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Cytotoxic Properties of Adamantyl Isothiocyanate and Potential In vivo Metabolite Adamantyl‐ N ‐Acetylcystein in Gynecological Cancer Cells
Author(s) -
Lange Thilo S.,
Horan Timothy C.,
Kim Kyu K.,
Singh Ajay P.,
Vorsa Nicholi,
Brard Laurent,
Moore Richard G.,
Singh Rakesh K.
Publication year - 2012
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/j.1747-0285.2011.01251.x
Subject(s) - viability assay , isothiocyanate , in vivo , chemistry , cancer cell , mtt assay , apoptosis , cytotoxic t cell , pharmacology , biochemistry , biology , in vitro , cancer , genetics , microbiology and biotechnology
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.