Identification of a thalidomide derivative that selectively targets tumorigenic liver progenitor cells and comparing its effects with lenalidomide and sorafenib

Ken Woo; Scott G Stewart; Geraldine S Kong; Megan L Finch-Edmondson; Benjamin J Dwyer; Sing Y Yeung; Lawrence J Abraham; Sven S Kampmann; Luke A Diepeveen; Adam M Passman; Caryn L Elsegood; Janina E E Tirnitz-Parker; Bernard A Callus; John K Olynyk; George C T Yeoh

doi:10.1016/j.ejmech.2016.03.015

Identification of a thalidomide derivative that selectively targets tumorigenic liver progenitor cells and comparing its effects with lenalidomide and sorafenib

Eur J Med Chem. 2016 Sep 14:120:275-83. doi: 10.1016/j.ejmech.2016.03.015. Epub 2016 Mar 9.

Authors

Affiliations

¹ The Centre for Medical Research, The Perkins Institute of Medical Research, Nedlands, WA 6009, Australia.
² School of Chemistry and Biochemistry, The University of Western Australia, Crawley, WA 6009, Australia.
³ School of Chemistry and Biochemistry, The University of Western Australia, Crawley, WA 6009, Australia; The Centre for Medical Research, The Perkins Institute of Medical Research, Nedlands, WA 6009, Australia.
⁴ School of Chemistry and Biochemistry, The University of Western Australia, Crawley, WA 6009, Australia; School of Biomedical Sciences and Curtin Health Innovation Research Institute, Curtin University, Bentley, WA, Australia.
⁵ School of Biomedical Sciences and Curtin Health Innovation Research Institute, Curtin University, Bentley, WA, Australia; School of Medicine and Pharmacology, University of Western Australia, Fremantle, WA 6959, Australia.
⁶ School of Chemistry and Biochemistry, The University of Western Australia, Crawley, WA 6009, Australia; School of Health Sciences, The University of Notre Dame Australia, WA 6959, Australia.
⁷ Department of Gastroenterology & Hepatology, Fiona Stanley Hospital, Bull Creek, WA, Australia; School of Biomedical Sciences and Curtin Health Innovation Research Institute, Curtin University, Bentley, WA, Australia; School of Veterinary Sciences, Murdoch University, Murdoch, WA, Australia.
⁸ School of Chemistry and Biochemistry, The University of Western Australia, Crawley, WA 6009, Australia; The Centre for Medical Research, The Perkins Institute of Medical Research, Nedlands, WA 6009, Australia. Electronic address: george.yeoh@uwa.edu.au.

PMID: 27208658
DOI: 10.1016/j.ejmech.2016.03.015

Abstract

Background & aims: The availability of non-tumorigenic and tumorigenic liver progenitor cell (LPC) lines affords a method to screen putative anti-liver cancer agents to identify those that are selectively effective. To prove this principle we tested thalidomide and a range of its derivatives and compared them to lenalidomide and sorafenib, to assess their growth-inhibitory effects.

Methods: Cell growth, the mitotic and apoptotic index of cell cultures were measured using the Cellavista instrument (SynenTec) using commercially available reagents.

Results: Neither lenalidomide nor thalidomide (100 μM) affected tumorigenic LPCs but killed their non-tumorigenic counterparts. Sorafenib arrested growth in both cell types. All but two derivatives of thalidomide were ineffective; of the two effective derivatives, one (thalidomide C1) specifically affected the tumorigenic cell line (10 μM). Mitotic and apoptotic analyses revealed that thalidomide C1 induced apoptotic cell death and not mitotic arrest.

Conclusions: This study shows that screens incorporating non-tumorigenic and tumorigenic liver cell lines are a sound approach to identify agents that are effective and selective. A high throughput instrument such as the Cellavista affords robust and reproducible objective measurements with a large number of replicates that are reliable. These experiments show that neither lenalidomide nor thalidomide are potentially useful for anti-liver cancer therapy as they kill non-tumorigenic liver cells and not their tumorigenic counterparts. Sorafenib in contrast, is highly effective, but not selective. One tested thalidomide derivative has potential as an anti-tumor drug since it induced growth arrest; and importantly, it selectively induced apoptotic cell death only in tumorigenic liver progenitor cells.

Keywords: Analogues; Apoptosis; Lenalidomide; Liver cancer; Mitosis; Progenitor cells; Sorafenib; Thalidomide.

MeSH terms

Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Apoptosis / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Humans
Lenalidomide
Liver Neoplasms / drug therapy*
Liver Neoplasms / pathology
Niacinamide / analogs & derivatives
Niacinamide / pharmacology
Phenylurea Compounds / pharmacology
Sorafenib
Stem Cells / drug effects*
Stem Cells / pathology
Thalidomide / analogs & derivatives
Thalidomide / pharmacology*

Substances

Antineoplastic Agents
Phenylurea Compounds
Niacinamide
Thalidomide
Sorafenib
Lenalidomide