Oncotarget

Research Papers:

Identification of drugs that restore primary cilium expression in cancer cells

Niamat Ali Khan, Nicolas Willemarck, Ali Talebi, Arnaud Marchand, Maria Mercedes Binda, Jonas Dehairs, Natalia Rueda-Rincon, Veerle W. Daniels, Muralidhararao Bagadi, Deepak Balaji Thimiri Govinda Raj, Frank Vanderhoydonc, Sebastian Munck, Patrick Chaltin, Johannes V. Swinnen _

PDF |  HTML  |  Author Information  |  Order a Reprint

Oncotarget. 2016; 7:9975-9992. https://doi.org/10.18632/oncotarget.7198

Metrics: PDF 643 views  |   HTML 614 views  |   ?  


Abstract

Niamat Ali Khan1, Nicolas Willemarck1, Ali Talebi1, Arnaud Marchand2, Maria Mercedes Binda1, Jonas Dehairs1, Natalia Rueda-Rincon1, Veerle W. Daniels1, Muralidhararao Bagadi1, Deepak Balaji Thimiri Govinda Raj3, Frank Vanderhoydonc1, Sebastian Munck4,5, Patrick Chaltin2,6, Johannes V. Swinnen1

1KU Leuven - University of Leuven, Department of Oncology, Laboratory of Lipid Metabolism and Cancer, 3000 Leuven, Belgium

2Cistim Leuven vzw, Bioincubator 2, 3001 Leuven, Belgium

3European Molecular Biology Laboratory (EMBL), Grenoble Outstation and Unit of Virus Host-Cell Interactions (UVHCI), UJF-EMBL-CNRS, CS 90181, France

4VIB Bio Imaging Core and Center for the Biology of Disease, 3000 Leuven, Belgium

5KU Leuven - University of Leuven, Center for Human Genetics, 3000 Leuven, Belgium

6Centre for Drug Design and Discovery (CD3) KU Leuven R & D, Bioincubator 2, 3001 Leuven, Belgium

Correspondence to:

Johannes V. Swinnen, e-mail: johan.swinnen@med.kuleuven.be

Keywords: cilium, cancer, small molecules, therapeutics, high content analysis

Received: July 12, 2015     Accepted: December 08, 2015     Published: February 04, 2016

ABSTRACT

The development of cancer is often accompanied by a loss of the primary cilium, a microtubule-based cellular protrusion that functions as a cellular antenna and that puts a break on cell proliferation. Hence, restoration of the primary cilium in cancer cells may represent a novel promising approach to attenuate tumor growth. Using a high content analysis-based approach we screened a library of clinically evaluated compounds and marketed drugs for their ability to restore primary cilium expression in pancreatic ductal cancer cells. A diverse set of 118 compounds stimulating cilium expression was identified. These included glucocorticoids, fibrates and other nuclear receptor modulators, neurotransmitter regulators, ion channel modulators, tyrosine kinase inhibitors, DNA gyrase/topoisomerase inhibitors, antibacterial compounds, protein inhibitors, microtubule modulators, and COX inhibitors. Certain compounds also dramatically affected the length of the cilium. For a selection of compounds (Clofibrate, Gefitinib, Sirolimus, Imexon and Dexamethasone) their ability to restore ciliogenesis was confirmed in a panel of human cancer cell line models representing different cancer types (pancreas, lung, kidney, breast). Most compounds attenuated cell proliferation, at least in part through induction of the primary cilium, as demonstrated by cilium removal using chloral hydrate. These findings reveal that several commonly used drugs restore ciliogenesis in cancer cells, and warrant further investigation of their antineoplastic properties.

Author Information

Niamat Ali Khan

Nicolas Willemarck

Ali Talebi

Arnaud Marchand

Maria Mercedes Binda

Jonas Dehairs

Natalia Rueda-Rincon

Veerle W. Daniels

Muralidhararao Bagadi

Deepak Balaji Thimiri Govinda Raj

Frank Vanderhoydonc

Sebastian Munck

Patrick Chaltin

Johannes V. Swinnen
Primary Contact  _


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 7198