Gamma-tocotrienol reverses multidrug resistance of breast cancer cells with a mechanism distinct from that of atorvastatin

J Steroid Biochem Mol Biol. 2017 Mar;167:67-77. doi: 10.1016/j.jsbmb.2016.11.009. Epub 2016 Nov 15.

Abstract

In addition to its antioxidant properties, γ-tocotrienol also has the ability to inhibit HMG-CoA reductase, which is the key enzyme in the mevalonate pathway for cholesterol biosynthesis. Statins, the competitive inhibitors of HMG-CoA reductase, display potent anticancer activity and reversal ability of multidrug resistance in a variety of tumor cells, which is believed to be due to their inhibition of HMG-CoA reductase. Here, we determined the role of the mevalonate pathway in γ-tocotrienol-mediated reversal of multidrug resistance in cancer cells. We found both γ-tocotrienol and atorvastatin effectively reversed multidrug resistance of MCF-7/Adr and markedly inhibited the intracellular levels of FPP and GGPP. Exogenous addition of mevalonate or FPP and GGPP almost completely prevented the reversal ability of atorvastatin but only partly attenuated the reversal effect of γ-tocotrienol on doxorubicin resistance. In addition, γ-tocotrienol actively inhibited the expression of P-gp and increased the accumulation of doxorubicin in cells, which led to the enhanced G2/M arrest and cell apoptosis. Taken together, γ-tocotrienol reversed the multidrug resistance of MCF-7/Adr with a mechanism distinct from that of atorvastatin. Instead of the mevalonate pathway, the inhibition of P-gp expression is a potential mechanism by which γ-tocotrienol reverses multidrug resistance in MCF-7/Adr.

Keywords: Atorvastatin; Mevalonate pathway; Multidrug resistance; γ-tocotrienol.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / metabolism
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Atorvastatin / pharmacology*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism*
  • Cell Cycle
  • Cell Line, Tumor
  • Chromans / pharmacology*
  • Dose-Response Relationship, Drug
  • Doxorubicin / pharmacology
  • Drug Resistance, Multiple*
  • Drug Resistance, Neoplasm*
  • Female
  • Humans
  • Hydroxymethylglutaryl CoA Reductases / metabolism
  • MCF-7 Cells
  • Membrane Potential, Mitochondrial
  • Mevalonic Acid / metabolism
  • Reactive Oxygen Species / metabolism
  • Vitamin E / analogs & derivatives*
  • Vitamin E / pharmacology

Substances

  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • Antineoplastic Agents
  • Chromans
  • Reactive Oxygen Species
  • Vitamin E
  • plastochromanol 8
  • Doxorubicin
  • Atorvastatin
  • HMGCR protein, human
  • Hydroxymethylglutaryl CoA Reductases
  • Mevalonic Acid