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Isothiocyanate NB7M causes selective cytotoxicity, pro-apoptotic signalling and cell-cycle regression in ovarian
R K Singh1, T S Lange, K K Kim
1Molecular Therapeutics Laboratory, Program in Women's Oncology, Department of Obstetrics and Gynecology, Women and Infants' Hospital, Brown University, Providence, RI 02905, USA.
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 microM), in contrast to control cells (TCL-1 and HTR-8; IC(50) approximately 15 microM). In a screen performed by the National Cancer Institute (NCI) (NCI(60) cancer cell-line assay) NB7M (NSC746077) reduced growth up to 100% with an IC(50) between 0.1 and 10 microM 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 alpha), transcription factor NF-kappaB, 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.
Insights
Indole-3-ethyl isothiocyanate NB7M demonstrates potent, selective cytotoxicity against ovarian cancer cell lines, inducing apoptosis and cell-cycle arrest. This compound shows promise as a potential therapeutic agent for ovarian cancer treatment.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Ovarian cancer remains a leading cause of cancer-related deaths globally.
- Novel therapeutic agents with selective cytotoxicity are urgently needed.
- Indole-3-ethyl isothiocyanate NB7M is a compound of interest for its potential anti-cancer properties.
Purpose of the Study:
- To evaluate the cytotoxic activity of NB7M against various cancer cell lines, with a focus on ovarian cancer.
- To elucidate the mechanisms underlying NB7M-induced cytotoxicity.
- To assess the potential of NB7M as a therapeutic drug for ovarian cancer.
Main Methods:
- In vitro screening of NB7M against a panel of cancer cell lines, including the NCI(60) assay.
- Detailed mechanistic studies using SKOV-3 ovarian cancer cells.
- Analysis of apoptosis markers, cell-cycle progression, and signaling pathways.
Main Results:
- NB7M exhibited potent and selective cytotoxicity against ovarian cancer cell lines (60-70% at 2.5 microM), with higher IC(50) values in control cells.
- NB7M induced classical hallmarks of apoptosis, including PARP-1 deactivation, caspase activation, and mitochondrial depolarization.
- Subcytotoxic doses of NB7M inhibited DNA synthesis, caused G1-phase cell-cycle arrest, and modulated key survival and proliferation signaling pathways.
Conclusions:
- NB7M is a selective cytotoxic agent effective against ovarian cancer cell lines in vitro.
- NB7M induces apoptosis and suppresses cell growth and proliferation through multiple molecular mechanisms.
- NB7M warrants further development as a potential therapeutic drug for ovarian cancer.
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