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Journal of Molecular Medicine

, Volume 98, Issue 2, pp 179–191 | Cite as

Novel lysophosphatidic acid receptor 6 antagonists inhibit hepatocellular carcinoma growth through affecting mitochondrial function

  • Davide Gnocchi
  • Saketh Kapoor
  • Patrizia Nitti
  • Maria Maddalena Cavalluzzi
  • Giovanni Lentini
  • Nunzio Denora
  • Carlo Sabbà
  • Antonio MazzoccaEmail author
Original Article

Abstract

Hepatocellular carcinoma (HCC) is one of the most prevalent cancers worldwide and the commonest liver cancer. It is expected to become the third leading cause of cancer-related deaths in Western countries by 2030. Effective pharmacological approaches for HCC are still unavailable, and the currently approved systemic treatments are unsatisfactory in terms of therapeutic results, showing many side effects. Thus, searching for new effective and nontoxic molecules for HCC treatment is of paramount importance. We previously demonstrated that lysophosphatidic acid (LPA) is an important contributor to the pathogenesis of HCC and that lysophosphatidic acid receptor 6 (LPAR6) actively supports HCC tumorigenicity. Here, we screened for novel LPAR6 antagonists and found that two compounds, 4-methylene-2-octyl-5-oxotetra-hydrofuran-3-carboxylic acid (C75) and 9-xanthenylacetic acid (XAA), efficiently inhibit HCC growth, both in vitro and in vitro, without displaying toxic effects at the effective doses. We further investigated the mechanisms of action of C75 and XAA and found that these compounds determine a G1-phase cell cycle arrest, without inducing apoptosis at the effective doses. Moreover, we discovered that both molecules act on mitochondrial homeostasis, by increasing mitochondrial biogenesis and reducing mitochondrial membrane potential. Overall, our results show two newly identified LPAR6 antagonists with a concrete potential to be translated into effective and side effect–free molecules for HCC therapy.

Keywords

Hepatocellular carcinoma (HCC) Lysophosphatidic acid receptor 6 (LPAR6) Lysophosphatidic acid receptor 6 antagonists Drug discovery and design Drug therapy 

Notes

Acknowledgments

We are grateful to Ms. Loredana Acquaro for her precious technical support.

Funding information

This work was supported by a research grant from AIRC (Italian Association for Cancer Research) to A. Mazzocca (Investigator Grant (IG) 2015 Id. 17758).

Compliance with ethical standards

All animal procedures were conducted in accordance with the national and international Guidelines for the Care and Use of Laboratory and were approved by the local Institutional Animal Care and Use Committee.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

109_2019_1862_MOESM1_ESM.pdf (2.5 mb)
ESM 1 (PDF 2559 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Interdisciplinary Department of MedicineUniversity of Bari School of MedicineBariItaly
  2. 2.Stem Cells and Regenerative Medicine CentreYenepoya Research Centre, Yenepoya (deemed to be University)MangaloreIndia
  3. 3.Department of Chemical and Pharmaceutical SciencesUniversity of TriesteTriesteItaly
  4. 4.Department of Pharmacy - Drug SciencesUniversity of Bari Aldo MoroBariItaly

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