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Br J Cancer. 2014 Jul 15;111(2):375-85. doi: 10.1038/bjc.2014.281. Epub 2014 Jun 3.

Dichloroacetate induces autophagy in colorectal cancer cells and tumours.

Author information

1
1] Cancer Research UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research London and Royal Marsden Hospital, Sutton, Surrey SM2 5PT, UK [2] Department of Medical Imaging and Intervention, Chang Gung Memorial Hospital at Linkou, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan.
2
Cancer Research UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research London and Royal Marsden Hospital, Sutton, Surrey SM2 5PT, UK.
3
Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research London, Sutton, Surrey SM2 5NG, UK.
4
CR-UK Cambridge Institute, Li Ka Shing Centre, Cambridge CB2 0RE, UK.
5
1] Cancer Research UK Cancer Imaging Centre, Division of Radiotherapy and Imaging, The Institute of Cancer Research London and Royal Marsden Hospital, Sutton, Surrey SM2 5PT, UK [2] Division of Imaging Sciences and Biomedical Engineering, Kings College London, The Rayne Institute, St Thomas Hospital, London SE1 7EH, UK.

Abstract

BACKGROUND:

Dichloroacetate (DCA) has been found to have antitumour properties.

METHODS:

We investigated the cellular and metabolic responses to DCA treatment and recovery in human colorectal (HT29, HCT116 WT and HCT116 Bax-ko), prostate carcinoma cells (PC3) and HT29 xenografts by flow cytometry, western blotting, electron microscopy, (1)H and hyperpolarised (13)C-magnetic resonance spectroscopy.

RESULTS:

Increased expression of the autophagy markers LC3B II was observed following DCA treatment both in vitro and in vivo. We observed increased production of reactive oxygen species (ROS) and mTOR inhibition (decreased pS6 ribosomal protein and p4E-BP1 expression) as well as increased expression of MCT1 following DCA treatment. Steady-state lactate excretion and the apparent hyperpolarised [1-(13)C] pyruvate-to-lactate exchange rate (k(PL)) were decreased in DCA-treated cells, along with increased NAD(+)/NADH ratios and NAD(+). Steady-state lactate excretion and k(PL) returned to, or exceeded, control levels in cells recovered from DCA treatment, accompanied by increased NAD(+) and NADH. Reduced k(PL) with DCA treatment was found in HT29 tumour xenografts in vivo.

CONCLUSIONS:

DCA induces autophagy in cancer cells accompanied by ROS production and mTOR inhibition, reduced lactate excretion, reduced k(PL) and increased NAD(+)/NADH ratio. The observed cellular and metabolic changes recover on cessation of treatment.

PMID:
24892448
PMCID:
PMC4102941
DOI:
10.1038/bjc.2014.281
[Indexed for MEDLINE]
Free PMC Article

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