SAMe may be a bad idea for aromatase inhibitor arthralgia; a really bad idea
Jacob Schor, ND, FABNO
September 5, 2015
A medical oncologist here in Denver, who I respect immensely, has been suggesting to his breast cancer patients, who are taking aromatase inhibitors (AI), that they might try taking the nutritional supplement SAMe in order to relieve some of the drug’s unwanted side effects, in particular the arthralgia often associated with AI use. While this may sound like a good idea at first consideration, there are some concerns about using this supplement for this patient group that I will attempt to explain here.
S-adenosylmethionine, or SAMe for short, is made in the body and is a chemical intermediary in a pathway called the transmethylation pathway (aka e the SAM cycle, the methionine cycle or the homocysteine cycle depending on from what perspective you look at it.) Methionine is converted to SAM on it’s way to becoming homocysteine. Or one might say homocysteine is broken down in combination with the aid of vitamin B-12 and folate (actually mthyl-hydoxy folate) and betaine into first methionine and then this becomes SAMe.
They say a picture is worth a thousand words so take a look at these two diagrams and this may save a few words:
SAMe is a relatively common nutritional supplement these days. It is often promoted to reduce pain from osteoarthritis. Some clinical trials suggest benefit  though not all do.  A 2006 Cochrane Review, that is a formalized systematic meta-analysis of past studies, concluded that the evidence was still inconclusive as to whether SAMe helped at all.
Aromatase inhibiting drugs used to treat breast cancer have a solid reputation for causing a type of joint pain quite reminiscent of osteoarthritis.  Thus one can see why using SAMe might seem a reasonable suggestion; it might help.
There’s another reason why SAMe might seem worth considering. There are published studies that suggest it may make chemotherapy more effective at stopping cancer cells.
Going back to 1994, we find a report that SAMe might reduces the heart damage caused as collateral damage when using doxorubicin. 
Despite these favorable reports, a paper from 2012 leaves me hesitant to feel comfortable about women taking SAMe during the same period of time they are taking aromatase inhibitors.
My caution comes from a paper by Keith Booher and colleagues from the University of California, Irvine, that was published in Cell Cycle in which they describe the impact of SAMe and its near relatives on cancer cells.  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3552924/
Both methionine and homocysteine are metabolites in the transmethylation pathway and lead to the synthesis of SAMe. Most cancer cells will stop growing under ‘methionine stress conditions’, that is when methionine is in short supply, even if it is provided with homocysteine, methionine’s immediate precursor in the pathway. Normal cells (non-cancerous cells) are able to grow under these same conditions, that is a shortage of methionine along as they have a supply of homocysteine.
This knowledge is fast becoming an attractive target in cancer therapy. Attempts are being made through diet and drugs to deplete methionine as a way to treat cancer.
Booher carefully selected breast cancer cells that would still grow normally while deprived with methionine but supplied with homocysteine. Typically breast cancer cells will not be able to grow under these conditions. Remarkably though, or more accurately, disturbingly, giving these selected cells SAMe allowed them to overcome their hesitancy to grow. Where we once thought that methionine deficiency was limiting breast cancer cell growth, these results, at least in Booher’s interpretation, is that this growth inhibition is actually a result of low levels of SAMe rather than low methionine.
My simple explanation to patients is going to be that breast cancer cells love methionine more than any other amino acid (perhaps an exaggeration) and that because SAMe supplies them with a concentrated easy to access dose of methionine, it will make them grow faster. Perhaps I may be distorting the chemistry slightly but the end result is the same. SAMe helps breast cancer cells grow so it’s better that women being treated for this cancer avoid use of this supplement.
There is another way to look at this that perhaps I should mention though I hesitate knowing that I will confuse some readers. If you do not understand this and need to know how it applies to you, just email me directly.
Recall that in the standard old-fashioned forms of chemotherapy, it is the faster growing cells that are more sensitive to chemotherapy. A January 2015 paper reported that SAMe increased the effect of doxorubicin in killing breast cancer cells in vitro. 
Because SAMe may speed up breast cancer cell growth, the cancer cells were more sensitive to this type of chemo drug. To quote the authors, "The methyl donor S-adenosylmethionine potentiates doxorubicin effects on apoptosis of hormone-dependent breast cancer cell line.” SAMe may speed breast cancer growth and leave it vulnerable to this chemo treatment. So perhaps there is an argument for using SAMe during chemotherapy, but aromatase inhibitors are not chemotherapy.
More about SAMe:
4. Russo S, Filippelli W, Ferraraccio F, Berrino L, Guarino V, Rossi F. Effects of S-adenosylmethionine (SAMe) on doxorubicin-induced cardiotoxicity in the rat. J Med. 1994;25(1-2):65-89.
5. Booher K, Lin DW, Borrego SL, Kaiser P. Downregulation of Cdc6 and pre-replication complexes in response to methionine stress in breast cancer cells.
Cell Cycle. 2012 Dec 1;11(23):4414-23. doi: 10.4161/cc.22767. Epub 2012 Nov 16.
6. Ilisso CP, Castellano M, Zappavigna S, Lombardi A, Vitale G, Dicitore A, Cacciapuoti G, Caraglia M, Porcelli M. The methyl donor S-adenosylmethionine potentiates doxorubicin effects on apoptosis of hormone-dependent breast cancer cell lines. Endocrine. 2015 Jan 11. [Epub ahead of print]