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Atorvastatin Exerts More Selective Inhibitory Effects on hMCT2 than on hMCT1 and hMCT4

Atsushi Yamaguchi1,2, Yuto Mukai2, Tomoya Sakuma2

  • 1Department of Pharmacy, Hokkaido University Hospital, Sapporo, Japan.

Anticancer Research
|June 23, 2023
PubMed
Abstract

Insights

Statins inhibit human monocarboxylate transporters (hMCTs) involved in cancer cell energy. Atorvastatin selectively inhibits hMCT2, offering potential for new anticancer drug development targeting this transporter.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Human monocarboxylate transporters (hMCT1, hMCT2, hMCT4) regulate cellular pH and energy via monocarboxylate transport.
  • Overexpression of hMCTs in cancer suggests their role in tumor growth and pH homeostasis.
  • Targeting hMCTs with inhibitors presents a potential anticancer therapeutic strategy, but isoform selectivity is crucial.

Purpose of the Study:

  • To investigate the inhibitory effects of various statins on hMCT1, hMCT2, and hMCT4.
  • To evaluate the isoform selectivity of statins as hMCT inhibitors.
  • To explore the potential of statins as anticancer agents by targeting hMCTs.

Main Methods:

  • Heterologous expression of hMCT1, hMCT2, and hMCT4 in Xenopus oocytes.
  • Inhibitory assays using a panel of statins including fluvastatin, atorvastatin, simvastatin, rosuvastatin, pravastatin, and pitavastatin.
  • Molecular docking simulations of statins with the hMCT2 structure to predict binding sites.

Main Results:

  • All tested statins demonstrated inhibitory activity against hMCT1, hMCT2, and hMCT4.
  • Atorvastatin emerged as a potent and isoform-selective inhibitor of hMCT2.
  • Docking simulations identified a potential binding site for atorvastatin involving transmembrane helices TM-2, TM-11, and the TM6/7 loop.

Conclusions:

  • Atorvastatin exhibits selective inhibition of hMCT2, differentiating it from other statins tested.
  • The findings elucidate the inhibitory mechanisms of statins on hMCTs.
  • This study provides a basis for developing novel, selective hMCT2 inhibitors as anticancer therapeutics.
Keywords:
AtorvastatinL-LactateMonocarboxylate transporterXenopus laevis oocyte

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