Skip to main content

Case Report: Sodium dichloroacetate (DCA) inhibition of the “Warburg Effect” in a human cancer patient: complete response in non-Hodgkin’s lymphoma after disease progression with rituximab-CHOP

An Erratum to this article was published on 08 May 2013

Abstract

The uptake of fluorodeoxyglucose Positron Emission Tomography in the tumors of various cancer types demonstrates the key role of glucose in the proliferation of cancer. Dichloroacetate is a 2-carbon molecule having crucial biologic activity in altering the metabolic breakdown of glucose to lactic acid. Human cell line studies show that dichloroacetate switches alter the metabolomics of the cancer cell from one of glycolysis to oxidative phosphorylation, and in doing so restore mitochondrial functions that trigger apoptosis of the cancer cell. Reports of dichloroacetate in human subjects are rare. The authors contacted individuals from Internet forums who had reported outstanding anti-cancer responses to self-medication with dichloroacetate. With informed consent, complete medical records were requested to document response to dichloroacetate, emphasizing the context of monotherapy with dichloroacetate. Of ten patients agreeing to such an evaluation, only one met the criteria of having comprehensive clinic records as well as pathology, imaging and laboratory reports, along with single agent therapy with dichloroacetate. That individual is the focus of this report. In this case report of a man with documented relapse after state-of-the-art chemotherapy for non-Hodgkin’s lymphoma, a significant response to dichloroacetate is documented with a complete remission, which remains ongoing after 4 years. Dichloroacetate appears to be a novel therapy warranting further investigation in the treatment of cancer.

This is a preview of subscription content, access via your institution.

References

  • Berendzen K, Theriaque DW, Shuster J, Stacpoole PW (2006) Therapeutic potential of dichloroacetate for pyruvate dehydrogenase complex deficiency. Mitochondrion 6:126–135

    CAS  Article  Google Scholar 

  • Bonnet S, Archer SL, Allalunis-Turner J, Haromy A, Beaulieu C, Thompson R et al (2007) A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell 11:37–51

    CAS  Article  Google Scholar 

  • Bui T, Thompson CB (2006) Cancer’s sweet tooth. Cancer Cell 9:419–420

    CAS  Article  Google Scholar 

  • Bustamante E, Pedersen PL (1977) High aerobic glycolysis of rat hepatoma cells in culture: role of mitochondrial hexokinase. Proc Natl Acad Sci U S A 74:3735–3739

    CAS  Article  Google Scholar 

  • Bustamante E, Morris HP, Pedersen PL (1981) Energy metabolism of tumor cells. Requirement for a form of hexokinase with a propensity for mitochondrial binding. J Biol Chem 256:8699–8704

    CAS  Google Scholar 

  • Cao W, Yacoub S, Shiverick KT, Namiki K, Sakai Y, Porvasnik S et al (2008) Dichloroacetate (DCA) sensitizes both wild-type and over expressing Bcl-2 prostate cancer cells in vitro to radiation. Prostate 68:1223–1231

    CAS  Article  Google Scholar 

  • Chen Z, Lu W, Garcia-Prieto C, Huang P (2007) The Warburg effect and its cancer therapeutic implications. J Bioenerg Biomembr 39:267–274

    CAS  Article  Google Scholar 

  • Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R et al (2008) The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature 452:230–233

    CAS  Article  Google Scholar 

  • Constantin-Teodosiu D, Simpson EJ, Greenhaff PL (1999) The importance of pyruvate availability to PDC activation and anaplerosis in human skeletal muscle. Am J Physiol 276:E472–E478

    CAS  Google Scholar 

  • Fang JS, Gillies RD, Gatenby RA (2008) Adaptation to hypoxia and acidosis in carcinogenesis and tumor progression. Semin Cancer Biol 18:330–337

    CAS  Article  Google Scholar 

  • Gatenby RA, Gawlinski ET (2003) The glycolytic phenotype in carcinogenesis and tumor invasion: insights through mathematical models. Cancer Res 63:3847–3854

    CAS  Google Scholar 

  • Heerdt BG, Houston MA, Augenlicht LH (2005) The intrinsic mitochondrial membrane potential of colonic carcinoma cells is linked to the probability of tumor progression. Cancer Res 65:9861–9867

    CAS  Article  Google Scholar 

  • Higashi T, Saga T, Nakamoto Y, Ishimori T, Mamede MH, Wada M et al (2002) Relationship between retention index in dual-phase (18)F-FDG PET, and hexokinase-II and glucose transporter-1 expression in pancreatic cancer. J Nucl Med 43:173–180

    CAS  Google Scholar 

  • Kuroda Y, Ito M, Toshima K, Takeda E, Naito E, Hwang TJ et al (1986) Treatment of chronic congenital lactic acidosis by oral administration of dichloroacetate. J Inherit Metab Dis 9:244–252

    CAS  Article  Google Scholar 

  • Madhok BM, Yeluri S, Perry SL, Hughes TA, Jayne DG (2010) Dichloroacetate induces apoptosis and cell-cycle arrest in colorectal cancer cells. Br J Cancer 102:1746–1752

    CAS  Article  Google Scholar 

  • Mathupala SP, Rempel A, Pedersen PL (1997) Aberrant glycolytic metabolism of cancer cells: a remarkable coordination of genetic, transcriptional, post-translational, and mutational events that lead to a critical role for type II hexokinase. J Bioenerg Biomembr 29:339–343

    CAS  Article  Google Scholar 

  • Mathupala SP, Rempel A, Pedersen PL (2001) Glucose catabolism in cancer cells: identification and characterization of a marked activation response of the type II hexokinase gene to hypoxic conditions. J Biol Chem 276:43407–43412

    CAS  Article  Google Scholar 

  • Michelakis ED, Webster L, Mackey JR (2008) Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer. Br J Cancer 99:989–994

    CAS  Article  Google Scholar 

  • Michelakis ED, Sutendra G, Dromparis P, Webster L, Haromy A, Niven E et al (2010) Metabolic modulation of glioblastoma with dichloroacetate. Sci Transl Med 2:31ra34

    CAS  Article  Google Scholar 

  • Pan JG, Mak TW (2007) Metabolic targeting as an anticancer strategy: dawn of a new era? Sci STKE 2007:14

    Google Scholar 

  • Remillard CV, Yuan JX (2004) Activation of K+ channels: an essential pathway in programmed cell death. Am J Physiol Lung Cell Mol Physiol 286:L49–L67

    CAS  Article  Google Scholar 

  • Stacpoole PW, Barnes CL, Hurbanis MD, Cannon SL, Kerr DS (1997) Treatment of congenital lactic acidosis with dichloroacetate. Arch Dis Child 77:535–541

    CAS  Article  Google Scholar 

  • Stacpoole PW, Kerr DS, Barnes C, Bunch ST, Carney PR, Fennell EM et al (2006) Controlled clinical trial of dichloroacetate for treatment of congenital lactic acidosis in children. Pediatrics 117:1519–1531

    Article  Google Scholar 

  • Stacpoole PW, Gilbert LR, Neiberger RE, Carney PR, Valenstein E, Theriaque DW et al (2008) Evaluation of long-term treatment of children with congenital lactic acidosis with dichloroacetate. Pediatrics 121:e1223–e1228

    Article  Google Scholar 

  • Sun RC, Fadia M, Dahlstrom JE, Parish CR, Board PG, Blackburn AC (2010) Reversal of the glycolytic phenotype by dichloroacetate inhibits metastatic breast cancer cell growth in vitro and in vivo. Breast Cancer Res Treat 120:253–260

    CAS  Article  Google Scholar 

  • Tong J, Xie G, He J, Li J, Pan F, Liang H (2011) Synergistic antitumor effect of dichloroacetate in combination with 5-fluorouracil in colorectal cancer. J Biomed Biotechnol 2011:740564

    Article  Google Scholar 

  • Vander Heiden MG (2010) Targeting cell metabolism in cancer patients. Sci Transl Med 2:31ed31

    Article  Google Scholar 

  • Wahl RL, Jacene H, Kasamon Y, Lodge MA (2009) From RECIST to PERCIST: evolving considerations for PET response criteria in solid tumors. J Nucl Med 50(Suppl 1):122S–150S

    CAS  Article  Google Scholar 

  • Wang Z (2004) Roles of K+ channels in regulating tumour cell proliferation and apoptosis. Pflugers Arch 448:274–286

    CAS  Article  Google Scholar 

  • Warburg O (1956a) On respiratory impairment in cancer cells. Science 124:269–270

    CAS  Google Scholar 

  • Warburg O (1956b) On the origin of cancer cells. Science 123:309–314

    CAS  Article  Google Scholar 

  • Warburg O, Wind F, Negelein E (1927) The metabolism of tumors in the body. J Gen Physiol 8:519–530

    CAS  Article  Google Scholar 

  • Wong JY, Huggins GS, Debidda M, Munshi NC, De Vivo I (2008) Dichloroacetate induces apoptosis in endometrial cancer cells. Gynecol Oncol 109:394–402

    CAS  Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Stephen B. Strum.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Strum, S.B., Adalsteinsson, Ö., Black, R.R. et al. Case Report: Sodium dichloroacetate (DCA) inhibition of the “Warburg Effect” in a human cancer patient: complete response in non-Hodgkin’s lymphoma after disease progression with rituximab-CHOP. J Bioenerg Biomembr 45, 307–315 (2013). https://doi.org/10.1007/s10863-012-9496-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10863-012-9496-2

Keywords

  • Dichloroacetate
  • DCA
  • non-Hodgkin’s lymphoma
  • NHL
  • PET
  • PET/CT
  • Glycolysis
  • Metabolomics
  • Warburg