Chemical activation of prolyl hydroxylase-2 by BBAP-1 down regulates hypoxia inducible factor-1α and fatty acid synthase for mammary gland chemoprevention. Issue 23 (4th April 2018)

• Record Type: Journal Article
• Authors: Singh, Manjari; Devi, Uma; Roy, Subhadeep; Gupta, Pushpraj S.; Kaithwas, Gaurav
• Is Part Of: RSC advances. Volume 8:Issue 23(2018)
• Page Start: 12848
• Page End: 12860
• Publication Date: 2018-04-04
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/c8ra01239c
• Languages: English
• ISSNs: 2046-2069

Abstract

Abstract : (4-[7-(Acetyloxy)-2-ethyl-2 H -chromen-3-yl] phenyl acetate) (BBAP-1) was identified as a potential prolyl hydroxylase-2 activator and tested for this activity using the 2-oxoglutarate dependent in vitro assay. Abstract : (4-[7-(Acetyloxy)-2-ethyl-2 H -chromen-3-yl] phenyl acetate) (BBAP-1) was identified as a potential prolyl hydroxylase-2 activator and tested for this activity using the 2-oxoglutarate dependent in vitro assay. BBAP-1 was evaluated for its cytotoxic potential against ER + MCF-7 cells, and N -methyl- N -nitrosourea induced estrogen positive mammary gland carcinoma model. The effect of BBAP-1 on cellular morphology was evaluated using in vitro acridine orange/ethidium bromide and JC-1 staining. The morphological symptoms of apoptosis were evident after BBAP-1 treatment when studied through cell staining using acridine orange/ethidium bromide and JC-1 dye. Flow cytometric analysis revealed that BBAP-1 treatment arrested the cell cycle in the G2/M phase. In vivo study revealed the morphological changes of mammary gland tissue when scrutinized using carmine staining, hematoxylin and eosin staining and scanning electron microscopy. BBAP-1 treatment produced a marked effect on histopathological and morphological features when scrutinized against N -methyl- N -nitrosourea induced mammary gland carcinoma. Treatment with BBAP-1 also attenuated the deleterious effects of N -methyl- N -nitrosourea as measured on the basis of oxidative stress markers. Immunoblotting and qRT-PCR analysis revealed the participation of BBAP-1 in the mitochondrial mediated death apoptosis pathway and BBAP-1 also downregulated the hypoxic pathway through activation of prolyl hydroxylase-2. It was concluded that BBAP-1 activated the prolyl hydroxylase-2 enzyme and curtailed the over expression of hypoxia inducible factor-1α and fatty acid synthase along with the mitochondrial mediated death apoptosis pathway.