Manipulating tumor acidification as a cancer treatment strategy

Husband11

http://www.ncbi.nlm.nih.gov/pubmed/21155627

Oasis of Hope Hospital and Whitaker Wellness Institute. markfmcarty@gmail.com

Abstract

Manipulation of the extracellular and/or intracellular pH of tumors may have considerable potential in cancer therapy. The extracellular space of most tumors is mildly acidic, owing to exuberant production of lactic acid. Aerobic glycolysis - attributable largely to chronic activation of hypoxia-inducible factor-1 (HIF-1) - as well as tumor hypoxia, are chiefly responsible for this phenomenon. Tumor acidity tends to correlate with cancer aggressiveness; in part, this reflects the ability of HIF-1 to promote invasiveness and angiogenesis. But there is growing evidence that extracellular acidity per se boosts the invasiveness and metastatic capacity of cancer cells; moreover, this acidity renders cancer cells relatively resistant to the high proportion of chemotherapeutic drugs that are mildly basic, and may impede immune rejection of tumors. Thus, practical strategies for raising the extracellular pH of tumors may have therapeutic utility. In rodents, oral administration of sodium bicarbonate can raise the extracellular pH of tumors, an effect associated with inhibition of metastasis and improved responsiveness to certain cytotoxic agents; clinical application of this strategy appears feasible. As an alternative approach, drugs that inhibit proton pumps in cancer cells may alleviate extracellular tumor acidity while lowering the intracellular pH of cancer cells; reduction of intracellular pH slows proliferation and promotes apoptosis in various cancer cell lines. Well-tolerated doses of the proton pump inhibitor esomeprazole have markedly impeded tumor growth and prolonged survival in nude mice implanted with a human melanoma. Finally, it may prove feasible to exploit the aerobic glycolysis of cancers in hyperacidification therapies; intense intracellular acidification of cancer cells achieved by induced hyperglycemia, concurrent administration of proton pump inhibitor drugs, and possibly dinitrophenol, may have the potential to kill cancer cells directly, or to potentiate their responsiveness to adjunctive measures. A similar strategy, but without proton pump inhibition, could be employed to maximize extracellular tumor acidity, enabling tumor-selective release of cytotoxic drugs encased in pH-sensitive nanoparticles.

Husband11

http://www.ncbi.nlm.nih.gov/pubmed/21663677 

Bicarbonate and dichloroacetate: evaluating pH altering therapies in a mouse model for metastatic breast cancer.

Robey IF, Martin NK.

Source

Arizona Respiratory Center, University of Arizona, Tucson, USA. robeyi@email.arizona.edu

Abstract

BACKGROUND:

The glycolytic nature of malignant tumors contributes to high levels of extracellular acidity in the tumor microenvironment. Tumor acidity is a driving force in invasion and metastases. Recently, it has been shown that buffering of extracellular acidity through systemic administration of oral bicarbonate can inhibit the spread of metastases in a mouse model for metastatic breast cancer. While these findings are compelling, recent assessments into the use of oral bicarbonate as a cancer intervention reveal limitations.

METHODS:

We posited that safety and efficacy of bicarbonate could be enhanced by dichloroacetate (DCA), a drug that selectively targets tumor cells and reduces extracellular acidity through inhibition of glycolysis. Using our mouse model for metastatic breast cancer (MDA-MB-231), we designed an interventional survival study where tumor bearing mice received bicarbonate, DCA, or DCA-bicarbonate (DB) therapies chronically.

RESULTS:

Dichloroacetate alone or in combination with bicarbonate did not increase systemic alkalosis in mice. Survival was longest in mice administered bicarbonate-based therapies. Primary tumor re-occurrence after surgeries is associated with survival rates. Although DB therapy did not significantly enhance oral bicarbonate, we did observe reduced pulmonary lesion diameters in this cohort. The DCA monotherapy was not effective in reducing tumor size or metastases or improving survival time. We provide in vitro evidence to suggest this outcome may be a function of hypoxia in the tumor microenvironment.

CONCLUSIONS:

DB combination therapy did not appear to enhance the effect of chronic oral bicarbonate. The anti-tumor effect of DCA may be dependent on the cancer model. Our studies suggest DCA efficacy is unpredictable as a cancer therapy and further studies are necessary to determine the role of this agent in the tumor microenvironment.

Husband11

http://www.ncbi.nlm.nih.gov/pubmed/19276390

Cancer Res. 2009 Mar 15;69(6):2260-8. Epub 2009 Mar 10.

Bicarbonate increases tumor pH and inhibits spontaneous metastases.

Robey IF, Baggett BK, Kirkpatrick ND, Roe DJ, Dosescu J, Sloane BF, Hashim AI, Morse DL, Raghunand N, Gatenby RA, Gillies RJ.

Source

Arizona Cancer Center, University of Arizona, Tucson, Arizona, USA.

Abstract

The external pH of solid tumors is acidic as a consequence of increased metabolism of glucose and poor perfusion. Acid pH has been shown to stimulate tumor cell invasion and metastasis in vitro and in cells before tail vein injection in vivo. The present study investigates whether inhibition of this tumor acidity will reduce the incidence of in vivo metastases. Here, we show that oral NaHCO(3) selectively increased the pH of tumors and reduced the formation of spontaneous metastases in mouse models of metastatic breast cancer. This treatment regimen was shown to significantly increase the extracellular pH, but not the intracellular pH, of tumors by (31)P magnetic resonance spectroscopy and the export of acid from growing tumors by fluorescence microscopy of tumors grown in window chambers. NaHCO(3) therapy also reduced the rate of lymph node involvement, yet did not affect the levels of circulating tumor cells, suggesting that reduced organ metastases were not due to increased intravasation. In contrast, NaHCO(3) therapy significantly reduced the formation of hepatic metastases following intrasplenic injection, suggesting that it did inhibit extravasation and colonization. In tail vein injections of alternative cancer models, bicarbonate had mixed results, inhibiting the formation of metastases from PC3M prostate cancer cells, but not those of B16 melanoma. Although the mechanism of this therapy is not known with certainty, low pH was shown to increase the release of active cathepsin B, an important matrix remodeling protease.

jenlee

Timothy, 

I am a newbie, not at all qualified to respond to your post.  It seems as though this is great research, but hasn't moved into treatment yet.  There are, however, websites about keeping a low acid - high alkaline diet as a cancer prevention & reduction tool....  Here's one:  http://www.chimachine4u.com/AA.html 

I never knew if there was an scientific basis for this theory, or just quackery.  So after reading their study, maybe there's something to it!  They also sell the "Chi Machine" which is meant to increase cellular oxygen.  I laughed at this too, but you never know.

Husband11

It's too early to say whether there is any application for the research on human breast cancer patients.  It is interesting to see that there is basis in fact for the idea that oral consumption of sodium bicarbonate can have an effect on the ph of a cancerous tumour, and this might influence the tumour.  Mistakedly, I once scoffed at the notion.  I believe its wise to avail oneself of proven treatments, and not forgo them based on false hopes of an alternative.  That said, there may be room for this as a complementary therapy, in the event it proves at the least to have no detrimental effect.

jenlee

I thought sodium bicarbonate sounded familiar -- baking soda?  Also an ingredient in some actacids. Some have been told to take actacids during chemo...  I'm going to check the ingredients on my collection of antacids.  

Kaara

I am currently following a high alkaline diet composed mainly of veggies, fruits, nuts and lean proteins like fish.  The goal is to keep my body in an alkaline state so that the cancer cells have difficulty growing.  Some of the studies you refer to tend to support this theory.  The diet has done me no harm and I feel much better.

barbiecorn

What is the best way of testing for acid in the body.  I bought the urine test strips and am following the diet and it seems that even with the baking soda, my ph is around 6-6.5 - when I take my pepcid which I need for stomach issues (acid reflux) had ondoscopy diagnosis - the pecid brings me into a high alkaline state.  I take it once a day for my acid reflux and it works well.  Any other methods for bringing the ph up?

Kaara

barbiecorn:  Following an alkaline diet of lots of green veggies, eliminating sugars and starches, which are very acidic, as well as red meat helps.  We do a lot of juicing and smoothies using green veggies, which will bring your alkaline levels up quickly.

Sometimes it takes a while to get there if your body has been acidic for a long time. 

Heidihill

Interesting. Thanks for posting, Timothy. Isn't aspirin acidic?  I suppose aspirin may prevent tumor formation and baking soda can reduce tumor size once formed. Many fruits and veggies also contain salicylate. Maybe the best strategy is to combine aspirin and baking soda. Lol. Now I'll have to buy those strips.

Kaara

I was about to start taking the asprin and then read up on it and found out it can cause a retinal hemorrage in people who have wet macular degeneration, which I have...yikes!  We need to check and cross check everything with all our health issues.

Heidihill

Sorry about that, Kaara. I stopped aspirin too because I was taking a plant extract for asthma (Umckaloabo) and fish oil for hayfever. Both are blood thinners.

dunesleeper

I think magnesium helps make your ph more alkaline. I read recently that the alkaline environment permits oxygen to penetrate our cells deeply. Cancer cells are anaerobic. So the increased oxygen is what kills them.

Now, where do you get the ph strips that give actual numbers? I have some strips but it just gives an idea by color of where you are on the ph scale.

Kaara

dunesleeper:  All I have are the color strips....didn't know the others existed.  I'll ask my son who is an avid alkaline foodie...he was on me for years to change my diet to one of more alkaline.  If you google Dr. Young, you might be able to find out because he is a huge advocate of the alkaline diet.

If you cut out all white starches and sugars, white flour, etc. and stick with fruits, veggies and lean protein, your body will become more alkaline.  We did a juice cleanse for about a week, then went on this diet and have been on it since October of 2011.  The results have been remarkable.  I've lost about 12 pounds (I was normal weight I thought) and the boyfriend has lost 20 pounds!  I had so much energy until the tamoxifen took a toll on that temporarily.  The main place I lost weight was around my middle where the body stores estrogen in women.  That has to be a benefit for ER+ bc. 

MsBliss

Thank you Timothy, very interesting study. Tumors have a way of acidifying their micro environment, and attempted therapies to alkalize seem to stimulate a kind of blow back response wherein the tumors amplify this acidic response. The paper seemed to indicate they are trying a method that will counter this effect. Here's hoping.



I actually went to the Whitaker Institute many years ago as a patient. While there, I met a woman who had a stroke. Her neck veins were like pencils and she looked very gray in skin tone. When I saw her four months later, the therapy they had used on her was kind of miraculous. Her neck was smooth with no evidence of sclerotic veins, and her color was pink and healthy looking. She looked fully recovered and had been enjoying good health.

dunesleeper

Kaara, can you tell me more about the juice cleanse? I don't have a juicer, so if I need one, is there one you would recommend? I know the Gerson diet requires a special juicer, but I'm not doing that. And congrats on losing around your middle. That is indeed so important.

Kaara

dunesleeper:  I didn't mean to ignore your post...it was lost somehow until this new format.  The juicer I have is the Champion but it is cumberson.  More recently we converted to a Vita Mix blender which will blend everything to the consistency of a smoothie.  In doing this you get the valuable pulp as well as the juice and the machine is so much easier to clean.  It also makes blended soups, chops, mills flour, etc.  It will do everythng a food processor will do and more.

If you're dead set on having the juicer, I would go with the Omega.  Hope this helps. 

Anonymous

Dune, Vitamix is the ultimate !  No waste, you get your much needed fiber as the machine reduces everything to a pulp.  You can make your own nut butters, etc., awesome machine 

http://www.vitamix.com/ 

dunesleeper

Thanks ladies for the info on the Vitamix.

fredntan

Is there a website to help me understand this stuff?



I recently checked out library book that maybe helpful. But its called Ani's Raw Food Essentionals by Anni Phyo.

She doesnt talk about PH.

Kaara

Fredntan:  If you google alkaline diet you will get lots of information on who promotes it and sites that give you more information.  Anyone who follows a diet that consists of no sugar or white carbs and focuses on veggies and fruits, nuts and seeds, plus lean protein, will become more alkaline.  There are test strips you can buy in the health food stores to test you alkalinity in your body.  If nothing else, you are guaranteed to feel better and lose some weight if you need to.

Anonymous

fredntan: this chart is a good start (simple enough), let me know what you think

www.rense.com/1.mpicons/acidalka.htm