Repurposing combination therapy of Voacamine with Vincristine for down regulation of HIF-1α/FASN co-axis and PHD2 activation in ER+ mammary neoplasia

Abstract 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.

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

10.21203/rs.3.rs-34012/v1 ◽

2020 ◽

Author(s):

Lakhveer Singh ◽

Manjari Singh ◽

Mohd. Nazam Ansari ◽

Abdulaziz S. Saeedan ◽

Gaurav Kaithwas

Keyword(s):

Mammary Gland ◽

Fatty Acid ◽

Combination Therapy ◽

Fatty Acid Synthase ◽

Hypoxia Inducible Factor ◽

Prolyl Hydroxylase ◽

Over Expression ◽

Hypoxia Inducible Factor 1Α ◽

Gland Carcinoma

Abstract 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.

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

RSC Advances ◽

10.1039/c8ra01239c ◽

2018 ◽

Vol 8 (23) ◽

pp. 12848-12860 ◽

Cited By ~ 7

Author(s):

Manjari Singh ◽

Uma Devi ◽

Subhadeep Roy ◽

Pushpraj S. Gupta ◽

Gaurav Kaithwas

Keyword(s):

Mammary Gland ◽

Fatty Acid ◽

Fatty Acid Synthase ◽

Chemical Activation ◽

Hypoxia Inducible Factor ◽

Prolyl Hydroxylase ◽

Phenyl Acetate ◽

Hypoxia Inducible Factor 1Α

(4-[7-(Acetyloxy)-2-ethyl-2H-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 dependentin vitroassay.

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Prolyl hydroxylase mediated inhibition of fatty acid synthase to combat tumor growth in mammary gland carcinoma

Breast Cancer ◽

10.1007/s12282-016-0683-6 ◽

2016 ◽

Vol 23 (6) ◽

pp. 820-829 ◽

Cited By ~ 10

Author(s):

Manjari Singh ◽

Uma Devi ◽

Subhadeep Roy ◽

Pushpraj S. Gupta ◽

Shubhini A. Saraf ◽

...

Keyword(s):

Mammary Gland ◽

Fatty Acid ◽

Tumor Growth ◽

Fatty Acid Synthase ◽

Prolyl Hydroxylase ◽

Mammary Gland Carcinoma ◽

Gland Carcinoma

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Repurposing Combination Therapy of Voacamine With Vincristine for Downregulation of Hypoxia-Inducible Factor-1α/Fatty Acid Synthase Co-axis and Prolyl Hydroxylase-2 Activation in ER+ Mammary Neoplasia

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.736910 ◽

2021 ◽

Vol 9 ◽

Author(s):

Lakhveer Singh ◽

Subhadeep Roy ◽

Anurag Kumar ◽

Shubham Rastogi ◽

Dinesh Kumar ◽

...

Keyword(s):

Fatty Acid ◽

Tumor Microenvironment ◽

Fatty Acid Synthesis ◽

Fatty Acid Synthase ◽

Regulatory Element ◽

Hypoxia Inducible Factor ◽

Acid Synthesis ◽

Prolyl Hydroxylase ◽

Proliferating Cells ◽

Hypoxia Inducible Factor 1Α

Graphical AbstractMechanism of VOA and VIN to inhibit fatty acid synthesis in DMBA-induced mammary gland carcinoma of albino Wistar rats. Hypoxia-activated HIF-1α enhances lactate acidosis in the tumor microenvironment, and dysregulated pH in the tumor microenvironment activates SREBP-1c and FASN expression to speed up the fatty acid synthesis required for plasma membrane synthesis in rapidly proliferating cells. VOA- and VIN-activated PHD-2 enhanced the proteolytic degradation of HIF, thus inhibiting fatty acid synthesis. HIF-1α, hypoxia-inducible factor-1α; SREBP-1c, sterol regulatory element-binding protein-1c; FASN, fatty acid synthesis; PHD-2, prolyl hydroxylase-2.

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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

Cell Biochemistry and Function ◽

10.1002/cbf.3513 ◽

2020 ◽

Vol 38 (5) ◽

pp. 591-603

Author(s):

Subhadeep Roy ◽

Manjari Singh ◽

Atul Rawat ◽

Dinesh Kumar ◽

Gaurav Kaithwas

Keyword(s):

Mammary Gland ◽

Fatty Acid ◽

Linolenic Acid ◽

Fatty Acid Synthase ◽

Hypoxia Inducible Factor ◽

Mitochondrial Apoptosis ◽

Gamma Linolenic Acid ◽

Hypoxia Inducible Factor 1Α ◽

Mammary Gland Cancer

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Effect of Voacamine upon inhibition of hypoxia induced fatty acid synthesis in a rat model of methyln-nitrosourea induced mammary gland carcinoma

BMC Molecular and Cell Biology ◽

10.1186/s12860-021-00371-9 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Lakhveer Singh ◽

Manjari Singh ◽

Shubham Rastogi ◽

Anurag Choudhary ◽

Dinesh Kumar ◽

...

Keyword(s):

Mammary Gland ◽

Fatty Acid ◽

Fatty Acid Synthesis ◽

Acid Synthesis ◽

Prolyl Hydroxylase ◽

Angiogenic Potential ◽

Mammary Gland Tissue ◽

Mammary Gland Carcinoma ◽

Gland Tissue ◽

Gland Carcinoma

Abstract Background In the present study, fatty acid synthesis is targeted to combat mammary gland carcinoma by activating prolyl hydroxylase-2 with Voacamine alone and in combination with Tamoxifen. It was hypothesized that the activation of prolyl hydroxylase-2 would inhibit the hypoxia-induced fatty acid synthesis and mammary gland carcinoma. Mammary gland carcinoma was induced with a single dose administration of N-methyl-N-nitrosourea (50 mg/kg,i.p.) and treatment with Voacamine and Tamoxifen 15 days after carcinogen administration. Results At the end of the study, hemodynamic profiling of animals was recorded to assess the cardiotoxic potential of the drug. Blood serum was separated and subjected to nuclear magnetic resonance spectroscopy. Carmine staining and histopathology of mammary gland tissue were performed to evaluate the anti-angiogenic potential of the drug. The antioxidant potential of the drug was measured with antioxidant markers. Western blotting was performed to study the effect of the drug at the molecular level. Conclusion Results of the study have shown that Voacamine treatment stopped further decrease in body weight of experimental animals. The hemodynamic study evidenced that Voacamine at a low dose is safe in cardiac patients. Microscopic evaluation of mammary gland tissue documented the anti-angiogenic potential of Voacamine and Tamoxifen therapy. Perturbed serum metabolites were also restored to normal along with antioxidant markers. Immunoblotting of mammary gland tissue also depicted restoration of proteins of the hypoxic and fatty acid pathway. Conclusively, Voacamine and its combination with Tamoxifen activated prolyl hydroxylase-2 to combat mammary gland carcinoma.

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