Cytotoxic properties of Adamantyl isothiocyanate and potential in vivo metabolite adamantyl-N-acetylcystein in gynecological cancer cells.

Abstract

This study determined the in vitro potential of novel compounds adamantyl-N-acetylcystein and adamantyl isothiocyanate to treat gynecological cancers. Adamantyl-N-acetylcystein is postulated to be an in vivo metabolite of adamantyl isothiocyanate as dietary isothiocyanates are converted to N-acetylcysteine-conjugates. A viability assay suggested that adamantyl isothiocyanate and adamantyl-N-acetylcystein are cytotoxic to cancer cells including gynecological cell lines. A NCI60 cancer cell assay revealed that growth-inhibition and cytotoxicity of adamantyl-N-acetylcystein were cell line, but not tissue type-specific. Cell cycle studies revealed that adamantyl-N-acetylcystein and adamantyl isothiocyanate arrest SKOV-3 ovarian cancer cells in G2/M phase. By TUNEL, immunoblotting, and viability studies employing caspase and p38 mitogen-activated protein kinase inhibitors, we proved that reduction in SKOV-3 viability is a consequence of DNA fragmentation and apoptosis. Cytotoxic action of adamantyl-N-acetylcystein in SKOV-3 and endometrial cancer (ECC-1, RL95-2, AN3CA, and KLE) cells required excess generation of reactive oxygen species which could be blocked by antioxidant co-treatment. Adamantyl-N-acetylcystein treatment led to modified expression or activation of apoptotic and oncogenic proteins such as JNK/SAPK, AKT, XIAP, and EGF-R for SKOV-3 and JNK/SAPK and ERK1/2 for ECC-1 cells. We suggest the further development of adamantyl-N-acetylcystein by sensitizing cells to the drug using signaling inhibitors or redox-modulating agents and by evaluating the drug efficacy in ovarian and endometrial in-vivo tumor models.

• Authors: Thilo S Lange, Timothy C Horan, Kyu K Kim, Ajay P Singh, Nicholi Vorsa, Laurent Brard, Richard G Moore, Rakesh K Singh
• Journal: Chemical biology & drug design (Chem Biol Drug Des) Vol. 79 Issue 1 Pg. 92-103 (Jan 2012) ISSN: 1747-0285 [Electronic] England
• PMID: 21974809 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 John Wiley & Sons A/S.

Chemical References

• Antineoplastic Agents
• Isothiocyanates
• Protein Kinase Inhibitors
• Reactive Oxygen Species
• adamantyl isothiocyanate
• adamantyl-N-acetylcystein
• isothiocyanic acid
• Mitogen-Activated Protein Kinases
• Adamantane
• Acetylcysteine

Topics

• Acetylcysteine (analogs & derivatives, chemistry, metabolism, toxicity)
• Adamantane (analogs & derivatives, chemical synthesis, chemistry, metabolism, toxicity)
• Antineoplastic Agents (chemical synthesis, chemistry, toxicity)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Drug Design
• Drug Screening Assays, Antitumor
• Female
• G2 Phase Cell Cycle Checkpoints
• Humans
• Isothiocyanates (chemical synthesis, chemistry, toxicity)
• Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)
• Ovarian Neoplasms
• Protein Kinase Inhibitors (chemical synthesis, chemistry, toxicity)
• Reactive Oxygen Species (metabolism)