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Dichloroacetate metabolically targeted therapy defeats cytotoxicity of standard anticancer drugs

Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

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Abstract

Purpose

The observation that the orphan drug dichloroacetate (DCA) selectively promotes mitochondria-regulated apoptosis and inhibits tumour growth in preclinical models by shifting the glucose metabolism in cancer cells from anaerobic to aerobic glycolysis attracted not only scientists’, clinicians’ but also patients’ interests and prompted us to further evaluate DCA effects against paediatric malignancies.

Methods

The effects of DCA on mitochondrial membrane potential (ΔΨm), cell viability and induction of apoptosis were evaluated in paediatric tumour cell lines and the non-malignant cell line HEK293. In addition, combinations of DCA with the standard anticancer drugs cisplatin, doxorubicin, and temozolomide were tested and intra- and extra-cellular platinum species analysed.

Results

DCA selectively induced phosphatidylserine externalisation and reduced ΔΨm in paediatric tumour cells compared to HEK293 cells, but DCA concentrations ≤10 mmol/L only moderately inhibited the growth of 18 paediatric tumour cell lines. DCA neither influenced the in vitro stability of cisplatin nor the cellular cisplatin uptake, but it abrogated the cytotoxicity of cisplatin in 7 out of 10 cell lines. DCA also affected the cytotoxicity of doxorubicin but did not influence the cytotoxicity of temozolomide. Despite phosphatidylserine externalisation, DCA failed to activate caspase 3/7 and, moreover, suppressed caspase 3/7 activation by cisplatin and doxorubicin.

Conclusions

Our results indicate that apart from the intriguing effects of DCA on the glucose metabolism of cancer cells, the use of DCA for cancer treatment has to be evaluated carefully. Moreover, compassionate use of the orally available drug by patients with cancer themselves without medical supervision is strongly discouraged at present.

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Acknowledgments

This work was supported by the Karl Bröcker Stiftung Weseke.

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Authors and Affiliations

  1. Department of Paediatric Haematology and Oncology, University Children’s Hospital, Albert-Schweitzer Str. 33, 48149, Muenster, Germany

    Dirk Heshe, Stephanie Hoogestraat, Joachim Boos & Claudia Lanvers-Kaminsky

  2. Institute of Inorganic and Analytical Chemistry, Corrensstr. 30/36, 48149, Muenster, Germany

    Christine Brauckmann & Uwe Karst

Authors
  1. Dirk Heshe
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  2. Stephanie Hoogestraat
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  3. Christine Brauckmann
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  4. Uwe Karst
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  5. Joachim Boos
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  6. Claudia Lanvers-Kaminsky
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Corresponding author

Correspondence to Claudia Lanvers-Kaminsky.

Additional information

This work fulfils the requirements for the medical doctoral thesis of Dirk Heshe.

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Heshe, D., Hoogestraat, S., Brauckmann, C. et al. Dichloroacetate metabolically targeted therapy defeats cytotoxicity of standard anticancer drugs. Cancer Chemother Pharmacol 67, 647–655 (2011). https://doi.org/10.1007/s00280-010-1361-6

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  • DOI: https://doi.org/10.1007/s00280-010-1361-6

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