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

Lakhveer Singh,Ritu Raj,Gaurav Kaithwas,Anurag Choudhary,Abdulaziz S Saeedan,Shubham Rastogi,Manjari Singh,Mohd Nazam Ansari,Dinesh Kumar

doi:10.1186/s12860-021-00371-9

Abstract

BackgroundIn 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.ResultsAt 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.ConclusionResults 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.

Highlights

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
When the tumor size increases and becomes symptomatic, it becomes irresponsive to radiotherapy and chemotherapy due to the development of hypoxia, a condition characterized by low oxygen [5]
Tamoxifen (TMX) is an approved drug for mammary gland carcinoma, and the presence of estrogen receptors (ER) on the cancer cells is a must for its activity

Summary

Introduction

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 originates in breast tissue cells, in the lobules (milk glands) or in the ducts, which connect the lobules with the nipple [1]. Uncontrolled dividing of these cells forms a mass or lump at the site of their origin, transforming itself into malignant neoplasm if it remains undiagnosed [2,3,4]. TMX fails to illicit its cytotoxic effect in solid hypoxic malignant tumors of the mammary gland

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Conclusion