NV-128, a Novogen Limited compound, induced cell death in Ovarian Cancer Stem Cells (OCSCs) in a dose-dependent manner. The study will be presented by Ayesha Alvero of Yale University School of Medicine, Department of Obstetrics, Gynaecology and Reproductive Science, at the 2009 Annual Meeting of the American Association for Cancer Research in Denver, 18-22 April, 2009.
Because ovarian cancer stem cells usually survive conventional chemotherapy, these cells are considered to be the potential source of recurrence. It appears that NV-128 promotes cell death in these cancer stem cells through inhibition of the mTOR pathway. These findings may open up a new avenue for treating ovarian cancer patients who become resistant to chemotherapy.
The team from Yale University, headed by professor Gil Mor, recently reported the identification and characterisation of the epithelial ovarian cancer stem cells using the marker CD44 and demonstrated the up-regulation of the mTOR survival pathway in these cells. They previously reported that the synthetic isoflavonoid compound, NV-128, is able to specifically induce mTOR dephosphorylation resulting in inhibition of both mTORC1 and mTORC2 activity. In epithelial ovarian cancer cell lines NV-128 caused substantial cell death in mice engrafted with human ovarian cancers, reducing tumour growth, but more importantly, this effect was achieved without apparent toxicity.
The objective of this study was to determine the cytotoxic effect of NV-128 on the ovarian cancer stem cells. NV-128 had a dramatic effect on the growth and differentiation of CD44+ ovarian cancer stem cells. CD44+ ovarian cancer stem cells were treated with increasing concentrations of NV-128 and positive results were observed as early as 15 minutes post-treatment. In addition, NV-128 prevented ovarian cancer stem cell differentiation in the Matrigel differentiation system.
"We are encouraged by the selective cytotoxic effects and the impact of NV-128 on ovarian cancer stem cells," said professor Alan Husband, group director of Research for the Novogen group.
"We have observed similar selective cytotoxicity with NV-128 in non-small cell lung cancer models and we look forward to the further clinical development of this compound so that these aggressive diseases may be more safely and effectively treated using this new opportunity presented by NV-128," said professor Husband.
When NV-128 is used in combination with the Marshall Edwards, Inc, compound phenoxodiol, apoptosis is enhanced because two pathways to cell death appear to be activated, according to pre-clinical studies completed in late 2008.
NV-128 does not rely on the traditional approach of caspase-mediated apoptosis, a death mechanism which is not effective in cancer cells that have become resistant to chemotherapy.
Novogen Limited is an Australian biotechnology company based in Sydney, Australia, that is developing a range of oncology therapeutics from its proprietary flavonoid synthetic chemistry technology platform.