DCA and CancerDCA as a Cancer Treatment - Sodium Dichloroacetate

In addition to the 'original' paper by Drs Archer and Michelakis shown here, other papers are now coming out on DCA and cancer, metabolic pathways and tumor inhibition. We will list these papers here.

1. The 2007 Michelakis paper

2. Dichloroacetate induces apoptosis in endometrial cancer cells.

3. Dichloroacetate (DCA) Sensitizes Both Wild-Type and Over Expressing Bcl-2 Prostate Cancer Cells In Vitro to Radiation

4. Pyruvate kinase M2 is a phosphotyrosine-binding protein

5. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth

6. Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer Michelakis, Webster and Mackey September 2008 Full paper

7. A translational research paradigm by using pharmacological agents that will mimic or couple with dietary energy restriction for breast cancer prevention. Zongjian Zhu, Weiqin Jiang, John N. McGinley, Elizabeth S. Neil, Jennifer L. Sells, Denise K. Rush, Henry J. Thompson. April 2009.

8. Reversal of the glycolytic phenotype by dichloroacetate inhibits metastatic breast cancer cell growth in vitro and in vivo. Ramon C. Sun, Mitali Fadia, Jane E. Dahlstrom, Christopher R. Parish, Philip G. Board, Anneke C. Blackburn June 2009.

9. Mitaplatin, a potent fusion of cisplatin and the orphan drug dichloroacetate. Shanta Dhar and Stephen J. Lippard. August 2009.

10. Investigation on the mechanism of dichloroacetate (DCA) induced apoptosis in breast cancer
L. Ko and J. Allalunis-Turner. 2009.

11. Dichloroacetate (DCA) enhances activities of sorafenib against hepatocellular carcinoma (HCC) via modulation of aberrant cellular metabolism of HCC cells. 2009. (I hear that DCA and sorafenib is a potent combination. See this link too.)

12. Sodium dichloroacetate (DCA) reduces apoptosis in colorectal tumor hypoxia

13. Metabolic Modulation of Glioblastoma with Dichloroacetate. 2010.

14. Dichloroacetate induces apoptosis and cell-cycle arrest in colorectal cancer cells. 2010.

15. Development of a less toxic dichloroacetate analogue by docking and descriptor analysis. 2010

16. Use of Oral Dicholoracetate for Palliation of Leg Pain Arising from Metastatic Poorly Differentiated Carcinoma: A Case Report. 2011.

17. Dichloroacetate (DCA) inhibits neuroblastoma growth by specifically acting against malignant undifferentiated cells. 2011.

18. Some comments given to theDCAsite by Dr. Conti on his paper, "Dichloroacetate (DCA) inhibits neuroblastoma growth by specifically acting against malignant undifferentiated cells."

19. Severe encephalopathy and polyneuropathy induced by dichloroacetate A letter to the Editors. Journal of Neurology Volume 257, Number 12, 2099-2100,.

20. Targeting metabolism with arsenic trioxide and dichloroacetate in breast cancer cells.Mol Cancer. 2011 Nov 18;10(1):142. [Epub ahead of print] Sun RC, Board PG, Blackburn AC. Complete paper.

21. In vitro effects of an in silico-modelled 17β-estradiol derivative in combination with dichloroacetic acid on MCF-7 and MCF-12A cells. Cell Prolif. 2011 Dec;44(6):567-81


A Mitochondria-K+ Channel Axis Is Suppressed in Cancer and Its Normalization Promotes Apoptosis and Inhibits Cancer Growth

Sébastien Bonnet1, Stephen L. Archer1, 2, Joan Allalunis-Turner3, Alois Haromy1, Christian Beaulieu4, Richard Thompson4, Christopher T. Lee5, Gary D. Lopaschuk5, 6, Lakshmi Puttagunta7, Sandra Bonnet1, Gwyneth Harry1, Kyoko Hashimoto1, Christopher J. Porter8, Miguel A. Andrade8, Bernard Thebaud1, 6 and Evangelos D. Michelakis1
1Pulmonary Hypertension Program and Vascular Biology Group, University of Alberta, Edmonton, AB T6G 2B7, Canada
2Department of Physiology, University of Alberta, Edmonton, AB T6G 2B7, Canada
3Department of Oncology, University of Alberta, Edmonton, AB T6G 2B7, Canada
4Department of Biomedical Engineering, University of Alberta, Edmonton, AB T6G 2B7, Canada
5Department of Pharmacology, University of Alberta, Edmonton, AB T6G 2B7, Canada
6Department of Pediatrics, University of Alberta, Edmonton, AB T6G 2B7, Canada
7Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB T6G 2B7, Canada
8Ontario Genomics Innovation Centre, Ottawa Health Research Institute, and Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1N 6N5, Canada

Received 25 November 2005; revised 12 July 2006; accepted 18 October 2006. Published: January 15, 2007. Available online 16 January 2007.

Abstract
The unique metabolic profile of cancer (aerobic glycolysis) might confer apoptosis resistance and be therapeutically targeted. Compared to normal cells, several human cancers have high mitochondrial membrane potential (ΔΨm) and low expression of the K+ channel Kv1.5, both contributing to apoptosis resistance. Dichloroacetate (DCA) inhibits mitochondrial pyruvate dehydrogenase kinase (PDK), shifts metabolism from glycolysis to glucose oxidation, decreases ΔΨm, increases mitochondrial H2O2, and activates Kv channels in all cancer, but not normal, cells; DCA upregulates Kv1.5 by an NFAT1-dependent mechanism. DCA induces apoptosis, decreases proliferation, and inhibits tumor growth, without apparent toxicity. Molecular inhibition of PDK2 by siRNA mimics DCA. The mitochondria-NFAT-Kv axis and PDK are important therapeutic targets in cancer; the orally available DCA is a promising selective anticancer agent.

A complete copy of the paper is available here

There is a link to Supplemental Data at the bottom of the above linked page

click here for a PDF version

List of Abbreviations .

Your guide to reading the paper faster. Maybe cut and paste this into Notepad or another program and print it for fast reference. The paper uses many abbreviations and does not include a guide to abbreviations.

ΔΨm - mitochondrial membrane potential
A549 - A non-small-cell lung cancer cell line (a human lung adenocarcinoma epithelial cell line)
AIF - Apoptosis Inducing Factor
AST - Aspartate aminotransferase
Ca2+ - Calcium ion
DAPI - 4',6-diamidino-2-phenylindole
DCA - Dichloroacetate
DIDS - 4'-diisothiocyano 2,2'-disulfonic acid
Em - plasma membrane potential
ETC - Electron Transport Chain
FADH2 - flavin adenine dinucleotide
FAO - fatty acid oxidation
FCCP - carbonylcyanide-ptrifluoromethoxyphenylhydrazone
g/l - gram per liter
GI - Glycolysis
GO - Glucose oxidation
GSK3 - Glycogen synthase kinase 3
HERG - a type of Kv channel (the hERG gene encodes the Kv11.1 potassium ion channel)
K+ - Potassium ion
KCl - Potassium chloride
Kir2.1 - "a K+ channel from a different family"
Kv - The voltage-gated family of K+ channels
lk - (outward) potassium current
M059K - a glioblastoma cell line
MCF-7 - a breast cancer cell line (taken from Sister Catherinee Francis Mallon)
mg/l - milligram per liter
MTP - mitochondrial transition pore
NADH - Nicotinamide adenine dinucleotide
NFAT - nuclear factor of activated T lymphocytes
NFAT1 -refesr to a specific member of the NFAT family
PASMC - pulmonary artery smooth muscle cells
PCNA - proliferating cell nuclear antigen
PDH - pyruvate dehydrogenase
PDK - Pyruvate dehydrogenase kinase
PDK1 - Pyruvate dehydrogenase kinase, isozyme 1
PET - Positron emission tomography
RNA - ribonucleic acid
mRNA - Messenger ribonucleic acid
siRNA - Small interfering ribonucleic acid
ROS - reactive oxygen species
SAEC - small airway epithelial cells
TMRM - tetramethyl rhodamine methyl ester
TTFA - thenoyltrifluoroacetone
TUNEL - Terminal deoxynucleotidyl Transferase Biotin-dUTP Nick End Labeling
VDAC - voltage-dependent anion channel


Dichloroacetate induces apoptosis in endometrial cancer cells.

link to full text

1: Gynecol Oncol. 2008 Apr 16 [Epub ahead of print]
Wong JY, Huggins GS, Debidda M, Munshi NC, De Vivo I.
Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston Massachusetts, USA.

PURPOSE: A recent landmark study demonstrated that Dichloroacetate (DCA) treatment promoted apoptosis in lung, breast, and glioblastoma cancer cell lines by shifting metabolism from aerobic glycolysis to glucose oxidation coupled with NFAT-Kv1.5 axis remodeling. The objective of this study was to determine whether DCA induces apoptosis in endometrial cancer cells and to assess apoptotic mechanism. METHODS: A panel of endometrial cancer cell lines with varying degrees of differentiation was treated with DCA and analyzed for apoptosis via flow cytometry. Biological correlates such as gene expression, intracellular Ca(2+), and mitochondrial membrane potential were examined to assess apoptotic mechanism. RESULTS: Initiation of apoptosis was observed in five low to moderately invasive cancer cell lines including Ishikawa, RL95-2, KLE, AN3CA, and SKUT1B while treatment had no effect on non-cancerous 293T cells. Two highly invasive endometrial adenocarcinoma cell lines, HEC1A and HEC1B, were found to be resistant to DCA-induced apoptosis. Apoptotic responding cell lines had a significant increase in early and late apoptotis, a decrease in mitochondrial membrane potential, and decreased Survivin transcript abundance, which are consistent with a mitochondrial-regulated mechanism. DCA treatment decreased intracellular calcium levels in most apoptotic responding cell lines which suggests a contribution from the NFAT-Kv1.5-mediated pathway. DCA treatment increased p53 upregulated modulator of apoptosis (PUMA) transcripts in cell lines with an apoptotic response, suggesting involvement of a p53-PUMA-mediated mechanism. CONCLUSIONS: Dichloroacetate effectively sensitizes most endometrial cancer cell lines to apoptosis via mitochondrial, NFAT-Kv1.5, and PUMA-mediated mechanisms. Further investigation of the cancer therapeutic potential of DCA is warranted.

PMID: 18423823 [PubMed - as supplied by publisher]
link to PubMed summary.

Their website: http://devivo.bwh.harvard.edu/


Dichloroacetate (DCA) Sensitizes Both Wild-Type and Over Expressing Bcl-2 Prostate Cancer Cells In Vitro to Radiation

link to full text

Wengang Cao,1,3 Saif Yacoub,1,3 Kathleen T. Shiverick,2,3
Kazunori Namiki,1,3 Yoshihisa Sakai,1,3 Stacy Porvasnik,1,3
Cydney Urbanek,1,3 and Charles J. Rosser1,2,3*
1Department of Urology,University of Florida,Gainesville, Florida
2Department of Pharmacologyand Therapeutics,University of Florida,Gainesville, Florida
3Prostate CancerTranslationalWorking Group,University of Florida,Gainesville, Florida


BACKGROUND. Bcl-2 protects cells from apoptosis and provides a survival advantage to cells
over-expressing this oncogene. In addition, over expression of Bcl-2 renders cell resistant to
radiation therapy. Recently, dichloroacetate (DCA) was proven to potentiate the apoptotic
machinery by interacting with Bcl-2. In this study,we investigated whether treating human prostate
cancer cells with DCA could modulate Bcl-2 expression and if the modulation in Bcl-2 expression
could render the Bcl-2 over expressing cells more susceptible to cytotoxicity effects of radiation.

METHODS. PC-3-Bcl-2 and PC-3-Neo human prostate cancer cells treated with DCA in addition
to irradiation were analyzed in vitro for changes in proliferation, clonogenic survival, apoptosis, cell
cycle phase distribution, mitochondrial membrane potential, and expression of Bcl-2, Bcl-xL, Bax, or
Bak proteins.

RESULTS. DCA alone produced significant cytotoxic effects and was associated with G1 cell cycle
arrest. Furthermore, DCA was associated with an increased rate of apoptosis. The combination of
DCA with irradiation sensitized both cell lines to radiation’s killing effects. Treatment of PC-3 Bcl-2
or PC-3-Neo with DCA and irradiation resulted in marked changes in various members of the Bcl-2
family. In addition, DCA therapy resulted in a significant change in mitochondria membrane
potential, thus supporting the notion that DCAs effect is on the mitochondria.

CONCLUSIONS. This is the first study to demonstrate DCA can effectively sensitize wild-type
and over expressing Bcl-2 human prostate cancer cells to radiation by modulating the expression
of key members of the Bcl-2 family. Together, these findings warrant further evaluation of the
combination of DCA and irradiation. Prostate #2008 Wiley-Liss, Inc.

KEY WORDS: dichloracetate; radiation; prostate cancer; Bcl-2


Pyruvate kinase M2 is a phosphotyrosine-binding protein

Heather R. Christofk, Matthew G. Vander Heiden, Ning Wu, John M. Asara & Lewis C. Cantley

Growth factors stimulate cells to take up excess nutrients and to use them for anabolic processes. The biochemical mechanism by which this is accomplished is not fully understood but it is initiated by phosphorylation of signalling proteins on tyrosine residues. Using a novel proteomic screen for phosphotyrosine-binding proteins, we have made the observation that an enzyme involved in glycolysis, the human M2 (fetal) isoform of pyruvate kinase (PKM2), binds directly and selectively to tyrosine-phosphorylated peptides. We show that binding of phosphotyrosine peptides to PKM2 results in release of the allosteric activator fructose-1,6-bisphosphate, leading to inhibition of PKM2 enzymatic activity. We also provide evidence that this regulation of PKM2 by phosphotyrosine signalling diverts glucose metabolites from energy production to anabolic processes when cells are stimulated by certain growth factors. Collectively, our results indicate that expression of this phosphotyrosine-binding form of pyruvate kinase is critical for rapid growth in cancer cells. Vol 452| 13 March 2008| doi:10.1038/nature06667

link to the full text Nature article ------- If the link fails, click here.


The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth

Heather R. Christofk, Matthew G. Vander Heiden, Marian H. Harris, Arvind Ramanathan,
Robert E. Gerszten, Ru Wei, Mark D. Fleming, Stuart L. Schreiber & Lewis C. Cantley

Vol 452| 13 March 2008| doi:10.1038/nature06734

Many tumour cells have elevated rates of glucose uptake but reduced rates of oxidative phosphorylation. This persistence of high lactate production by tumours in the presence of oxygen known as aerobic glycolysis, was first noted by Otto Warburg more than 75 yr ago1. How tumour cells establish this altered metabolic phenotype and whether it is essential for tumorigenesis is as yet unknown. Here we show that a single switch in a splice isoform of the glycolytic enzyme pyruvate kinase is necessary for the shift in cellular metabolism to aerobic glycolysis and that this promotes tumorigenesis. Tumour cells have been shown to express exclusively the embryonic M2 isoform of pyruvate kinase2. Here we use short hairpin RNA to knockdown pyruvate kinase M2 expression in human cancer cell lines and replace it with pyruvate kinase M1. Switching pyruvate kinase expression to the M1 (adult) isoform leads to reversal of the Warburg effect, as judged by reduced lactate production and increased oxygen consumption, and this correlates with a reduced ability to form tumours in nude mouse xenografts. These results demonstrate that M2 expression is necessary for aerobic glycolysis and that this metabolic phenotype provides a selective growth advantage for tumour cells in vivo.

Link to full text letter ---------- if the link fails, click here


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


ED Michelakis*,1, L Webster1 and JR Mackey2
1Department of Medicine, University of Alberta, Edmonton, Canada; 2Department of Oncology, University of Alberta, Edmonton, Canada

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.

British Journal of Cancer advance online publication, 2 September 2008; doi:10.1038/sj.bjc.6604554 www.bjcancer.com& 2008 Cancer Research UK

http://www.nature.com/bjc/journal/vaop/ncurrent/full/6604554a.html

(note: DCA is already being used clinically. For example, The Medicor Cancer Centres in Toronto uses DCA, along with a ChemoFit test to help determine potential sensitivity of the cancer to DCA)


Dichloroacetate (DCA) inhibits neuroblastoma growth by specifically acting against malignant undifferentiated cells.

Comments by Dr. Matteo Conti. I contacted Dr. Conti, one of the authors of the paper. Here is a summary of their work, in his words: (September 2011)

"The work shows that DCA is active in Neuroblastoma.
In neuroblastoma, Dr. Pagano differentiates three cell types at various degree of malignancy. The less differentiated type is more malignant.

DCA acts principally against those cells that are more malignant, and less differentiated.

DCA's action is mainly anti-proliferative, it slows growth and multiplication of malignant stem cells. Alone, it does not kill them.

The effect is very marked.

In mice bearing the tumor, all three cell types being present, DCA exhibist a tumor inhibiting effect, however it is not able to eradicate the tumor.
Alone, DCA despite being effective, is probably not enough for a complete cure.

We are now looking for synergizers, however the idea is that they could be tumor of even cell type specific.

Cocktails for specific type of tumors could possibly be a way to improve DCA efficacy.

These results prompt us many questions. A few of them:

1. Why is that DCA is more active against more malignant cells? An answer is that probably the metabolism and the mitochondrial status of malignant cells is very different from that of slow turning cells. DCA can decrease malignancy of a tumor mass, slowing malignant cells at the expense of other cells in the same mass.

2. Can metabolism be manipulated, in addition to DCA, in order to switch malignancy of tumors?

3. Are there ways of boosting DCA effect to promote killing of cells sensitized by DCA? Apparently yes.

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