
      targets.
FAU - Fais, Stefano
AU  - Fais S
AD  - a Anti-tumor Drug Section, Department of Therapeutic Research, Medicines 
      Evaluation Istituto Superiore di Sanita (National Institute of Health) , Rome , 
      Italy.
LA  - eng
PT  - Journal Article
PT  - Review
DEP - 20160314
PL  - England
TA  - J Enzyme Inhib Med Chem
JT  - Journal of enzyme inhibition and medicinal chemistry
JID - 101150203
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Proton Pump Inhibitors)
RN  - 0 (Proton Pumps)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/chemistry/*pharmacology
MH  - Humans
MH  - Neoplasms/*drug therapy/metabolism/pathology
MH  - Proton Pump Inhibitors/chemistry/*pharmacology
MH  - Proton Pumps/metabolism
OTO - NOTNLM
OT  - Acidity
OT  - cancer nonmainstream
OT  - cannibalism
OT  - exosome
OT  - therapy
EDAT- 2016/03/15 06:00
MHDA- 2017/02/17 06:00
CRDT- 2016/03/15 06:00
PHST- 2016/03/15 06:00 [entrez]
PHST- 2016/03/15 06:00 [pubmed]
PHST- 2017/02/17 06:00 [medline]
AID - 10.3109/14756366.2016.1156105 [doi]
PST - ppublish
SO  - J Enzyme Inhib Med Chem. 2016 Dec;31(6):882-9. doi: 
      10.3109/14756366.2016.1156105. Epub 2016 Mar 14.