Cytotoxic Properties of Adamantyl Isothiocyanate and Potential In vivo Metabolite Adamantyl-N-Acetylcystein in Gynecological Cancer Cells

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.