Novel Compounds for Cancer Therapy via the Induction of RASSF1A
Section: For Industry
Categories: "Cancer Therapeutics"
Reference #: 2006-010, 2008-017
OTC Contact: Blaine Hackman, Ph.D. (Directory Information | Send a Message)
Description
Ras-association domain family 1A (RASSF1A) is a frequently inactivated protein in many human cancers. A commonly found aberration in human tumors is promoter methylation of the RASSF1A gene, which results in a loss of RASSF1A protein expression. Novel derivatives of the naturally occurring alkaloid, mahanine, have been synthesized and shown to be effective for treating cancer by inducing expression of RASSF1A by inhibition of DNA methyltransferase in prostate cancer (PC) cells. These compounds treat both androgen sensitive and androgen independent prostate cancers. Select derivatives have the advantage of containing fluorescent moieties to confirm intracellular delivery and reveal cellular localization. Furthermore, studies have revealed that selected derivatives are more potent than mahanine for inhibiting the growth of prostate cancer cells and have low toxicity, and thus are promising new leads for cancer treatment.
Applications
These novel compounds can be used to treat cancer by inducing expression of the tumor suppressing Ras-association domain family 1A (RASSF1A) protein in cancer cells.Advantages
- These compounds have the potential to treat a wide variety of cancers, as RASSF1A gene methylation has been reported in at least 37 tumor types
- Mahanine has been consumed for hundreds of years by Asian populations, particularly in Ayurvedic medicine
- The novel derivatives show no toxic effects
- Fluorescent moieties allow certain derivatives to be traced for intracellular delivery
- While therapies are available for androgen sensitive PC, there are no therapies for androgen independent PC and these compounds show promise for treating both
Stage of Development
The mahanine mimetics were evaluated for their effects on prostate cancer PC-3 cell proliferation, RASSF1A, cyclin D1 and DNA methyltransferase (DNMT) activity, and in an in vivo human prostate tumor model. The 50% growth inhibition (GI50) values for the mahanine derivatives were observed to be as low as 1.5µM, compared to 2.5 µM for mahanine itself. Additionally, RASSF1A expression was induced, while cyclin D1 was shown to be down regulated in the presence of the compounds. Mice injected with PC-3 cells and treated with these derivatives showed significantly reduced tumor volumes compared to control. No toxicity was observed in mouse models for the mahanine mimetics.Relevant Publications
Sinha, S., et al., Mahanine inhibits growth and induces apoptosis in prostate cancer cells through the deactivation of Akt and activation of caspases. Prostate 2006. 661257-65.
INVENTORS: Partha Banerjee, Milton Brown, Kathryn Ditmer, Shankar Jagadeesh and Mikell Paige
Patent Status
Patents are currently pending.
