title: Suppression of inflammatory cascade is implicated in methyl amooranin-mediated inhibition of experimental mammary carcinogenesis.
abstract: Breast cancer represents the second leading cause of cancer-related deaths among women worldwide and preventive therapy could reverse or delay the devastating impact of this disease. Methyl-amooranin (methyl-25-hydroxy-3-oxoolean-12-en-28-oate, AMR-Me), a novel synthetic oleanane triterpenoid, reduced the incidence and burden of 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary tumors in rats through antiproliferative and proapoptotic effects. Since chronic inflammation plays an important role in the pathogenesis of breast cancer and several synthetic oleanane compounds are known potent anti-inflammatory agents, we aim to investigate anti-inflammatory mechanisms of AMR-Me by monitoring various proinflammatory and stress markers, such as cyclooxygenase-2 (COX-2) and heat shock protein 90 (HSP90), and nuclear factor-κB (NF-κB) signaling during DMBA mammary tumorigenesis in rats. Mammary tumors were harvested from a chemopreventive study in which AMR-Me (0.8-1.6 mg/kg) was found to inhibit mammary carcinogenesis in a dose-response manner. The expressions of COX-2, HSP90, NF-κB, and inhibitory κB-α (IκB-α) were determined by immunohistochemistry and reverse transcription-polymerase chain reaction. AMR-Me downregulated the expression of intratumor COX-2 and HSP90, suppressed the degradation of IκB-α, and reduced the translocation of NF-κB from cytosol to nucleus. Our present study provides the first in vivo evidence that NF-κB-evoked inflammatory cascade is a major target of AMR-Me in breast cancer. Our current results together with our previous findings suggest that disruption of NF-κB signaling contributes to anti-inflammatory, antiproliferative, and apoptosis-inducing mechanisms involved in AMR-Me-mediated chemoprevention of rat mammary carcinogenesis. These encouraging mechanistic results coupled with a safety profile should facilitate the clinical development of AMR-Me as breast cancer chemopreventive drug.
authors.affiliation: Department of Pharmaceutical Sciences College of Pharmacy, Northeast Ohio Medical University, Rootstown, Ohio.
authors.forename: Animesh
authors.initials: A
authors.lastname: Mandal
authors.forename: Deepak
authors.initials: D
authors.lastname: Bhatia
authors.forename: Anupam
authors.initials: A
authors.lastname: Bishayee
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D063646:Carcinogenesis / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D018890:Chemoprevention / Q000379:methods; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000893:Anti-Inflammatory Agents; D016588:Anticarcinogenic Agents; D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606206:Nfkbia protein, rat; C530744:methyl 25-hydroxy-3-oxoolean-12-en-28-oate; D000072000:NF-KappaB Inhibitor alpha; D009828:Oleanolic Acid; D051546:Cyclooxygenase 2
keywords: COX-2; DMBA; HSP90; NF-κB; breast tumor; inflammation; oleanane triterpenoid