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Non-Hodgkin's Lymphoma Reversal with Dichloroacetate

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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
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,
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
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
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
++ 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
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.
The help from Jimmy Xu at Carnegie Mellon University is
gratefully acknowledged. This work was supported by the
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... DCA has been used in medicine for over 30 years to treat metabolic disorders, including lactic acidosis [7,8]. Furthermore, DCA has shown clinical efficacy for the treatment of glioblastoma [9] and complete remission of a patient with non-Hodgkin's lymphoma was reported after self-administration of DCA [10]. However, the mechanisms responsible for DCA-induced tumor regression have not been clearly elucidated and the effect of DCA in different tumors is still controversial [10][11][12][13][14][15][16]. ...
... Furthermore, DCA has shown clinical efficacy for the treatment of glioblastoma [9] and complete remission of a patient with non-Hodgkin's lymphoma was reported after self-administration of DCA [10]. However, the mechanisms responsible for DCA-induced tumor regression have not been clearly elucidated and the effect of DCA in different tumors is still controversial [10][11][12][13][14][15][16]. ...
Full-text available
Manipulation of metabolic pathways in hematological cancers has therapeutic potential. Here, we determined the molecular mechanism of action of the metabolic modulator dichloroacetate (DCA) in leukemic cells. We found that DCA induces the AMP-activated protein kinase (AMPK)/p53 pathway with increased efficacy in tumors expressing wild type (wt p53). Clinically relevant, low concentrations of doxorubicin synergize in vitro and in vivo with DCA to further enhance p53 activation and to block tumor progression. Leukemia cell lines and primary leukemic cells containing mutant p53 are resistant to the above-described combination approach. However, DCA synergized with the Hsp90 inhibitor 17-AAG to specifically eliminate these cells. Our studies strongly indicate that depending on the p53 status, different combination therapies would provide better treatment with decreased side effects in hematological cancers.
... 5,6 A mixture of in vitro and case studies has linked the compound to the inhibition of breast cancer, 7 colon cancer, 8 prostate cancer, 9 glioblastoma, 10 and lung cancer, 11 as well as other forms of cancer. [12][13][14][15][16][17] The mechanism of action of DCA is suggested to be metabolic modulation that, for tumor cells, targets the Warburg effect via pyruvate dehydrogenase kinase (PDK) inhibition. 5,18 The Warburg effect, where cancer cells exhibit a metabolic preference towards anaerobic glycolysis for energy production, 19 is accompanied by cancer-promoting phenotypes including ample anabolic pathway support, extracellular acidosis facilitating metastatic potential, and mitochondrial damage that inhibits both oxidative phosphorylation and pro-apoptotic pathways. ...
... This standard protocol screen involves applying compounds at 0.01 mM concentrations to more than 60 human tumor cell lines and monitoring for growth inhibition or death. 15 Because our compounds just started to show effects on viability in the 10 mM range, the screen did not provide conclusive results (Fig. S1). ...
Dichloroacetate (DCA) is an inhibitor of pyruvate dehydrogenase kinase (PDK) that has been shown to reverse the Warburg effect and cause tumor cell death. Clinical research into the anti-cancer activity of DCA revealed high dosage requirements and reports of toxicity. While there have been subsequent mechanistic investigations, a search for DCA alternatives could result in a safer and more effective anticancer therapy. This study evaluates eight small compounds with a conserved dichloric terminal and their in vitro and in vivo potential for anticancer activity. Initial viability screening across six cancer cell lines reveals even at 10 mg/mL, compound treatments do not result in complete cell death which suggests minimal compound cytotoxicity. Furthermore, in vivo data demonstrates that cationic dichloric compounds DCAH and DCMAH, which were selected for further testing based on highest in vitro viability impact, inhibit tumor growth in the U87 model of glioblastoma, suggesting their clinical potential as accessible anti-cancer drugs. Immunoblotting signaling data from tumor lysates demonstrates that the mechanism of actions of cationic DCAH and DCMAH are unlikely to be consistent with that of the terminally carboxylic DCA and warrants further independent investigation.
... After four months of DCA intake, PET/CT showed complete remission of NHL. However, this single observation was not associated with any follow-up period (10). ...
Full-text available
Curative therapy for Follicular lymphomas (FLs) has not yet been established. FLs respond well to chemotherapy and radiation. The large number of current studies confirmed an improved overall response if rituximab was added to chemotherapy. Dichloroacetate (DCA) can be used to inhibit tumor growth. There have been reports that DCA leads to neuropathy. In Non Hodgkin's Lymphoma (NHL) DCA drives to antineoplastic action against cell lines and to apoptosis of tumor cells, which reduces the metabolism and the number of tumor cells. We present a patient with NHL-FL Grade 3a who took alternatively DCA therapy. In our case report DCA did not show any treatment benefit, but only serious senso-motor neuropathy as a result of DCA therapy
... As a consequence, the interest in the Warburg effect in oncology has been ignited once again [44][45][46]. The clinical use of DCA in oncology has slowly been gaining momentum, as demonstrated primarily by anecdotal case reports [47][48][49][50], and more recently, phase I and II trials [41,40,51]. ...
... DCA is used in USA for the treatment of several metabolic diseases and is currently in clinical trials for the treatment of cancers, notably glioblastoma [44]. Moreover, at least one patient with non-Hodgkin's lymphoma was cured using DCA as an auto-medication [45]. The patient showed a minimal peripheral neuropathy that was resolved upon co-treatment with thiamine. ...
Full-text available
Tumor cells, including leukemic cells, remodel their bioenergetic system in favor of aerobic glycolysis. This process is called "the Warburg effect" and offers an attractive pharmacological target to preferentially eliminate malignant cells. In addition, recent results show that metabolic changes can be linked to tumor immune evasion. Mouse models demonstrate the importance of this metabolic remodeling in leukemogenesis. Some leukemias, although treatable, remain incurable and resistance to chemotherapy produces an elevated percentage of relapse in most leukemia cases. Several groups have targeted the specific metabolism of leukemia cells in preclinical and clinical studies to improve the prognosis of these patients, i.e. using L-asparaginase to treat pediatric acute lymphocytic leukemia (ALL). Additional metabolic drugs that are currently being used to treat other diseases or tumors could also be exploited for leukemia, based on preclinical studies. Finally, we discuss the potential use of several metabolic drugs in combination therapies, including immunomodulatory drugs (IMiDs) or immune cell-based therapies, to increase their efficacy and reduce side effects in the treatment of hematological cancers.
Full-text available
Dichloroacetate (DCA) is a substance that is being used for medical treatment of rare congenital forms of lactic acidosis, particularly pyruvate dehydrogenase complex (PDC) deficiency. The current interest in DCA as a cancer remedy evolved after the publication of a scientific article in 2007 that reported the ability of this compound to cause selective death of human cancer cells studied in tissue culture or after implantation into animal hosts. Subsequent claims by various non-scientific, for-profit groups were directed at the lay public regarding DCA’s purported anti-cancer effectiveness, based on results from the original pre-clinical studies and subsequent mostly unverifiable testimonials. Following the initial report, several independent researchers have confirmed and extended the original findings of DCA’s anti-neoplastic activity in a variety of human cancer cells and animal models. These studies provide evidence that DCA interacts with fundamental metabolic and signalling pathways to inhibit malignant cell proliferation and could increase the effect of several anti-cancer substances. No controlled clinical trials of DCA are available. The results of four small phase I trials, in which safety was the primary outcome, suggest that chronic administration of DCA as a single substance is generally well tolerated and might have effects against some human tumours. Though one study was terminated prematurely due to safety concerns, there is evidence that doses up to 6.25 mg/kg body weight twice daily can be administered safely to most subjects.
Metabolic oncology is an exciting new field in cancer research, offering a new window to cancer's molecular plasticity and promise for the development of effective, cancer-selective therapies and novel biomarkers. It is based on the realization that cancer's unique metabolism (known since Warburg's report in 1923) with suppression of mitochondrial glucose oxidation and upregulation of cytoplasmic glycolysis is not a secondary but a primary event, offering many growth advantages to cancer cells. Many mechanisms have been revealed, including growth factors, oncogenes, and mutations, all contributing to a suppression of mitochondria, similar to what takes place in hypoxia. This suppression leads to inhibition of mitochondria-driven apoptosis, promotes proliferation, and enhances angiogenesis and metastatic potential. A number of molecular tools and small molecules targeting metabolic enzymes, including pyruvate kinase, pyruvate dehydrogenase kinase, isocitrate dehydrogenase, and lactate dehydrogenase, have been developed, inhibiting cancer growth in vitro and in vivo in several cancer types. Several have already entered early-phase trials, a great translational success considering the young age of the field (less than 10 years). Here we review the mechanisms and effects of these metabolic modulators and the rationale for further development. This rapidly accumulating knowledge allows some optimism that this may prove to be a paradigm shift in the way we understand and treat cancer.
Otto Warburg first described cancers preference for aerobic glycolysis more than eight dec-ades ago. Backed by solid data from positron emission tomography (PET) scanning, there is now a growing body of evidence that this phenomenon provides an important metabolic dif-ference and that this can be selectively exploited for diagnostic and therapeutic gain. Under-standing the molecular mechanisms which underlie altered cancer metabolism may provide us with new targets for anti-cancer therapy. In this review, we provide a brief overview of the Warburg phenomenon together with the most likely targets for therapeutic exploitation. In particular, attention is focused on the pyruvate dehydrogenase/pyruvate dehydrogenase kinase system, which acts as a key regulator of mitochondrial activity and plays an impor-tant role in the switch of metabolism from oxidative phosphorylation to aerobic glycolysis that accompanies malignant transformation.
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Understanding of mitochondrial dysfunction in CFS will clearly benefit from more study. Our findings warrant detailed studies on larger patient and control populations. The siting of mitochondrial impairment may lead to approaches for alleviating some of the symptoms of CFS. Studies on the effects of cytokines on cellular and mitochondrial bioenergetics are important to see whether cytokines or similar molecules are involved in linking CFS immune disturbances to mitochondrial dysfunction, and to better understand the consequences of cytokine therapies for cancer and viral infection.
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This study aims to improve the health of patients suffering from chronic fatigue syndrome (CFS) by interventions based on the biochemistry of the illness, specifically the function of mitochondria in producing ATP (adenosine triphosphate), the energy currency for all body functions, and recycling ADP (adenosine diphosphate) to replenish the ATP supply as needed. Patients attending a private medical practice specializing in CFS were diagnosed using the Centers for Disease Control criteria. In consultation with each patient, an integer on the Bell Ability Scale was assigned, and a blood sample was taken for the "ATP profile" test, designed for CFS and other fatigue conditions. Each test produced 5 numerical factors which describe the availability of ATP in neutrophils, the fraction complexed with magnesium, the efficiency of oxidative phosphorylation, and the transfer efficiencies of ADP into the mitochondria and ATP into the cytosol where the energy is used. With the consent of each of 71 patients and 53 normal, healthy controls the 5 factors have been collated and compared with the Bell Ability Scale. The individual numerical factors show that patients have different combinations of biochemical lesions. When the factors are combined, a remarkable correlation is observed between the degree of mitochondrial dysfunction and the severity of illness (P<0.001). Only 1 of the 71 patients overlaps the normal region. The "ATP profile" test is a powerful diagnostic tool and can differentiate patients who have fatigue and other symptoms as a result of energy wastage by stress and psychological factors from those who have insufficient energy due to cellular respiration dysfunction. The individual factors indicate which remedial actions, in the form of dietary supplements, drugs and detoxification, are most likely to be of benefit, and what further tests should be carried out.
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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.
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.