Format

Send to

Choose Destination
Biomed Res Int. 2018 Jan 9;2018:3683026. doi: 10.1155/2018/3683026. eCollection 2018.

Combination of Mitochondrial and Plasma Membrane Citrate Transporter Inhibitors Inhibits De Novo Lipogenesis Pathway and Triggers Apoptosis in Hepatocellular Carcinoma Cells.

Author information

1
Department of Physiology, Faculty of Medical Science, Naresuan University, Phitsanulok 65000, Thailand.
2
Clinical Research Unit, Faculty of Medicine, Naresuan University, Phitsanulok 65000, Thailand.
3
Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok 65000, Thailand.
4
KaLy-Cell, 20A rue du Général Leclerc, 67115 Plobsheim, France.
5
Laboratoire de Toxicologie Cellulaire, Université de Bourgogne Franche-Comté, EA 4267, Besançon, France.
6
Department of Medicine, Faculty of Medicine, Naresuan University, Phitsanulok 65000, Thailand.
7
Centre of Excellence in Medical Biotechnology, Faculty of Medical Science, Naresuan University, Phitsanulok 65000, Thailand.
8
Center of Excellence in Petroleum, Petrochemicals and Advanced Materials, Faculty of Science, Naresuan University, Phitsanulok 65000, Thailand.

Abstract

Increased expression levels of both mitochondrial citrate transporter (CTP) and plasma membrane citrate transporter (PMCT) proteins have been found in various cancers. The transported citrates by these two transporter proteins provide acetyl-CoA precursors for the de novo lipogenesis (DNL) pathway to support a high rate of cancer cell viability and development. Inhibition of the DNL pathway promotes cancer cell apoptosis without apparent cytotoxic to normal cells, leading to the representation of selective and powerful targets for cancer therapy. The present study demonstrates that treatments with CTP inhibitor (CTPi), PMCT inhibitor (PMCTi), and the combination of CTPi and PMCTi resulted in decreased cell viability in two hepatocellular carcinoma cell lines (HepG2 and HuH-7). Treatment with citrate transporter inhibitors caused a greater cytotoxic effect in HepG2 cells than in HuH-7 cells. A lower concentration of combined CTPi and PMCTi promotes cytotoxic effect compared with either of a single compound. An increased cell apoptosis and an induced cell cycle arrest in both cell lines were reported after administration of the combined inhibitors. A combination treatment exhibits an enhanced apoptosis through decreased intracellular citrate levels, which consequently cause inhibition of fatty acid production in HepG2 cells. Apoptosis induction through the mitochondrial-dependent pathway was found as a consequence of suppressed carnitine palmitoyl transferase-1 (CPT-1) activity and enhanced ROS generation by combined CTPi and PMCTi treatment. We showed that accumulation of malonyl-CoA did not correlate with decreasing CPT-1 activity. The present study showed that elevated ROS levels served as an inhibition on Bcl-2 activity that is at least in part responsible for apoptosis. Moreover, inhibition of the citrate transporter is selectively cytotoxic to HepG2 cells but not in primary human hepatocytes, supporting citrate-mediating fatty acid synthesis as a promising cancer therapy.

PMID:
29546056
PMCID:
PMC5818947
DOI:
10.1155/2018/3683026
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Hindawi Limited Icon for PubMed Central
Loading ...
Support Center