title: Identification of a thalidomide derivative that selectively targets tumorigenic liver progenitor cells and comparing its effects with lenalidomide and sorafenib.
abstract: OBJECTIVE
  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.
authors.affiliation: The Centre for Medical Research, The Perkins Institute of Medical Research, Nedlands, WA 6009, Australia.
authors.forename: Ken
authors.initials: K
authors.lastname: Woo
authors.affiliation: School of Chemistry and Biochemistry, The University of Western Australia, Crawley, WA 6009, Australia.
authors.forename: Scott G
authors.initials: SG
authors.lastname: Stewart
authors.affiliation: School of Chemistry and Biochemistry, The University of Western Australia, Crawley, WA 6009, Australia.
authors.forename: Geraldine S
authors.initials: GS
authors.lastname: Kong
authors.affiliation: School of Chemistry and Biochemistry, The University of Western Australia, Crawley, WA 6009, Australia.
authors.forename: Megan L
authors.initials: ML
authors.lastname: Finch-Edmondson
authors.affiliation: 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.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Dwyer
authors.affiliation: School of Chemistry and Biochemistry, The University of Western Australia, Crawley, WA 6009, Australia.
authors.forename: Sing Y
authors.initials: SY
authors.lastname: Yeung
authors.affiliation: School of Chemistry and Biochemistry, The University of Western Australia, Crawley, WA 6009, Australia.
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Abraham
authors.affiliation: School of Chemistry and Biochemistry, The University of Western Australia, Crawley, WA 6009, Australia.
authors.forename: Sven S
authors.initials: SS
authors.lastname: Kampmann
authors.affiliation: 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.
authors.forename: Luke A
authors.initials: LA
authors.lastname: Diepeveen
authors.affiliation: School of Chemistry and Biochemistry, The University of Western Australia, Crawley, WA 6009, Australia.
authors.forename: Adam M
authors.initials: AM
authors.lastname: Passman
authors.affiliation: 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.
authors.forename: Caryn L
authors.initials: CL
authors.lastname: Elsegood
authors.affiliation: 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.
authors.forename: Janina E E
authors.initials: JE
authors.lastname: Tirnitz-Parker
authors.affiliation: 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.
authors.forename: Bernard A
authors.initials: BA
authors.lastname: Callus
authors.affiliation: 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.
authors.forename: John K
authors.initials: JK
authors.lastname: Olynyk
authors.affiliation: 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.
authors.forename: George C T
authors.initials: GC
authors.lastname: Yeoh
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D000077269:Lenalidomide; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology; D000077157:Sorafenib; D013234:Stem Cells / Q000187:drug effects* / Q000473:pathology; D013792:Thalidomide / Q000031:analogs & derivatives / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D009536:Niacinamide; D013792:Thalidomide; D000077157:Sorafenib; D000077269:Lenalidomide
keywords: Analogues; Apoptosis; Lenalidomide; Liver cancer; Mitosis; Progenitor cells; Sorafenib; Thalidomide