New drug for all types of cancer?

[Clara]

"Cheap, safe drug kills most cancers..."
http://www.newscientist.com/article/...t-cancers.html

[AlaskaAngel]

Hello Barcelona Clara! Very interesting post. I wonder if it is just coincidence that a number of us managed to deliberately achieve significant weight loss within a year or two prior to being diagnosed, as discussed recently in the main forum. Maybe we had been forcing more cellular glycolysis at the time, perhaps at a time when hormonally we were more vulnerable to cancer estrogenically.

AlaskaAngel

P.S. I still think a lot of treatment for bc misses the boat because there is so little focus on the endocrine system, including how it operates on metabolism...

[Christine MH-UK]

I think the article was perhaps too pessimistic at the end about funding. I know that the charity Cancer Research UK has recently announced that it will be supporting studies using non patented medicines, so that would be one source of funding. Of course, in the US the National Cancer Institute has been a generous funder of trials.

[AlaskaAngel]

A brief article commenting about recent research conclusions regarding proposed use of dichloroacetate for the congenital disease MELAS:

http://rarediseases.about.com/b/a/257426.htm

Pessimistic review:

http://www.deanesmay.com/posts/1169297117.shtml

The number of people who make money from cancer is pretty huge, including faces we see every day. What do those faces have to say about DCA?

AlaskaAngel

[Clara]

Well, I even found a study in Pubmed saying that DCA can induce liver cancer, so may be it's not that safe (but isn't cancer also a possible side effect of chemotherapy and radiotherapy?)
Anyway, here is the researcher's web page:

http://www.depmed.ualberta.ca/dca/



Whatever happens, it's nice to watch the videos! I found it uplifting.
Best wishes to you all

[AlaskaAngel]

If it has real merit, the cat is out of the bag and despite any bureaucratic aggravations, a way will be found eventually. Both government and private enterprise have a vested interest in anything that would save enough money on health care to make it happen.

AlaskaAngel

[Merridith]

Interesting article. Especially for people who are coming to the end of their options.

I know that I for one would be willing to take a chance on a drug like this..... one that has already been tried in humans with very few side effects. I mean, a few side effects seem to be a lot less threatening next to the chance of winning a terminal disease, versus the guarantee of letting the disease win.

I'll bet it won't be long before dichloroacetate (DCA), shows up in a country near you............Mexico, India or China.

I am also optimistic that a drug this promising will be getting a lot of public support and donations. Think of the "Walk to End Breast Cancer" that is coming up fairly soon...............that raises MILLIONS all around the world. What if it just this once went to fund this particular drug? We can do this. It will happen.

Let's keep our fingers crossed that THIS is the winner!

Good luck to all,
Merridith

[Christine MH-UK]

From the University of Alberta Department of Medicine: http://www.depmed.ualberta.ca/dca/ . I put the interesting bit into bold:

Investigators at the University of Alberta have recently reported that a drug previously used in humans for the treatment of rare disorders of metabolism is also able to cause tumor regression in a number of human cancers growing in animals. This drug, dichloroacetate (DCA), appears to suppress the growth of cancer cells without affecting normal cells, suggesting that it might not have the dramatic side effects of standard chemotherapies.
At this point, the University of Alberta, the Alberta Cancer Board and Capital Health do not condone or advise the use of dichloroacetate (DCA) in human beings for the treatment of cancer since no human beings have gone through clinical trials using DCA to treat cancer. However, the University of Alberta and the Alberta Cancer Board are committed to performing clinical trials in the immediate future in consultation with regulatory agencies such as Health Canada. We believe that because DCA has been used on human beings in Phase 1 and Phase 2 trials of metabolic diseases, the cancer clinical trials timeline for our research will be much shorter than usual."

[AlaskaAngel]

I think the practice of conducting tests first on humans with mets and last on the newly diagnosed has one possible serious flaw, and that is, that most of the things tried on mice are then tried on humans whose cells have been whacked but good by various treatments. So I just hope they use this mitochondria waker-upper first on human mitochondria that are just sleeping and not chemo/rads-mutations....

AlaskaAngel

[heblaj01]

AlaskaAngel,
I understand your point that trying experimental drugs on advanced disease runs the risk of total failure which may stop further research & perhaps prevents finding their potential on early disease.
But using patients with early stage disease in clinical trials would be of no concern if the disease were not a deadly one. And since there are usually effective treatments for these patients, putting them through an uncertain process is a potentially high risk choice for the patient & an ethical problem for the prescribing MD who is supposed,before all, to cause no harm.

On the other hand for patients who have exhausted all approved treatments & are in dire condition, I don't understand why it is almost never possible to get access to an experimental treatment. Except, maybe,this is the result of the fear of legal procedures by the medical community & by the government agencies.

[AlaskaAngel]

Yes, it is a question of balancing risks and benefits. But in the case of DCA, where the risks have already been established in patients and it is FDA approved for other purposes, I hope to goodness the tests are done on the newly diagnosed so that we don't miss the boat entirely on this one just because we "always" test patients with mets first instead of patients who correlate to the mice, whose cells have never been compromised by other therapies first.

AlaskaAngel

[Christine MH-UK]

The University of Alberta's medical school website http://www.depmed.ualberta.ca/dca/has a section of their website that provides all of the articles. After reading them, I can see why this is a big deal. Apparently because DCA has been safely used in humans, including children before, this could get into use fairly quickly. I figure that if it works this could help some cancer patients who currently lack good treatments, such as patients in the world's poorest countries, and those who suffer more from very harsh treatments, such as children and the very old.

The scientists need to get approval for a trial and the money together as well. They are trying to raise at least some of the money necessary through their website. It's nice to see a scientists at least try to get a trial moving on a non-patented medicine. The strategy I am using is to give them a little now so they can do their phase I/II trial and then, if it works out, I will give them more.

http://www.depmed.ualberta.ca/dca/

[Rich66]

Source for purchase: http://www.pharma-dca.com/dca.html

1: Br J Cancer. 2008 Oct 7;99(7):989-94. Epub 2008 Sep 2. Links

Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer.

Michelakis ED, Webster L, Mackey JR.
Department of Medicine, University of Alberta, Edmonton, Canada. evangelos.michelakis@capitalhealth.ca
The unique metabolism of most solid tumours (aerobic glycolysis, i.e., Warburg effect) is not only the basis of diagnosing cancer with metabolic imaging but might also be associated with the resistance to apoptosis that characterises cancer. The glycolytic phenotype in cancer appears to be the common denominator of diverse molecular abnormalities in cancer and may be associated with a (potentially reversible) suppression of mitochondrial function. The generic drug dichloroacetate is an orally available small molecule that, by inhibiting the pyruvate dehydrogenase kinase, increases the flux of pyruvate into the mitochondria, promoting glucose oxidation over glycolysis. This reverses the suppressed mitochondrial apoptosis in cancer and results in suppression of tumour growth in vitro and in vivo. Here, we review the scientific and clinical rationale supporting the rapid translation of this promising metabolic modulator in early-phase cancer clinical trials.
PMID: 18766181 [PubMed - indexed for MEDLINE]

1: Breast Cancer Res Treat. 2009 Jun 19. [Epub ahead of print] Links

Reversal of the glycolytic phenotype by dichloroacetate inhibits metastatic breast cancer cell growth in vitro and in vivo.

Sun RC, Fadia M, Dahlstrom JE, Parish CR, Board PG, Blackburn AC.
Molecular Genetics Group, John Curtin School of Medical Research, Australian National University, P.O. Box 334, Canberra, 2601, Australia.
The glycolytic phenotype is a widespread phenomenon in solid cancer forms, including breast cancer. Dichloroacetate (DCA) has recently been proposed as a novel and relatively non-toxic anti-cancer agent that can reverse the glycolytic phenotype in cancer cells through the inhibition of pyruvate dehydrogenase kinase. We have examined the effect of DCA against breast cancer cells, including in a highly metastatic in vivo model. The growth of several breast cancer cell lines was found to be inhibited by DCA in vitro. Further examination of 13762 MAT rat mammary adenocarcinoma cells found that reversal of the glycolytic phenotype by DCA correlated with the inhibition of proliferation without any increase in cell death. This was despite a small but significant increase in caspase 3/7 activity, which may sensitize cancer cells to other apoptotic triggers. In vivo, DCA caused a 58% reduction in the number of lung metastases observed macroscopically after injection of 13762 MAT cells into the tail vein of rats (P = 0.0001, n >/= 9 per group). These results demonstrate that DCA has anti-proliferative properties in addition to pro-apoptotic properties, and can be effective against highly metastatic disease in vivo, highlighting its potential for clinical use.
PMID: 19543830

Proc Natl Acad Sci U S A. 2009 Dec 29;106(52):22199-204. Epub 2009 Dec 10.
Mitaplatin, a potent fusion of cisplatin and the orphan drug dichloroacetate.

Dhar S, Lippard SJ.
Department of Chemistry and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
The unique glycolytic metabolism of most solid tumors, known as the Warburg effect, is associated with resistance to apoptosis that enables cancer cells to survive. Dichloroacetate (DCA) is an anticancer agent that can reverse the Warburg effect by inhibiting a key enzyme in cancer cells, pyruvate dehydrogenase kinase (PDK), that is required for the process. DCA is currently not approved for cancer treatment in the USA. Here, we present the synthesis, characterization, and anticancer properties of c,t,c-[Pt(NH(3))(2)(O(2)CHCl(2))(2)Cl(2)], mitaplatin, in which two DCA units are appended to the axial positions of a six-coordinate Pt(IV) center. The negative intracellular redox potential reduces the platinum to release cisplatin, a Pt(II) compound, and two equivalents of DCA. By a unique mechanism, mitaplatin thereby attacks both nuclear DNA with cisplatin and mitochondria with DCA selectively in cancer cells. The cytotoxicity of mitaplatin in a variety of cancer cell lines equals or exceeds that of all known Pt(IV) compounds and is comparable to that of cisplatin. Mitaplatin alters the mitochondrial membrane potential gradient (Deltapsi(m)) of cancer cells, promoting apoptosis by releasing cytochrome c and translocating apoptosis inducing factor from mitochondria to the nucleus. Cisplatin formed upon cellular reduction of mitaplatin enters the nucleus and targets DNA to form 1,2-intrastrand d(GpG) cross-links characteristic of its own potency as an anticancer drug. These properties of mitaplatin are manifest in its ability to selectively kill cancer cells cocultured with normal fibroblasts and to partially overcome cisplatin resistance.

PMID: 20007777 [PubMed - in process]


On the other hand....


Cancer Chemother Pharmacol. 2010 May 26. [Epub ahead of print]
Dichloroacetate metabolically targeted therapy defeats cytotoxicity of standard anticancer drugs.

Heshe D, Hoogestraat S, Brauckmann C, Karst U, Boos J, Lanvers-Kaminsky C.
Department of Paediatric Haematology and Oncology, University Children's Hospital, Albert-Schweitzer Str. 33, 48149, Muenster, Germany.
Abstract

PURPOSE: The observation that the orphan drug dichloroacetate (DCA) selectively promotes mitochondria-regulated apoptosis and inhibits tumour growth in preclinical models by shifting the glucose metabolism in cancer cells from anaerobic to aerobic glycolysis attracted not only scientists', clinicians' but also patients' interests and prompted us to further evaluate DCA effects against paediatric malignancies. METHODS: The effects of DCA on mitochondrial membrane potential (DeltaPsim), cell viability and induction of apoptosis were evaluated in paediatric tumour cell lines and the non-malignant cell line HEK293. In addition, combinations of DCA with the standard anticancer drugs cisplatin, doxorubicin, and temozolomide were tested and intra- and extra-cellular platinum species analysed. RESULTS: DCA selectively induced phosphatidylserine externalisation and reduced DeltaPsim in paediatric tumour cells compared to HEK293 cells, but DCA concentrations DCA neither influenced the in vitro stability of cisplatin nor the cellular cisplatin uptake, but it abrogated the cytotoxicity of cisplatin in 7 out of 10 cell lines. DCA also affected the cytotoxicity of doxorubicin but did not influence the cytotoxicity of temozolomide. Despite phosphatidylserine externalisation, DCA failed to activate caspase 3/7 and, moreover, suppressed caspase 3/7 activation by cisplatin and doxorubicin. CONCLUSIONS: Our results indicate that apart from the intriguing effects of DCA on the glucose metabolism of cancer cells, the use of DCA for cancer treatment has to be evaluated carefully. Moreover, compassionate use of the orally available drug by patients with cancer themselves without medical supervision is strongly discouraged at present.

PMID: 20502900 [PubMed - as supplied by publisher]



Cancer Lett. 2010 May 25. [Epub ahead of print]
Sodium dichloroacetate (DCA) reduces apoptosis in colorectal tumor hypoxia.

Shahrzad S, Lacombe K, Adamcic U, Minhas K, Coomber BL.
Department of Biomedical Sciences, University of Guelph, Guelph, ON, Canada N1G 2W1.
Abstract

We examined the effect of hypoxia on apoptosis of human colorectal cancer (CRC) cells in vitro and in vivo. All cell lines tested were susceptible to hypoxia-induced apoptosis. DCA treatment caused significant apoptosis under normoxia in SW480 and Caco-2 cells, but these cells displayed decreased apoptosis when treated with DCA combined with hypoxia, possibly through HIF-1alpha dependent pathways. DCA treatment also induced significantly increased growth of SW480 tumor xenografts, and a decrease in TUNEL positive nuclei in hypoxic but not normoxic regions of treated tumors. Thus DCA is cytoprotective to some CRC cells under hypoxic conditions, highlighting the need for further investigation before DCA can be used as a reliable apoptosis-inducing agent in cancer therapy. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

PMID: 20537792 [PubMed - as supplied by publisher]

Big ole PDF on DCA:
http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6WWK-4MV1J7C-4-2&_cdi=7133&_user=10&_coverDate=01%2F31%2F2007&_sk=%23TOC%237133%232007%23999889998%23641847%23FL A%23display%23Volume_11,_Issue_1,_Pages_1-98_(January_2007)%23tagged%23Volume%23first%3D11%2 3Issue%23first%3D1%23date%23(January_2007)%23&view=c&_gw=y&wchp=dGLbVlb-zSkzS&md5=f7cc053b9ccdf19c8df8d20ce51ef944&ie=/sdarticle.pdf

Anticancer Res. 2009 Nov;29(11):4579-88.
In vitro effects of dichloroacetate and CO2 on hypoxic HeLa cells.

Anderson KM, Jajeh J, Guinan P, Rubenstein M.
Hektoen Institute LLC, Chicago, IL, USA. Kanderso427@sbcglobal.net
HeLa and PANC-1 cells were exposed to conflicting signals promoting anaerobic or aerobic energy-generating processes and their viability, cell numbers and the ability of HeLa cells to form colonies were assessed. Under conventional aerobic cell culture with 5% CO(2), dichloroacetate (DCA), an inhibitor of the enzyme pyruvate dehydrogense kinase with subsequent stimulation of pyruvate dehydrogenase that redirects energy metabolism toward the Kreb cycle, reduced HeLa and PANC-1 cellular proliferation and viability. With nitrogen-induced hypoxia, the number of control cells and cells cultured with 12.5 mM DCA paradoxically was greater than that of normoxic controls under similar conditions. A higher medium pH of cells cultured under nitrogen contributed to these differences. In 96-well experiments, 95% nitrogen with 5% CO(2) reduced the numbers of hypoxic cells and medium pH toward that of the aerobic controls, with retention of the DCA-induced hypoxic compared to normoxic cell numbers. The media of these cells cultured with DCA still exhibited an increased pH. Increased hypoxia-inducible factor 1, alpha subunit (HIF1A) mRNA expression in hypoxic HeLa cells and their greater reliance on D-glucose for metabolic energy confirmed the reliability of the incubation conditions. Compared with normoxic cells, hypoxic cells initially increased their synthesis of ATP, but once proliferation ceased, this no longer closely correlated with cell numbers. Type 1 apoptosis, which was somewhat greater in hypoxic than normoxic cells, contributed to hypoxia and DCA-induced cell death. Colony counts of hypoxic, DCA-inhibited cells subsequently switched to normoxia exceeded those of similarly treated normoxic DCA cells. Despite inhibition in certain hypoxic environments of pyruvate dehydrogenase kinase by DCA and its contribution to increased cellular apoptosis and necrosis, hypoxic cells generally outnumbered normoxic control cells, as did hypoxic DCA-treated cells compared with comparable DCA-treated normoxic cells. Since in vivo hypoxic cells are considered a major factor contributing to therapeutic failure, and as DCA redirects energy metabolism toward the more energy efficient Kreb citric acid cycle, associated with increased medium (and inferred cellular) pH, similar circumstances in vivo could promote proliferation and survival of hypoxic cell clones with the potential for developing unwanted properties.

PMID: 20032407 [PubMed - indexed for MEDLINE]

http://www.thedcasite.com/ New DCA Websites: Netherlands Italy France

New possible mechanism for DCA synergy with caffeine Link

Colo-Rectal with Mets on Liver Link (6 March 2009)

Brain Cancer Success Story Link (10 February 2009)

Tim's Lymphoma Story Link (20 January 2009)

Vince reports all Sarcoidosis symptoms are now gone. Link (24 Dec 2008)

Update on Kidney Cancer Report
Doctor's reports and scans Link (19 Dec 2008)

Norwegian Glioblastoma-DCA story (updated 3 December 2008)
Link1 Link2 Medicore and recent post

---

OUTRAGE IN BELGIUM! (25 Oct. 2008)

After the news story in the Belgium press of two terminally ill cancer patients who used DCA and are now on the road to recovery, the Belgium people are asking questions. "It has brought a lot commotion in Belgium. All the people are wondering why they haven’t heard from DCA any sooner! And they wonder why it isn’t recognized yet as an official medicine for cancer! They are shocked!" (additional Belgium link) (Google-translated English versions 1, 2)

More Dutch DCA + cancer articles:
http://galgangcarcinoom.blogspot.com...reeg-papa.html(English translation) This article discusses the press coverage of DCA

http://uwchemo.nl/alternatieve-genee...eneest-kanker/
(English translation) This doctor says he was cured of prostate cancer for 35 Euros

We would like to see the people of Belgium start a campaign to get DCA approved for use there. Please email us and help get things started. We can help connect people interested in starting a political action movement.

---

Colo-Rectal Cancer Story Link (17 November 2008)

Wim Huppes' Prostate Cancer Story Link (14 November 2008)

Gastro-Intestinal Stromal Tumor Link (10 November 2008)

Pancreatic Cancer short report (23 Sept 2008)

Lymphoma Remission Reported.
Scans and doctor's reports included. Link (9 Sept 2008)

Medicor Cancer Centres DCA Reports
Link to their September 2008 Report / December 2007 report

New DCA articles published New paper (April 2009) by Zongjian Zhu et. al., Colorado State U shows "DCA significantly reduced the number of mammary adenocarcinoma per rat" Link --------- Latest 'Michelakis' paper (Sept 2008) ----------- 'Dichloroacetate induces apoptosis in endometrial cancer cells.' link to full text "Dichloroacetate (DCA) Sensitizes Both Wild-Type and Over Expressing Bcl-2 Prostate Cancer Cells In Vitro to Radiation" Link to full text

DCA reports and emails Click here (Updated 20 March 2009) DCA with Caffeine has been connected to a number of remissions, including these: #3, cholangiocarcinoma Click #4, a NSCLC Click #5 canine bladder cancer Click #6 Lymphoma Click Warning: Brain cancer patients who take DCA are at risk. click here

Full DCA-Caffeine Survey Results Click here (updated August 24, 2008)

DCA clinical trials: The Safety and Efficacy of DCA for the Treatment of Brain Cancer Combining Radiotherapy and Temozolomide With Dichloracetate in Patients With Newly Diagnosed Glioblastoma

Welcome to The DCA Site

This site is to help inform people of the exciting research done on DCA by scientists at the University of Alberta. In January 2007, a team of scientists at the University of Alberta published a paper in the scientific journal, Cancer Cell, describing the discovery that a simple, cheap molecule, DCA, worked to reactivate the apoptosis mechanism of cancer cells, causing rapid shrinkage of tumors in rats. Mitochondrial reactivation represents an entirely new approach to treating cancer.

The tumors shrank 70% in three weeks.

DCA is not patentable as a molecule. There is no incentive for private companies to spend the millions of dollars needed to get DCA approved as a cancer treatment by the FDA. This is where we, all of us, need to step in. We intend for TheDCAsite.com to be the meeting place, for the world, where all the important information on DCA is gathered and shared.

This site gives the results of the Michelakis research, a look at the possible side effects of DCA and the prospects of it being used by YOU. We have posted the best summaries we can reach on dosages, side effect concerns and additional measures to take to help you fight cancer. Questions are answered and a chat room is provided.

To avoid any legal issues, we must state we are not doctors and cannot give medical advice.

DCA has not been approved by the Food and Drug Administration for the treatment of cancer. It can be prescribed "off-label" by your physician.
Please note that DCA is not active against all cancers. An excellent analysis by "Willis", which is supported by the limited feedback we are getting, indicates that sarcomas, for example, are not controlled by DCA. (Note. sarcoma patients, read this). However, many cancers are definitely responding to DCA. Non small cell lung cancer patients, even in Stage 4 are showing good responses. We are seeing lymphatic, bladder and other cancers responding very well to DCA.
DCA is serious medicine. Study the material on the site. Read our dosage page.

We want to encourage everyone to use the Chat Room or ask the questions you want answered. We strongly recommend you join and register as a chat room user.
The site was first uploaded late on February 5, 2007. The chat room was added February 8, 2007.

[Rich66]

Sci Transl Med. 2010 May 12;2(31):31ra34.
Metabolic modulation of glioblastoma with dichloroacetate.

Michelakis ED, Sutendra G, Dromparis P, Webster L, Haromy A, Niven E, Maguire C, Gammer TL, Mackey JR, Fulton D, Abdulkarim B, McMurtry MS, Petruk KC.
Department of Medicine, University of Alberta, Edmonton, Alberta, Canada. em2@ualberta.ca
Abstract

Solid tumors, including the aggressive primary brain cancer glioblastoma multiforme, develop resistance to cell death, in part as a result of a switch from mitochondrial oxidative phosphorylation to cytoplasmic glycolysis. This metabolic remodeling is accompanied by mitochondrial hyperpolarization. We tested whether the small-molecule and orphan drug dichloroacetate (DCA) can reverse this cancer-specific metabolic and mitochondrial remodeling in glioblastoma. Freshly isolated glioblastomas from 49 patients showed mitochondrial hyperpolarization, which was rapidly reversed by DCA. In a separate experiment with five patients who had glioblastoma, we prospectively secured baseline and serial tumor tissue, developed patient-specific cell lines of glioblastoma and putative glioblastoma stem cells (CD133(+), nestin(+) cells), and treated each patient with oral DCA for up to 15 months. DCA depolarized mitochondria, increased mitochondrial reactive oxygen species, and induced apoptosis in GBM cells, as well as in putative GBM stem cells, both in vitro and in vivo. DCA therapy also inhibited the hypoxia-inducible factor-1alpha, promoted p53 activation, and suppressed angiogenesis both in vivo and in vitro. The dose-limiting toxicity was a dose-dependent, reversible peripheral neuropathy, and there was no hematologic, hepatic, renal, or cardiac toxicity. Indications of clinical efficacy were present at a dose that did not cause peripheral neuropathy and at serum concentrations of DCA sufficient to inhibit the target enzyme of DCA, pyruvate dehydrogenase kinase II, which was highly expressed in all glioblastomas. Metabolic modulation may be a viable therapeutic approach in the treatment of glioblastoma.

PMID: 20463368 [PubMed - in process]



Oncogene. 2011 Apr 18. [Epub ahead of print]
Role of SLC5A8, a plasma membrane transporter and a tumor suppressor, in the antitumor activity of dichloroacetate.

Babu E, Ramachandran S, Coothankandaswamy V, Elangovan S, Prasad PD, Ganapathy V, Thangaraju M.

FULL TEXT

Source

Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Health Sciences University, Augusta, GA, USA.

Abstract

There has been growing interest among the public and scientists in dichloroacetate (DCA) as a potential anticancer drug. Credible evidence exists for the antitumor activity of this compound, but high concentrations are needed for significant therapeutic effect. Unfortunately, these high concentrations produce detrimental side effects involving the nervous system, thereby precluding its use for cancer treatment. The mechanistic basis of the compound's antitumor activity is its ability to activate the pyruvate dehydrogenase complex through inhibition of pyruvate dehydrogenase kinase. As the compound inhibits the kinase at micromolar concentrations, it is not known why therapeutically prohibitive high doses are needed for suppression of tumor growth. We hypothesized that lack of effective mechanisms for the entry of DCA into tumor cells may underlie this phenomenon. Here we show that SLC5A8 transports DCA very effectively with high affinity. This transporter is expressed in normal cells, but expression is silenced in tumor cells by epigenetic mechanisms. The lack of the transporter makes tumor cells resistant to the antitumor activity of DCA. However, if the transporter is expressed in tumor cells ectopically, the cells become sensitive to the drug at low concentrations. This is evident in breast cancer cells, colon cancer cells and prostate cancer cells. Normal cells, which constitutively express the transporter, are however not affected by the compound, indicating tumor cell-selective therapeutic activity. The mechanism of the compound's antitumor activity still remains its ability to inhibit pyruvate dehydrogenase kinase and force mitochondrial oxidation of pyruvate. As silencing of SLC5A8 in tumors involves DNA methylation and its expression can be induced by treatment with DNA methylation inhibitors, our findings suggest that combining DCA with a DNA methylation inhibitor would offer a means to reduce the doses of DCA to avoid detrimental effects associated with high doses but without compromising antitumor activity.

Oncogene advance online publication, 18 April 2011; doi:10.1038/onc.2011.113.

PMID:

21499304

[Rich66]

PLaceholder...............................

[jhandley]

q10 activates the bcl-2 gene which is responsible for programmed cell suicide. It is well known that Q10 helps the mitachondria function better.