A Novel Acetylenic Tricyclic bis-(Cyano Enone) Potently Induces Phase 2 Cytoprotective Pathways and Blocks Liver Carcinogenesis Induced by Aflatoxin
- 12 August 2008
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 68 (16), 6727-6733
- https://doi.org/10.1158/0008-5472.can-08-1123
Abstract
A novel acetylenic tricyclic bis-(cyano enone), TBE-31, is a lead compound in a series of tricyclic compounds with enone functionalities in rings A and C. Nanomolar concentrations of this potent multifunctional molecule suppress the induction of the inflammatory protein, inducible nitric oxide synthase, activate phase 2 cytoprotective enzymes in vitro and in vivo, block cell proliferation, and induce differentiation and apoptosis of leukemia cells. Oral administration of TBE-31 also significantly reduces formation of aflatoxin-DNA adducts and decreases size and number of aflatoxin-induced preneoplastic hepatic lesions in rats by >90%. Because of the two cyano enones in rings A and C, TBE-31 may directly interact with DTT and protein targets such as Keap1 that contain reactive cysteine residues. The above findings suggest that TBE-31 should also be tested for chemoprevention and chemotherapy in relevant models of cancer and against other chronic, degenerative diseases in which inflammation and oxidative stress contribute to disease pathogenesis. [Cancer Res 2008;68(16):6727–33]Keywords
This publication has 35 references indexed in Scilit:
- Platforms and networks in triterpenoid pharmacologyDrug Development Research, 2007
- A cytokine-mediated link between innate immunity, inflammation, and cancerJCI Insight, 2007
- Triterpenoids and rexinoids as multifunctional agents for the prevention and treatment of cancerNature Reviews Cancer, 2007
- Novel Tricyclic Compounds Having Acetylene Groups at C-8a and Cyano Enones in Rings A and C: Highly Potent Anti-inflammatory and Cytoprotective AgentsJournal of Medicinal Chemistry, 2007
- Id1 restrains myeloid commitment, maintaining the self-renewal capacity of hematopoietic stem cellsProceedings of the National Academy of Sciences, 2007
- Cancer Statistics, 2007CA: A Cancer Journal for Clinicians, 2007
- The Consensus Coding Sequences of Human Breast and Colorectal CancersScience, 2006
- Transcriptional regulation via cysteine thiol modification: A novel molecular strategy for chemoprevention and cytoprotectionMolecular Carcinogenesis, 2006
- Efficient synthesis of (−)- and (+)-tricyclic compounds with enone functionalities in rings A and C. A novel class of orally active anti-inflammatory and cancer chemopreventive agentsOrganic & Biomolecular Chemistry, 2003
- Inflammation and cancerNature, 2002