title: Synthetic retinoid CD437 induces apoptosis and acts synergistically with TRAIL receptor-2 agonist in malignant melanoma.
abstract: The novel synthetic retinoid, CD437, shows potent anti-tumor activity in a range of different cancer cell lines and now serves as a prototype for development of new retinoid related molecules (RRMs). The purpose of this study was to examine the effect and cellular targets of CD437 in the human metastatic melanoma cell lines FEMX-1 and WM239. We showed that treatment with CD437 led to cell cycle arrest and induced apoptosis through both the extrinsic- and intrinsic pathways (caspase 8, -9 and PARP cleavage) in both cell lines. Interestingly, apoptosis was induced independently of DNA-fragmentation in FEMX-1 cells, and appeared partially caspase-independent in the WM239 cells. Additionally, up-regulation of CHOP mRNA and cathepsin D protein expression, following retinoid treatment, suggests involvement of the endoplasmatic reticulum (ER) and lysosomes, respectively. Combination of suboptimal concentrations of CD437 and lexatumumab, a TRAIL death receptor-2 agonist, resulted in synergistic reduction of viable cells, along with increased PARP cleavage. These results indicate that CD437 has a strong anti-neoplastic effect alone and in combination with lexatumumab in melanoma cell lines.
authors.affiliation: Department of Pathology, Institute for Cancer Research, The Norwegian Radium Hospital, 0424 Oslo, Norway.
authors.forename: Gry Irene
authors.initials: GI
authors.lastname: Magnussen
authors.forename: Anne Katrine
authors.initials: AK
authors.lastname: Ree Rosnes
authors.forename: Susan
authors.initials: S
authors.lastname: Shahzidi
authors.forename: Hiep Phuc
authors.initials: HP
authors.lastname: Dong
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Emilsen
authors.forename: Birgit
authors.initials: B
authors.lastname: Engesæter
authors.forename: Vivi Ann
authors.initials: VA
authors.lastname: Flørenes
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002402:Cathepsin D / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D008545:Melanoma / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists* / Q000096:biosynthesis; D012176:Retinoids / Q000494:pharmacology*; D012878:Skin Neoplasms / Q000378:metabolism*; D051742:Transcription Factor CHOP / Q000096:biosynthesis; D015854:Up-Regulation; D019014:fas Receptor / Q000096:biosynthesis
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C099555:CD 437; C497249:DDIT3 protein, human; C491901:FAS protein, human; D012333:RNA, Messenger; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D012176:Retinoids; D019014:fas Receptor; D051742:Transcription Factor CHOP; C510234:lexatumumab; D011065:Poly(ADP-ribose) Polymerases; D053181:Caspase 8; D053453:Caspase 9; D002402:Cathepsin D