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Pure Low Price 99% DCA You can Trust
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
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)
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