Arginine and Melanoma

Dear Life Enhancement,

Your several pieces about arginine are great and detailed.

I have been seeking, without success, an answer to my question, relevant for practitioners with patients who have had melanoma excision, and therefore are at risk for metastasis for at least 10 years.

Melanoma is auxotrophic for arginine. Is arginine therefore contraindicated for them, despite its proven proximal benefits and the unlikely remote possibility for metastases in these stage 1 or in situ patients?

I am becoming despondent of a reply—I have sent many requests. At least an answer would be courteous, if not definitive. I don’t expect words of infinite and incontrovertible wisdom—just an up-to-date update on the state of the art opinion on this touchy subject. These patients are healthy and worried, and if suggestions were not “gospel,” they still would be appreciated as opposed to the deep silence of self-protective disregard. Disclaimer may be expected and understandable. Disinterest is not.

RJ Glen Ellen, CA

Dear RJ,

Sorry for the delay in getting a response to you. I just received your question, and had not previously seen it. I suspect the LE staff was overwhelmed by the complexity of your question, as I was. I had to do some homework.

Unfortunately, I don’t know if anyone can give you the definitive answer you seek to your question.

Melanoma cells frequently lack argininosuccinate synthetase (see Fig. 1), an essential enzyme for the conversion of citrulline to arginine via the urea cycle.1 As a result, the melanoma cells become dependent on the availability of exogenous arginine for further growth. Arginine deprivation induces apoptosis (cell death which occurs as a normal part of growth or development) in argininosuccinate synthetase (ASS)(−) melanoma cell lines,2,3 and also activates AMPK, which in turn inhibits mTOR activity (which is another potential anti-cancer mechanism).


Figure 1. Crystallographic structure of human argininosuccinate synthetase.
ASS-negative malignant pleural mesothelioma (MPM) cell lines do not grow in arginine-depleted culture medium, while the same cell lines will grow in arginine-containing medium. However ASS-positive cell lines grow in either medium.4Thus, while arginine deprivation therapy inhibits the growth of ASS(-) melanoma and MPM cell lines, and may be a useful approach to the treatment of these tumors, it is not likely to be useful in patients with melanomas which are ASS-positive.

Most of the clinical studies used arginine deprivation therapy in conjunction with, and as a tool to promote, the efficacy of chemotherapeutic drugs. However, the arginine deprivation was not obtained through dietary restriction, but by means of an arginine-depleting drug. The most commonly-used drug to effect arginine depletion is the enzyme arginine deiminase (ADI) bound co-valiantly with polyethylene glycol (PEG). The optimal formulation appears to be succinimidyl succinate (ADI-PEG20).5

There are no studies of which I am aware that involved dietary restriction as a means of effecting arginine deprivation. Nevertheless, if you are ASS(-), it may not be a good idea to tempt fate and potentially aggravate any remaining melanoma cells by providing those cells with exogenous arginine by way of arginine-rich dietary supplements. On the other hand, the benefits of arginine or citrulline supplementation to enhance endothelial function to prevent or treat a variety of age-relate diseases is a sound reason to include them in your regimen. I think the decision must be made on an individual basis.

I hope this clarifies somewhat this still-murky question.

Ward Dean, MD

References

  1. Savaraj N, You M, Wu C, Wangpaichitr M, Kuo MT, Feun LG. Arginine Deprivation, Autophagy, Apoptosis (AAA) for the Treatment of Melanoma. Curr Mol Med. 2010 Jun; 10(4): 405–12.
  2. Savaraj N, Wu C, Kuo M, You M, Wangpaichitr M, Robles C, Spector S, Feun L. The Relationship of Arginine Deprivation, Argininosuccinate Synthetase and Cell Death in Melanoma. Drug Target Insights. 2007;2:119–28.
  3. Feun L, Wu C, Kuo M, Wangpaichitr M, Spector S, Savaraj N. Arginine Deprivation as a Targeted Therapy for Cancer. Curr Pham Des. 2008;14:1049–57.
  4. Szlosarek PW, Klabatsa A, Pallaska A, et al. In vivo loss of expression of argininosuccinate synthetase in malignant pleural mesothelioma is a biomarker for susceptibility to arginine depletion. Clin Cancer Res. 2006;12(23):7126–31.
  5. Yoon JK, Frankel AE, Feun LG, Ekmekcioglu S, and Kim KB. Arginine deprivation therapy for malignant melanoma. Clin Pharmacol. 2013; 5: 11–9.

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