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

Singh, Lakhveer; Roy, Subhadeep; Kumar, Anurag; Rastogi, Shubham; Kumar, Dinesh; Ansari, Mohd Nazam; Saeedan, Abdulaziz S.; Singh, Manjari; Kaithwas, Gaurav

doi:10.3389/fcell.2021.736910

Cited by 9 publications

(7 citation statements)

References 67 publications

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“…In addition, up-regulation of HIF-1α level was found to be closely associated with dysfunction of mitochondria, which can induce mammary gland carcinoma progression (Singh et al, 2021b). Polyl hydroxylase (PHD-2) activation was considered as a novel strategy to control HIF-1α to modulate mitochondrial stress in mammary gland pathophysiology of ER + subtype (Singh et al, 2021a). Meanwhile, down-regulation of HIF-1α/fatty acid synthase co-axis was shown to combat tumor growth in mammary gland carcinoma by activating PHD-2 (Gautam et al, 2018) (Manral et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Roxadustat (FG-4592) Facilitates Recovery From Renal Damage by Ameliorating Mitochondrial Dysfunction Induced by Folic Acid

et al. 2022

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Incomplete recovery from acute kidney injury induced by folic acid is a major risk factor for progression to chronic kidney disease. Mitochondrial dysfunction has been considered a crucial contributor to maladaptive repair in acute kidney injury. Treatment with FG-4592, an inhibitor of hypoxia inducible factor prolyl-hydroxylase, is emerging as a new approach to attenuate renal damage; however, the underlying mechanism has not been fully elucidated. The current research demonstrated the protective effect of FG-4592 against renal dysfunction and histopathological damage on the 7th day after FA administration. FG-4592 accelerated tubular repair by promoting tubular cell regeneration, as indicated by increased proliferation of cell nuclear antigen-positive tubular cells, and facilitated structural integrity, as reflected by up-regulation of the epithelial inter-cellular tight junction molecule occludin-1 and the adherens junction molecule E-cadherin. Furthermore, FG-4592 ameliorated tubular functional recovery by restoring the function-related proteins aquaporin1, aquaporin2, and sodium chloride cotransporter. Specifically, FG-4592 pretreatment inhibited hypoxia inducible factor-1α activation on the 7th day after folic acid injection, which ameliorated ultrastructural abnormalities, promoted ATP production, and attenuated excessive reactive oxygen species production both in renal tissue and mitochondria. This was mainly mediated by balancing of mitochondrial dynamics, as indicated by down-regulation of mitochondrial fission 1 and dynamin-related protein 1 as well as up-regulation of mitofusin 1 and optic atrophy 1. Moreover, FG-4592 pretreatment attenuated renal tubular epithelial cell death, kidney inflammation, and subsequent interstitial fibrosis. In vitro, TNF-α-induced HK-2 cells injury could be ameliorated by FG-4592 pretreatment. In summary, our findings support the protective effect of FG-4592 against folic acid-induced mitochondrial dysfunction; therefore, FG-4592 treatment can be used as a useful strategy to facilitate tubular repair and mitigate acute kidney injury progression.

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Section: Discussionmentioning

confidence: 99%

Roxadustat (FG-4592) Facilitates Recovery From Renal Damage by Ameliorating Mitochondrial Dysfunction Induced by Folic Acid

et al. 2022

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“…IX-53) at 4× magnification. [34,35] 2.4.5 | Histopathology using haematoxylin and eosin (H&E) staining H&E staining was utilised to ascertain morphological shifts that had occurred in the architecture of the mammary gland. In a nutshell, tissue specimens were fixed in a formalin solution containing 10% formaldehyde and casted inside wax blocks.…”

Section: Carmine Stainingmentioning

confidence: 99%

Novel furan chalcone modulates PHD‐2 induction to impart antineoplastic effect in mammary gland carcinoma

Rastogi,

Ansari,

Saeedan

et al. 2024

J Biochem & Molecular Tox

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Normoxic inactivation of prolyl hydroxylase‐2 (PHD‐2) in tumour microenvironment paves the way for cancer cells to thrive under the influence of HIF‐1α and NF‐κB. Henceforth, the present study is aimed to identify small molecule activators of PHD‐2. A virtual screening was conducted on a library consisting of 265,242 chemical compounds, with the objective of identifying molecules that exhibit structural similarities to the furan chalcone scaffold. Further, PHD‐2 activation potential of screened compound was determined using in vitro 2‐oxoglutarate assay. The cytotoxic activity and apoptotic potential of screened compound was determined using various staining techniques, including 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl tetrazolium bromide, 4′,6‐diamidino‐2‐phenylindole (DAPI), 1,1′,3,3′‐tetraethylbenzimi‐dazolylcarbocyanine iodide (JC‐1), and acridine orange/ethidium bromide (AO/EB), against MCF‐7 cells. 7,12‐Dimethylbenz[a]anthracene (DMBA) model of mammary gland cancer was used to study the in vivo antineoplastic efficacy of screened compound. [(E)‐1‐(4‐fluorophenyl)‐3‐(furan‐2‐yl) prop‐2‐en‐1‐one] (BBAP‐7) was screened and validated as a PHD‐2 activator by an in vitro 2‐oxo‐glutarate assay. The IC50 of BBAP‐7 on MCF‐7 cells is 18.84 µM. AO/EB and DAPI staining showed nuclear fragmentation, blebbing and condensation in MCF‐7 cells following BBAP‐7 treatment. The red‐to‐green intensity ratio of JC‐1 stained MCF‐7 cells decreased after BBAP‐7 treatment, indicating mitochondrial‐mediated apoptosis. DMBA caused mammary gland dysplasia, duct hyperplasia and ductal carcinoma in situ. Carmine staining, histopathology, and scanning electron microscopy demonstrated that BBAP‐7, alone or with tirapazamine, restored mammary gland surface morphology and structural integrity. Additionally, BBAP‐7 therapy significantly reduced oxidative stress and glycolysis. The findings reveal that BBAP‐7 activates PHD‐2, making it a promising anticancer drug.

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“…Many studies have reported that FASN activity is required for lipid biosynthesis and cellular proliferation in various cancer pathologies ( Currie et al, 2013 ; Zaidi et al, 2013 ). Moreover, downregulation of FASN was found to promote breast cancer prognosis ( Roy et al, 2020 ; Singh et al, 2021b ; 2021a ) ( Singh et al, 2016 ; Roy et al, 2017 ; Singh M. et al, 2018 ; Devi et al, 2019a ). It has been suggested that FASN activity is upregulated in response to an increase in the expression of SREBP-1c by HIF-1α ( Furuta et al, 2008 ; Singh L. et al, 2018 ).…”

Section: How Do Tumor Cells Adapt Under Hypoxia?mentioning

confidence: 99%

NF-κB mediated regulation of tumor cell proliferation in hypoxic microenvironment

et al. 2023

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Hypoxia is caused by a cancer-promoting milieu characterized by persistent inflammation. NF-κB and HIF-1α are critical participants in this transition. Tumor development and maintenance are aided by NF-κB, while cellular proliferation and adaptability to angiogenic signals are aided by HIF-1α. Prolyl hydroxylase-2 (PHD-2) has been hypothesized to be the key oxygen-dependent regulator of HIF-1α and NF-transcriptional B’s activity. Without low oxygen levels, HIF-1α is degraded by the proteasome in a process dependent on oxygen and 2-oxoglutarate. As opposed to the normal NF-κB activation route, where NF-κB is deactivated by PHD-2-mediated hydroxylation of IKK, this method actually activates NF-κB. HIF-1α is protected from degradation by proteasomes in hypoxic cells, where it then activates transcription factors involved in cellular metastasis and angiogenesis. The Pasteur phenomenon causes lactate to build up inside the hypoxic cells. As part of a process known as lactate shuttle, MCT-1 and MCT-4 cells help deliver lactate from the blood to neighboring, non-hypoxic tumour cells. Non-hypoxic tumour cells use lactate, which is converted to pyruvate, as fuel for oxidative phosphorylation. OXOPHOS cancer cells are characterized by a metabolic switch from glucose-facilitated oxidative phosphorylation to lactate-facilitated oxidative phosphorylation. Although PHD-2 was found in OXOPHOS cells. There is no clear explanation for the presence of NF-kappa B activity. The accumulation of the competitive inhibitor of 2-oxo-glutarate, pyruvate, in non-hypoxic tumour cells is well established. So, we conclude that PHD-2 is inactive in non-hypoxic tumour cells due to pyruvate-mediated competitive suppression of 2-oxo-glutarate. This results in canonical activation of NF-κB. In non-hypoxic tumour cells, 2-oxoglutarate serves as a limiting factor, rendering PHD-2 inactive. However, FIH prevents HIF-1α from engaging in its transcriptional actions. Using the existing scientific literature, we conclude in this study that NF-κB is the major regulator of tumour cell growth and proliferation via pyruvate-mediated competitive inhibition of PHD-2.

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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

Cited by 9 publications

References 67 publications

Roxadustat (FG-4592) Facilitates Recovery From Renal Damage by Ameliorating Mitochondrial Dysfunction Induced by Folic Acid

Roxadustat (FG-4592) Facilitates Recovery From Renal Damage by Ameliorating Mitochondrial Dysfunction Induced by Folic Acid

Novel furan chalcone modulates PHD‐2 induction to impart antineoplastic effect in mammary gland carcinoma

NF-κB mediated regulation of tumor cell proliferation in hypoxic microenvironment

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