PMID- 25279352
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20141003
LR  - 20211021
IS  - 2234-943X (Print)
IS  - 2234-943X (Electronic)
IS  - 2234-943X (Linking)
VI  - 4
DP  - 2014
TI  - Increasing Superoxide Production and the Labile Iron Pool in Tumor Cells may 
      Sensitize Them to Extracellular Ascorbate.
PG  - 249
LID - 10.3389/fonc.2014.00249 [doi]
LID - 249
AB  - Low millimolar concentrations of ascorbate are capable of inflicting lethal 
      damage on a high proportion of cancer cells lines, yet leave non-transformed cell 
      lines unscathed. Extracellular generation of hydrogen peroxide, reflecting 
      reduction of molecular oxygen by ascorbate, has been shown to mediate this 
      effect. Although some cancer cell lines express low catalase activity, this 
      cannot fully explain the selective sensitivity of cancer cells to hydrogen 
      peroxide. Ranzato and colleagues have presented evidence for a plausible new 
      explanation of this sensitivity - a high proportion of cancers, via NADPH oxidase 
      complexes or dysfunctional mitochondria, produce elevated amounts of superoxide. 
      This superoxide, via a transition metal-catalyzed transfer of an electron to the 
      hydrogen peroxide produced by ascorbate, can generate deadly hydroxyl radical 
      (Haber-Weiss reaction). It thus can be predicted that concurrent measures which 
      somewhat selectively boost superoxide production in cancers will enhance their 
      sensitivity to i.v. ascorbate therapy. One way to achieve this is to increase the 
      provision of substrate to cancer mitochondria. Measures which inhibit the 
      constitutive hypoxia-inducible factor-1 (HIF-1) activity in cancers (such as 
      salsalate and mTORC1 inhibitors, or an improvement of tumor oxygenation), or that 
      inhibit the HIF-1-inducible pyruvate dehydrogenase kinase (such as 
      dichloroacetate), can be expected to increase pyruvate oxidation. A ketogenic 
      diet should provide more lipid substrate for tumor mitochondria. The 
      cancer-killing activity of 42 degrees C hyperthermia is to some degree contingent on an 
      increase in oxidative stress, likely of mitochondrial origin; reports that 
      hydrogen peroxide synergizes with hyperthermia in killing cancer cells suggest 
      that hyperthermia and i.v. ascorbate could potentiate each other's efficacy. A 
      concurrent enhancement of tumor oxygenation might improve results by decreasing 
      HIF-1 activity while increasing the interaction of ascorbic acid with oxygen. An 
      increased pool of labile iron in cancer cells may contribute to the selective 
      susceptibility of many cancers to i.v. ascorbate; antagonism of NF-kappaB 
      activity with salicylate, and intravenous iron administration, could be employed 
      to further elevate free iron in cancers.
FAU - McCarty, Mark Frederick
AU  - McCarty MF
AD  - Oasis of Hope Hospital , Tijuana , Mexico.
FAU - Contreras, Francisco
AU  - Contreras F
AD  - Oasis of Hope Hospital , Tijuana , Mexico.
LA  - eng
PT  - Journal Article
PT  - Review
DEP - 20140916
PL  - Switzerland
TA  - Front Oncol
JT  - Frontiers in oncology
JID - 101568867
PMC - PMC4165285
OTO - NOTNLM
OT  - Haber-Weiss
OT  - ascorbate
OT  - cancer
OT  - dichloroacetate
OT  - elesclomol
OT  - intravenous
OT  - ketosis
OT  - superoxide
EDAT- 2014/10/04 06:00
MHDA- 2014/10/04 06:01
PMCR- 2014/01/01
CRDT- 2014/10/04 06:00
PHST- 2014/07/07 00:00 [received]
PHST- 2014/09/01 00:00 [accepted]
PHST- 2014/10/04 06:00 [entrez]
PHST- 2014/10/04 06:00 [pubmed]
PHST- 2014/10/04 06:01 [medline]
PHST- 2014/01/01 00:00 [pmc-release]
AID - 10.3389/fonc.2014.00249 [doi]
PST - epublish
SO  - Front Oncol. 2014 Sep 16;4:249. doi: 10.3389/fonc.2014.00249. eCollection 2014.