Chemical activation of prolyl hydroxylase-2 by BBAP-1 down regulates hypoxia inducible factor-1α and fatty acid synthase for mammary gland chemoprevention

Cell Biochemistry & Function

Roy

et al. 2019

Self Cite

The present study was undertaken to inquest the chemical activation of prolyl hydroxylase-2 for the curtailment of hypoxia-inducible factor-1α and fatty acid synthase. It was well documented that hypoxia-inducible factor-1α and fatty acid synthase were overexpressed in mammary gland carcinomas. After screening a battery of compounds, BBAP-2 was retrieved as a potential prolyl hydroxylase-2 activator and validates its activity using ER + MCF-7 cell line and n-methyl-n-nitrosoureainduced rat in vivo model, respectively. BBAP-2 was palpable for the morphological characteristics of apoptosis along with changes in the mitochondrial intergrity as visualized by acridine orange/ethidium bromide and JC-1 staining against ER + MCF-7 cells. BBAP-2 also arrest the cell cycle of ER + MCF-7 cells at G2/M phase. Afterward, BBAP-2 has scrutinized against n-methyl-n-nitrosourea-induced mammary gland carcinoma in albino Wistar rats. BBAP-2 restored the morphological architecture when screened through carmine staining, haematoxylin and eosin staining, and scanning electron microscopy. BBAP-2 also delineated the markers of oxidative stress favourably. The immunoblotting and mRNA expression analysis validated that BBAP-2 has a potentialty activate the prolyl hydroxylase-2 with sequential downregulating effect on hypoxia-inducible factor-1α and its downstream checkpoint. BBAP-2 also fostered apoptosis through mitochondrial-mediated death pathway. The present study elaborates the chemical activation of prolyl hydroxylase-2 by which the increased expression of HIF-1α and FASN can be reduced in mammary gland carcinoma.

Section: Discussionmentioning

confidence: 93%

Section: Whereas Cells Having Low Mitochondrial Membrane Potential Jc-1mentioning

confidence: 93%

Section: Docking and Toxicity Assessmentmentioning

confidence: 99%

Section: In Vitro Phd-2 Assaymentioning

confidence: 99%

See 2 more Smart Citations

Activation of prolyl hydroxylase‐2 for stabilization of mitochondrial stress along with simultaneous downregulation of HIF‐1α/FASN in ER + breast cancer subtype

Devi

Cell Biochemistry & Function

Roy

et al. 2019

Self Cite

“…But in case of hypoxic solid tumor, reduced level of oxygen deactivates the PHD-2 and activated HIF-1α. Earlier, our research group conjectured that chemical activation of PHD-2 could curtail the upsurged level of HIF-1α and FASN in mammary gland carcinoma [9][10][11].…”

Section: Introductionmentioning

confidence: 98%

Repurposing Combination Therapy of Voacamine with Vincristine for Down Regulation of HIF-1α/FASN Co-Axis and PHD2 Activation in ER+ Mammary Neoplasia

Ansari

et al. 2020

Preprint

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Background: The current study was attempted to inquest the role of combination therapy of Voacamine and Vincristine for the prevention of mammary gland carcinoma through prolyl hydroxylase‐2 activation. The prolyl hydroxylase‐2 activation leads the downregulation of hypoxia‐inducible factor‐1α and fatty acid synthase. Over expression of hypoxia inducible factor-1α and fatty acid synthase is previously reported in solid tumor of mammary gland. Methods: After screening a battery of natural compounds which were similar to vincristine, vocamine was selected as a possible prolyl hydroxylase‐2 activator and justify its activity using 7, 12-Dimethylbenz[a]anthracene induced rat model. The combination therapy was evaluated for cardiac toxicity using hemodynamic profile. The angiogenic markers were evaluated using carmine staining. Monotherapy and combination therapy were also evaluated for liver and kidney toxicity through haematoxylin and eosin staining. The combination therapy also delineated the markers of oxidative stress favorably. Afterwards, the disruption of fatty acids was evaluated using gas chromatography. Results: The immunoblotting analysis validated that combination therapy has a potential to switch on the prolyl hydroxylase‐2 activity and thus initiate proteolytic degradation of hypoxia‐inducible factor‐1α and its consequence effects. The combination therapy also stimulated programmed cell death (apoptosis) in rapidly dividing cancer cells.Conclusion: The present study explores the role of voacamine in activation of prolyl hydroxylase‐2 which can decrease over expression of hypoxia‐inducible factor‐1α and fatty acid synthase in cells of mammary gland carcinoma.

Mitochondrial apoptosis and curtailment of hypoxia‐inducible factor‐1α/fatty acid synthase: A dual edge perspective of gamma linolenic acid in ER+ mammary gland cancer

Roy

Cell Biochemistry & Function

Rawat

et al. 2020

Gamma linolenic acid is a polyunsaturated fatty acid having selective anti‐tumour properties with negligible systemic toxicity. In the present study, the anti‐cancer potential of gamma linolenic acid and its effects on mitochondrial as well as hypoxia‐associated marker was evaluated. The effect of gamma linolenic acid was scrutinised against ER + MCF‐7 cells by using fluorescence microscopy, JC‐1 staining, dot plot assay and cell cycle analysis. The in vitro results were also confirmed using carcinogen (n‐methyl‐n‐nitrosourea) induced in vivo model. The early and late apoptotic signals in the conjugation with mitochondrial depolarisation were found once scrutinised through mitochondrial membrane potential and life death staining after gamma linolenic acid treatment. Gamma linolenic acid arrested the cell cycle in G0/G1 phase with the majority of cell populations in the early apoptotic stage. The translocation of phosphatidylserine was studied through annexin‐V FITC dot plot assay. The markers of cellular proliferation (decreased alveolar bud count, histopathological architecture restoration and loss of tumour micro‐vessels) were diminished after gamma linolenic acid treatment. Gamma linolenic acid ameliorates the biological effects of n‐methyl‐n‐nitrosourea persuading the mitochondrial mediated death pathway and impeding the hypoxic microenvironment to make a halt in palmitic acid synthesis.SignificanceThe present study elaborates the effect of gamma linolenic acid on mammary gland cancer by following mitochondrial‐mediated death apoptosis pathway. Gamma linolenic acid also inhibits cell‐wall synthesis by the curtailment of HIF‐1α and FASN level in mammary gland cancer.