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Dichloroacetate metabolically targeted therapy defeats cytotoxicity of standard anticancer drugs
Dirk Heshe1, Stephanie Hoogestraat, Christine Brauckmann
1Department of Paediatric Haematology and Oncology, University Children's Hospital, Muenster, Germany.
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.
Insights
Dichloroacetate (DCA) shows potential in preclinical cancer models but has limited efficacy in paediatric tumour cell lines. DCA also interferes with standard chemotherapy, warranting careful evaluation for cancer treatment.
Area of Science:
- Oncology
- Mitochondrial Biology
- Cancer Metabolism
Background:
- Dichloroacetate (DCA) is an orphan drug investigated for its potential to inhibit tumor growth by altering cancer cell metabolism.
- Preclinical studies suggest DCA promotes apoptosis and shifts cancer cells towards aerobic glycolysis.
Purpose of the Study:
- To evaluate the effects of DCA on paediatric malignancies.
- To assess DCA's impact on mitochondrial function, cell viability, and apoptosis in paediatric tumor cell lines.
- To investigate DCA's synergistic or antagonistic effects when combined with standard chemotherapeutic agents.
Main Methods:
- Assessed DCA's effects on mitochondrial membrane potential (ΔΨm), cell viability, and apoptosis induction in paediatric tumor cell lines and HEK293 cells.
- Tested combinations of DCA with cisplatin, doxorubicin, and temozolomide.
- Analyzed intra- and extracellular platinum species.
Main Results:
- DCA selectively induced phosphatidylserine externalization and reduced ΔΨm in paediatric tumor cells.
- DCA concentrations ≤ 10 mmol/L showed only moderate inhibition of paediatric tumor cell growth.
- DCA abrogated the cytotoxicity of cisplatin in 7/10 cell lines and affected doxorubicin's cytotoxicity, but not temozolomide's.
- DCA suppressed caspase 3/7 activation by cisplatin and doxorubicin, despite inducing phosphatidylserine externalization.
Conclusions:
- DCA's efficacy in paediatric malignancies requires careful evaluation, despite its metabolic effects.
- The combination of DCA with standard chemotherapies like cisplatin and doxorubicin may be detrimental.
- Self-administration of DCA by cancer patients without medical supervision is strongly discouraged.
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