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Non-Hodgkin's Lymphoma Reversal with Dichloroacetate

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Abstract and Figures

In June 2007, a 48-year-old male patient, diagnosed with Stage 4 Non-Hodgkin's Follicular Lymphoma (NHL), was treated for 3 months with conventional chemotherapy resulting in a complete remission. Almost one year later tumors returned in the nasopharynx and neck lymph glands. Refusing all suggested chemotherapies, the patient began self-administering dichloroacetate (DCA) 900 mg daily with a PET scan showing complete remission four months later. Since his last PET scan, May, 2009, he remains tumor-free from continuous DCA usage.
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Hindawi Publishing Corporation
Journal of Oncology
Volume 2010, Article ID 414726, 4pages
doi:10.1155/2010/414726
Case Report
Non-Hodgkin’s Lymphoma Reversal with Dichloroacetate
Dana F. Flavin1, 2
1Klinik im Alpenpark, Defreggerweg 2-6, Ringsee, 83707 Tegernsee, Germany
2Foundation for Collaborative Medicine and Research, 24 Midwood Drive, Greenwich, CT 06830, USA
Correspondence should be addressed to Dana F. Flavin, dana@collmed.com
Received 4 June 2010; Accepted 23 July 2010
Academic Editor: Michael A. Carducci
Copyright © 2010 Dana F. Flavin. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
In June 2007, a 48-year-old male patient, diagnosed with Stage 4 Non-Hodgkin’s Follicular Lymphoma (NHL), was treated for
3 months with conventional chemotherapy resulting in a complete remission. Almost one year later tumors returned in the
nasopharynx and neck lymph glands. Refusing all suggested chemotherapies, the patient began self-administering dichloroacetate
(DCA) 900 mg daily with a PET scan showing complete remission four months later. Since his last PET scan, May, 2009, he remains
tumor-free from continuous DCA usage.
1. Introduction
Non-Hodgkin’s lymphoma (NHL), a cancer of the lymph
system that can start anywhere in body, aects 400,000+
people in the United States with 66,000 new cases in
2009 [1]. NHL often presents as a low grade fever with
sweating, swollen lymph nodes, general malaise, and fatigue.
Although it responds well to established therapies, including
chemotherapy and radiation [2], more aggressive newer
treatments are being developed, including chemotherapy
with whole body radiation followed by stem cell transplants
[3]. While these treatments have resulted in complete remis-
sion in some patients [4], other patients, aware of the quality
of life compromises sustained with aggressive therapies [3],
seek alternate avenues of treatment with professionals or
on their own, many of which are nonconventional or in
experimental stages. One such therapy is dichloroacetate
(DCA) [5].
DCA is a by-product of water chlorination [6,7] that
inhibits aerobic glycolysis. It has been used in medicine
for over 30 years [8] as an investigational drug to treat
severe metabolic disorders such as diabetes and hypercholes-
terolemia [5,9]aswellasthetreatmentofcongenitallactic
acidosis in North American children [10]. The bioavailability
[11] and pharmacokinetics [12]ofDCAhavebeenwell
researched over several decades in adults [6], children [13,
14], and animals [15]. As a medicinal, DCA is generally well
tolerated from dosages between 10 mg/Kg and 50 mg/Kg,
although prolonged exposure is associated with peripheral
neuropathy [16]. Its activation of the pyruvate dehydroge-
nase enzyme (PDH) of the mitochondria decreases glycolysis
and reactivates glucose oxidation, a favorable approach to
ameliorate lactic acidosis [9].
Cancer cells predominantly utilize a system of glycolysis
for energy instead of the glucose oxidation used by healthy
cells. Cancer appears to be a form of intracellular lactic
acidosis caused by a block in the oxidation of glucose at
the level of PDH (pyruvate dehydrogenase). The glycolysis
metabolism of glucose increases cancer cells’ lactic acid and
reduces the intracellular pH [7] resulting major shifts in the
intracellular biochemistry. Aerobic glycolysis, known as the
Warburg Eect”[17], inactivates mitochondrial respiration
whichallowscancercellgrowth[18]. DCA reverses this
glycolysis causing several major detrimental changes in the
cancer tumor cells.
First and foremost DCA inhibits pyruvate dehydrogenase
kinase (PDK). PDK blocks pyruvate dehydrogenase (PDH)
through its phosphorylation activity. When this kinase is
inhibited by DCA, the PDH is reactivated causing the
mitochondria to no longer be hyperpolarized, instead the
membrane and the mitochondria are depolarized, reacti-
vating the mitochondrial K+channels which then decreases
cytosolic K+. When PDH is inhibited in cancer cells by PDK,
an excess cytosolic K+occurs that inactivates the caspases
2Journal of Oncology
3 and 9, important factors in apoptosis. DCA reactivates
these caspases along with an increase in H2O2intracellularly,
allowing the release of cytochrome c from the mitochondria.
The release of cytochrome c is a major activating step for cell
apoptosis as it triggers the caspase cascade [19]. The results
of DCA on cancers are seen both in vitro and in vivo. These
eects are not seen in normal cells.
Dichloroacetate’s other major eect on cancer cells is
the release of mitochondrial calcium (Ca++). The increase
of Ca++ in cancer cells is associated with the increase
and proliferation of transcription factors. Calcium also
activates ornithine decarboxylase, the rate limiting enzyme
in DNA synthesis [20], and the antiapoptosis factor NFAT
(nuclear factor of activated T lymphocytes) [21]. When the
calcium decreases with the introduction of DCA, the cell
is further directed toward apoptosis and a decrease in cell
replication. In addition to DCA causing a major shift in the
mitochondria, cytoplasm, and cellular membrane [19], the
end eect of DCA is a cell cycle arrest in the Gap 1 phase
(G1), which also increases apoptosis [22].
2. Materials and Method
After being successfully treated with six treatments of
Rituxan plus CHOP (cyclophosphamide, doxorubicin
hydrochloride, vincristine, and prednisolone) regime over
a period of three months in 2007, a positron emission
tomography (PET) scan showed a complete remission of the
NHL. With no further treatments by August 2008, the PET
showed his tumors returned in the nasopharynx and neck
lymph glands which presented with a low grade fever of 99.8,
sweating and fatigue.
The Non-Hodgkin’s Lymphoma patient refused conven-
tional therapy, instead personally obtaining dichloroacetate
(DCA) he began self-administering 900 mg daily at 10 mg/kg
in August 2008, adding a daily 750 mg of thiamine to
protect his nerves from toxicity [15,23]. Four months later a
PET scan showed complete remission (see Figure 2). He has
remained tumor-free on the continued regime of DCA and
thiamine since his last PET in May 2009. Monthly blood tests
are showing that all of his parameters are normal.
3. Results
In August 2008, an NHL patient, who had been in remission
for almost a year after chemotherapy, complained of soreness
and tenderness in his neck area where protrusions were
visible upon examination. A PET was taken to investigate the
nature of the problem and the extent of lymph involvement.
Figure 1 shows that several new hypermetabolic foci
within the head and neck compatible with recurrent
lymphoma; new hypermetabolism in the right postlateral
aspect of the nasopharynx, measuring 3.2 ×2.2 cm; new
hypermetabolic adenopathy within the right neck involving
the right jugulo digastric region, right jugular chain, and
right posterior triangle extending to the base of the neck;
the largest node measuring approximately 1.9 ×1.9 cm;
several smaller hypermetabolic lymph nodes in the posterior
RL
Figure 1: August 2008 PET scan.
Figure 2: December 2008 PET scan.
triangle extending to the base of the neck; a single focal
area of hypermetabolism within the left posterior triangle
corresponding to a small lymph node which measured 1.0
×0.5 cm.
Four months after the patient’s daily self-medication with
750 mg of DCA, a PET scan showed no visible signs of
lymphoma. Symptoms disappeared after several weeks and
the results of the PET scan 4 months later in Figure 2 show
that the previously seen foci of abnormal activity within
the nasopharynx and neck had resolved; no abnormal foci
of metabolic activity were seen; no evidence of recurrent
disease.
4. Discussion
The medical community is seeing more and more patients
who are seeking forms of therapy on their own with
varying results; some are deleterious and endangering while
others may prolong their lives but should still be done
under medical supervision. Understandably physicians fre-
quently cannot ethically advise or administer the use of the
patents’ preferences, leaving the patient to their own devices.
Although this case, and others anecdotally, resulted in a
successful outcome that might be explained by the existing
extensive research on the pharmacology and toxicology
of the dicholoroacetate treatment the patient chose, the
compound’s application in cancer patients is still under
investigation. We are presently looking at in vitro tumor
samples for testing sensitivity to DCA. We are also looking at
laboratory parameters for a possible laboratory correlation in
responders to specific enzyme levels as some patients’ cancers
respond positively or are resolved, DCA does not appear to
be not tumor type specific.
Journal of Oncology 3
Tumor cells preferentially use glycolysis to generate
adenosine triphosphate (ATP) even in the presence of
oxygen, a phenomenon known as aerobic glycolysis or
the “Warburg Eect”[17]. Pyruvate dehydrogenase (PDH),
a gate-keeping enzyme for the entry of pyruvate into
the mitochondrial tricarboxylic acid (TCA) cycle [24], is
inhibited in cancer cells by phosphorylation from the enzyme
pyruvate dehydrogenase kinase (PDK) [18]. This inhibition
of PDH by PDK results in a shift from glucose oxidation
to glycolysis, which favors tumor growth [19]. DCA has
been shown to block this phosphorylation by PDK at
the mitochondrial membrane level and decrease glycolysis
in favor of glucose oxidation. This return to a normal
metabolism of glucose allows for major changes including
adecreaseinCa
++ intracellularly, and stabilization of the
mitochondria allowing a reactivation of caspases in cancer
cells leading to apoptosis [19].
The eects of DCA, caused by reactivation of mitochon-
drial respiration, are not without complications although
it inexplicably seems to be predominantly limited to can-
cer cells while most normal cells remain unaected [24].
A reversible, minimal nerve damage can be considerably
reduced by a daily thiamine intake of several hundred
milligrams for humans [23] and animals [15]. The thiamine
amount varies from 50 mg/day to 100 mg/day depending on
whether it is administered orally or injected intramuscularly
[23].
Correcting mitochondrial dysfunction may be one of the
major future pharmacological targets for treating many dis-
eases, as many diseases’ mitochondrial dysfunction appears
to be a common pathological denominator. Lactic acidosis is
also seen as a complication in malaria [25] indicating mito-
chondrial involvement, and more recently Chronic Fatigue
Syndrome [26]. DCA has also been shown to help consider-
ably in diabetes [27] and familial hypercholesterolemia [28].
5. Conclusion
A Non-Hodgkin’s lymphoma patient taking 10 mg/kg
[750 mg] of dichloroacetate daily of his own accord, had
a complete remission of his Non-Hodgkin’s lymphoma
cancer after four months that has continued to date by his
maintaining his DCA dosage in addition to taking 750 mg
thiamine to protect against the slight tingling and numbness
in the nerves of the fingers and toes, without compromising
his quality of life or aecting the treatment’s ecacy.
Ignoring medical advice not to self-medicate he has con-
tinued his DCA/thiamine regimen, stating his concern that
discontinuing DCA may allow a recurrence of the disease.
There is too little data to draw absolute conclusions on
DCAs usage for cancer. Controlled research needs to be
conducted for validation and confirmation of DCAs ecacy
and maintenance levels in the spectrum of cancer therapies.
Conflict of Interests
The author reports no conflict of interests. The author alone
is responsible for the content and writing of the paper.
Acknowledgments
The help from Jimmy Xu at Carnegie Mellon University is
gratefully acknowledged. This work was supported by the
ValerieBethSchwartzFoundation.
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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.
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Dichloroacetate (DCA) is an investigational drug for the treatment of genetic mitochondrial diseases. Its primary site of action is the pyruvate dehydrogenase (PDH) complex, which it stimulates by altering its phosphorylation state and stability. DCA is metabolized by and inhibits the bifunctional zeta-1 family isoform of glutathione transferase/maleylacetoacetate isomerase. Polymorphic variants of this enzyme differ in their kinetic properties toward DCA, thereby influencing its biotransformation and toxicity, both of which are also influenced by subject age. Results from open label studies and controlled clinical trials suggest chronic oral DCA is generally well-tolerated by young children and may be particularly effective in patients with PDH deficiency. Recent in vitro data indicate that a combined DCA and gene therapy approach may also hold promise for the treatment of this devastating condition.
As a result of a spectrum of mitochondrial defects, tumor cells often preferentially use glycolysis to generate adenosine triphosphate (ATP), even in the presence of oxygen, a phenomenon known as aerobic glycolysis, or the "Warburg effect." Dichloroacetate (DCA) is an inhibitor of mitochondrial pyruvate dehydrogenase kinase (PDK), which inhibits pyruvate dehydrogenase (PDH), a gatekeeping enzyme for the entry of pyruvate into the mitochondrial tricarboxylic acid (TCA) cycle. In mice, DCA treatment appears to reactivate mitochondrial respiration in tumor cells, induces their selective killing, and suppresses cancer growth. These observations provide intriguing insights into the plasticity of tumor metabolism that may offer new opportunities for therapeutic intervention.