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
| العنوان: | 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 |
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| المؤلفون: | Abdulaziz S. Saeedan, Gaurav Kaithwas, Lakhveer Singh, Mohd Nazam Ansari, Subhadeep Roy, Dinesh Kumar, Shubham Rastogi, Anurag Kumar, Manjari Singh |
| المصدر: | Frontiers in Cell and Developmental Biology Frontiers in Cell and Developmental Biology, Vol 9 (2021) |
| بيانات النشر: | Frontiers Media S.A., 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Programmed cell death, hypoxia inducible factor-1α (HIF-1α), Combination therapy, biology, QH301-705.5, Chemistry, repurposable drugs, voacamine, Cell Biology, fatty acid synthase (FASN), Blot, Fatty acid synthase, Cell and Developmental Biology, Downregulation and upregulation, Hypoxia-inducible factors, Apoptosis, Cancer cell, biology.protein, Cancer research, prolyl hydroxylase-2, mammary gland carcinoma, Biology (General), Developmental Biology, Original Research |
| الوصف: | The current study investigated the role of combination therapy with voacamine and vincristine in preventing mammary gland carcinoma through prolyl hydroxylase-2 activation. Prolyl hydroxylase-2 activation leads to the downregulation of hypoxia-inducible factor-1α and fatty acid synthase. Overexpression of hypoxia-inducible factor-1α and fatty acid synthase has been previously reported in solid tumors of the mammary gland. After screening a battery of natural compounds similar to vincristine, voacamine was selected as a possible prolyl hydroxylase-2 activator, and its activity was evaluated using a 7,12-dimethylbenz[a]anthracene-induced rat model. The combination therapy was evaluated for cardiac toxicity using a hemodynamic profile. Angiogenic markers were evaluated by carmine staining. Monotherapy and combination therapy were also evaluated for liver and kidney toxicity using hematoxylin and eosin staining. The antioxidant potential was delineated using oxidative stress markers. The serum metabolomic profile was studied using NMR spectroscopy, and the disruption of fatty acids was evaluated using gas chromatography. Western blotting of proteins involved in hypoxic pathways was performed to decipher the action of therapy at the molecular level. Immunoblotting analysis validated that combination therapy has potential toss with prolyl hydroxylase-2 activity and thus initiates proteolytic degradation of hypoxia-inducible factor-1α and its consequent effects. Combination therapy also stimulated programmed cell death (apoptosis) in rapidly dividing cancer cells. The present study explored the role of voacamine inactivation of prolyl hydroxylase-2, which can decrease the overexpression of hypoxia-inducible factor-1α and fatty acid synthase in mammary gland carcinoma cells. Graphical Abstract Mechanism 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. |
| اللغة: | English |
| تدمد: | 2296-634X |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::fb985b21c1295c11c3d3580ef38a5941 http://europepmc.org/articles/PMC8637442 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....fb985b21c1295c11c3d3580ef38a5941 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 2296634X |
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