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: Gry Irene Magnussen, Anne Katrine Ree Rosnes, Susan Shahzidi, Hiep Phuc Dong, Elisabeth Emilsen, Birgit Engesæter, Vivi Ann Flørenes
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 420 Issue 3 Pg. 516-22 (Apr 13 2012) ISSN: 1090-2104 [Electronic] United States
• PMID: 22446330 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• Antibodies, Monoclonal
• Antineoplastic Agents
• CD 437
• DDIT3 protein, human
• FAS protein, human
• RNA, Messenger
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• Retinoids
• fas Receptor
• Transcription Factor CHOP
• lexatumumab
• Poly(ADP-ribose) Polymerases
• Caspase 8
• Caspase 9
• Cathepsin D

Topics

• Antibodies, Monoclonal (pharmacology)
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Caspase 8 (metabolism)
• Caspase 9 (metabolism)
• Cathepsin D (metabolism)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Drug Synergism
• Humans
• Melanoma (metabolism)
• Poly(ADP-ribose) Polymerases (metabolism)
• RNA, Messenger (biosynthesis)
• Receptors, TNF-Related Apoptosis-Inducing Ligand (agonists, biosynthesis)
• Retinoids (pharmacology)
• Skin Neoplasms (metabolism)
• Transcription Factor CHOP (biosynthesis)
• Up-Regulation
• fas Receptor (biosynthesis)