1. ¹Molecular Therapeutics Laboratory, Program in Women's Oncology, Department of Obstetrics and Gynecology, Women and Infants' Hospital, Brown University, Providence, RI 02905, USA
2. ²Division of Biology and Medicine, Brown University, Providence, RI 02912, USA
3. ³Department of Plant Biology and Pathology, Rutgers University, NJ 08901, USA

Correspondence: Dr L Brard, Molecular Therapeutics Laboratory, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Women and Infants Hospital of RI, 101 Dudley Street, Providence, RI 02905, USA; E-mail: lbrard@wihri.org

⁴These authors contributed equally to this work.

Revised 13 October 2008; Accepted 20 October 2008; Published online 11 November 2008.

Abstract

The present report identifies indole-3-ethyl isothiocyanate NB7M as a potent cytotoxic agent with selective activity against cell lines derived from various tumour types. Ovarian cancer cell lines showed sensitivity to NB7M (60–70% cytotoxicity at 2.5 M), in contrast to control cells (TCL-1 and HTR-8; IC₅₀ 15 M). In a screen performed by the National Cancer Institute (NCI) (NCI₆₀ cancer cell-line assay) NB7M (NSC746077) reduced growth up to 100% with an IC₅₀ between 0.1 and 10 M depending on the cell line studied. Using SKOV-3 ovarian cancer cells as a model, mechanisms of cytotoxicity were analysed. NB7M caused hallmarks of apoptosis such as PARP-1 deactivation, chromatin condensation, DNA nicks, activation of caspases-9, -8, -3, loss of mitochondrial transmembrane depolarisation potential and upregulation of pro-apoptotic mitogen activated protein kinases (p38, SAP/JNK). NB7M downregulated phosphorylation of prosurvival kinases (PI-3K, AKT, IKK), transcription factor NF-B, and expression of DNA-Pk and AXL receptor tyrosine kinase. Subcytotoxic doses of NB7M inhibited DNA synthesis, caused G1-phase cell-cycle arrest and upregulated p27 expression. The present report suggests that NB7M is a selective cytotoxic agent in vitro for cell lines derived from ovarian and certain other tumours. In addition, NB7M acts as a growth/cell-cycle-suppressing agent and may be developed as a potential therapeutic drug to treat ovarian cancer.