Page 183 - Read Online

Israël. J Cancer Metastasis Treat 2019;5:12 I http://dx.doi.org/10.20517/2394-4722.2018.78 Page 11 of 12

hope that neutralizing these antibodies would give protection. The GABA deficiency may have other causes,
a vitamin B6 deficiency for example, since it is the co-factor for GAD. Indeed, conditions that inhibit GAD
[10]
or neutralize vitamin B6 (pesticides, amines and others) have been found to be carcinogenic ; this is also

the case for diseases that genetically affects GAD. In Stiff person syndrome for example, the neurological

symptoms prevail, but the cancer incidence is more elevated. It would be an interesting perspective to look
for anti-GAD antibodies long before cancer develops and eventually find out procedures for neutralizing
them, and develop “an anticancer vaccination”. It is certainly a difficult project, particularly if we consider
the difficulty encountered for the diabetes type 1 vaccination attempt. Checking GABA metabolism and
preserving this control system of the pancreas that depends of vitamins (B6) and nutrition, might decrease
cancer incidence, particularly if its alteration by pesticides and other compounds that affect GAD is avoided.
Moreover, it might be an interesting perspective to explore the pancreatic GABA system in relation to
cancer, using noninvasive imaging methods for GABA as those developed for brain.

The other more practical perspective is to try to normalize the rewiring process that was presented in
detail, even though many parts were deduced, and require more experimental work. A few compounds
such as isocitrate, lipoic acid and others, gave encouraging results in animal cancer models (the list of
compounds is given in previous publications) [5,11,13,20] . However, only a small number of potentially useful
compounds were tested, in spite of the fact that many more should be given for normalizing the complex
rewiring processes associated to cancer. One would gain to suppress the metabolic advantage given to stem
cells by cutting their supply of ketone bodies; or to block the effect of GH on ATGL, which increases DAG,
[22]
[21]
inhibitors of ATGL have been developed ; or to control the cAMP and AMP ratio, and AMP kinase ; or
[23]
the mitochondria citrate efflux ; or to decrease the DAG activation of PKC, there are several PKC inhibitors
[13]
discussed in reference ; or to inhibit the fatty acid synthesis pathway. A final remark concerns the direct
effects of GABA on pancreatic ductal adenocarcinoma and presumably on other cancers. Apparently, GABA
B receptor activation mediates a decrease of adenylate cyclase that attenuates the progression of pancreatic
[24]
cancer . This does not contradict the fact that a GABA deficiency of Beta cell fails to terminate insulin
release, which desensitizes insulin receptors, while glucagon is released, leading to the described metabolic
rewiring process that initiates cancer.

The best mixtures that will reverse the rewiring process still remain to be compared, in animal cancer
models, then in properly built clinical trials. It is also essential to find an adequate diet and control the
amino acid supplied, in order to attenuate the effects of the metabolic rewiring process in cancer; and then
develop a metabolic treatment with non-toxic mixtures that would normalize cancer metabolism. In our
opinion, this would be useful for backing up, if necessary, present cancer therapies.

DECLARATIONS
Authors’ contributions
Israël M solely contributed to this study.

Availability of data and materials
Not applicable.

Financial support and sponsorship
None.

Conflicts of interest
The author declared that there are no conflicts of interest.

Ethical approval and consent to participate
Not applicable.