Breast cancer represents one of the most frequently diagnosed
cancers and predominant causes of death in women worldwide. The value of preventive
therapy to limit the devastating impact of
breast cancer is well established. Various plant
triterpenoids and their synthetic analogs have shown significant promise as potent chemopreventive agents in
breast cancer. The current study was initiated to investigate mechanism-based chemopreventive potential of a novel synthetic
oleanane triterpenoid (methyl-25-hydroxy-3-oxoolean-12-en-28-oate, AMR-Me) against
7,12-dimethylbenz(a)anthracene (DMBA)-initiated rat mammary
carcinogenesis, an experimental rodent
tumor model that closely resembles human
mammary cancer. Rats were orally administered with
AMR-Me (0.8, 1.2 and 1.6 mg/kg) three times per week for 18 weeks. Following two weeks of
AMR-Me treatment, mammary
carcinogenesis was initiated by
oral administration of DMBA (50 mg/kg
body weight). At the end of the study (16 weeks following DMBA exposure),
AMR-Me exhibited a striking inhibition of DMBA-induced mammary
tumor incidence, total
tumor burden, average
tumor weight and reversed histopathological alterations without toxicity.
AMR-Me dose-dependently suppressed abnormal cell proliferation, induced apoptosis, up-regulated
pro-apoptotic protein Bax and down-regulated antiapoptotic
protein Bcl-2 in mammary
tumors.
AMR-Me upregulated the transcriptional levels of Bax, Bad,
caspase-3,
caspase-7 and
poly(ADP-ribose) polymerase and down-regulated Bcl-2. These results clearly demonstrate for the first time that novel
triterpenoid AMR-Me exerts chemopreventive efficacy in the classical DMBA model of
breast cancer by suppressing abnormal cell proliferation and inducing apoptosis mediated through mitochondrial pro-apoptotic mechanisms.
AMR-Me could be developed as a chemopreventive
drug to reduce the risk of human
breast cancer that remains a devastating disease.