2. Academic Validation
  3. Choline Kinase Alpha Inhibition by EB-3D Triggers Cellular Senescence, Reduces Tumor Growth and Metastatic Dissemination in Breast Cancer

Choline Kinase Alpha Inhibition by EB-3D Triggers Cellular Senescence, Reduces Tumor Growth and Metastatic Dissemination in Breast Cancer

  • Cancers (Basel). 2018 Oct 22;10(10):391. doi: 10.3390/cancers10100391.
Elena Mariotto 1,  Giampietro Viola 2 3,  Roberto Ronca 4,  Luca Persano 5 6,  Sanja Aveic 7,  Zaver M Bhujwalla 8,  Noriko Mori 9,  Benedetta Accordi 10 11,  Valentina Serafin 12,  Luisa Carlota López-Cara 13,  Roberta Bortolozzi 14
Affiliations

Affiliations

  • 1 Pediatric Hematooncology Laboratory, Department of Women's and Children's health, University of Padova, 35128 Padova, Italy. [email protected].
  • 2 Pediatric Hematooncology Laboratory, Department of Women's and Children's health, University of Padova, 35128 Padova, Italy. [email protected].
  • 3 Fondazione Istituto di Ricerca Pediatrica Città della Speranza, 35127 Padova, Italy. [email protected].
  • 4 Experimental Oncology and Immunology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy. [email protected].
  • 5 Pediatric Hematooncology Laboratory, Department of Women's and Children's health, University of Padova, 35128 Padova, Italy. [email protected].
  • 6 Fondazione Istituto di Ricerca Pediatrica Città della Speranza, 35127 Padova, Italy. [email protected].
  • 7 Fondazione Istituto di Ricerca Pediatrica Città della Speranza, 35127 Padova, Italy. [email protected].
  • 8 In Vivo Cellular Molecular Imaging Center Program, Russell H. Morgan Department of Radiology and Radiological Science, John Hopkins University, Baltimore, MD 21205, USA. [email protected].
  • 9 In Vivo Cellular Molecular Imaging Center Program, Russell H. Morgan Department of Radiology and Radiological Science, John Hopkins University, Baltimore, MD 21205, USA. [email protected].
  • 10 Pediatric Hematooncology Laboratory, Department of Women's and Children's health, University of Padova, 35128 Padova, Italy. [email protected].
  • 11 Fondazione Istituto di Ricerca Pediatrica Città della Speranza, 35127 Padova, Italy. [email protected].
  • 12 Pediatric Hematooncology Laboratory, Department of Women's and Children's health, University of Padova, 35128 Padova, Italy. [email protected].
  • 13 Department of Pharmaceutical Chemistry and Organic, Faculty of Pharmacy, Cartuja Campus, University of Granada, 18011 Granada, Spain. [email protected].
  • 14 Pediatric Hematooncology Laboratory, Department of Women's and Children's health, University of Padova, 35128 Padova, Italy. [email protected].
PMID: 30360374 DOI: 10.3390/cancers10100391
Abstract

Choline kinase (ChoK) is the first Enzyme of the Kennedy pathway leading to the biosynthesis of phosphatidylcholine (PtdCho), the most abundant phospholipid in eukaryotic cell membranes. EB-3D is a novel choline kinase α1 (ChoKα1) inhibitor with potent antiproliferative activity against a panel of several Cancer cell lines. ChoKα1 is particularly overexpressed and hyperactivated in aggressive breast Cancer. By NMR analysis, we demonstrated that EB-3D is able to reduce the synthesis of phosphocholine, and using flow cytometry, immunoblotting, and q-RT-PCR as well as proliferation and invasion assays, we proved that EB-3D strongly impairs breast Cancer cell proliferation, migration, and invasion. EB-3D induces senescence in breast Cancer cell lines through the activation of the metabolic sensor AMPK and the subsequent dephosphorylation of mTORC1 downstream targets, such as p70S6K, S6 ribosomal protein, and 4E-BP1. Moreover, EB-3D strongly synergizes with drugs commonly used for breast Cancer treatment. The antitumorigenic potential of EB-3D was evaluated in vivo in the syngeneic orthotopic E0771 mouse model of breast Cancer, where it induces a significant reduction of the tumor mass at low doses. In addition, EB-3D showed an antimetastatic effect in experimental and spontaneous metastasis models. Altogether, our results indicate that EB-3D could be a promising new Anticancer agent to improve aggressive breast Cancer treatment protocols.

Keywords

Choline Kinase α; breast cancer; senescence; small molecules.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-115463
    99.54%, ChoKα Inhibitor