Chemical activation of prolyl hydroxylase-2 by BBAP-1 down regulates hypoxia inducible factor-1α and fatty acid synthase for mammary gland chemoprevention.
作者信息
Singh Manjari, Devi Uma, Roy Subhadeep, Gupta Pushpraj S, Kaithwas Gaurav
机构信息
Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University (A Central University) Vidya Vihar, Raebareli Road Lucknow-226025 UP India
Department of Pharmaceutical Sciences, Faculty of Health and Medical Sciences, Sam Higginbottom University of Agricultural Sciences and Technology Naini Allahabad UP India.
出版信息
RSC Adv. 2018 Apr 4;8(23):12848-12860. doi: 10.1039/c8ra01239c. eCollection 2018 Apr 3.
(4-[7-(Acetyloxy)-2-ethyl-2-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 assay. BBAP-1 was evaluated for its cytotoxic potential against ER + MCF-7 cells, and -methyl--nitrosourea induced estrogen positive mammary gland carcinoma model. The effect of BBAP-1 on cellular morphology was evaluated using 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. 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 -methyl--nitrosourea induced mammary gland carcinoma. Treatment with BBAP-1 also attenuated the deleterious effects of -methyl--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.