ReferenceID 6238
Squalene deters drivers of RCC disease progression beyond VHL status
Cell Biol Toxicol
Identifying drug candidates to target cellular events/signaling that evades von Hippel-Lindau tumor suppressor (VHL) gene interaction is critical for the cure of renal cell carcinoma (RCC). Recently, we characterized a t
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Record Fields
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- Reference Id
- 6238
- Evidence Id
- 22828
- Core Evidence Id
- 22828
- Source Reference Id
- 5756
- Herb2 Reference Id
- HBREF006553
- Subject Paper Key
- HBIN044654_33219891
- Pubmed Id
- 33219891
- Doi
- 10.1007/s10565-020-09566-w
- Paper Title
- Squalene deters drivers of RCC disease progression beyond VHL status
- Paper Abstract
- Identifying drug candidates to target cellular events/signaling that evades von Hippel-Lindau tumor suppressor (VHL) gene interaction is critical for the cure of renal cell carcinoma (RCC). Recently, we characterized a triterpene-squalene derived from marine brown alga. Herein, we investigated the potential of squalene in targeting HIF-signaling and other drivers of RCC progression. Squalene inhibited cell proliferation, induced cell dealth and reverted the cells' metastatic state (migration, clonal expansion) independent of their VHL status. Near-identical inhibition of HIF-1alpha and HIF-2alpha and the regulation of downstream targets in VHL wild type and mutant cell lines demonstrated squalene efficacy beyond VHL-HIF interaction. In a rat model of chemically induced RCC, squalene displayed chemopreventive capabilities by substantial reversal of lipid peroxidation, mitochondrial redox regulation, maintaining psim, inflammation [Akt, nuclear factor kappaB (NF-kappaB)], angiogenesis (VEGFalpha), metastasis [matrix metalloproteinase 2 (MMP-2)], and survival (Bax/Bcl2, cytochrome-c, Casp3). Squalene restored glutathione, glutathione reductase, glutathione-s-transferase, catalase, and superoxide dismutase and stabilized alkaline phosphatase, alkaline transaminase, and aspartate transaminase. The correlation of thiobarbituric acid reactive substance with VEGF/NF-kappaB and negative association of GSH with Casp3 show that squalene employs reduction in ROS regulation. Cytokinesis-block micronuclei (CBMN) assay in VHLwt/mut cells revealed both direct and bystander effects of squalene with increased micronucleus (MN) frequency. Clastogenicity analysis of rat bone marrow cells demonstrated an anti-clastogenic effect of squalene, with increased polychromatic erythrocytes (PCEs), decreased MNPCE,s and MN normochromatic erythrocytes. Squalene could effectively target HIF signaling that orchestrate RCC evolution. The efficacy of squalene is similar in VHLwt and VHLmut RCC cells, and hence, squalene could serve as a promising drug candidate for an RCC cure beyond VHL status and VHL-HIF interaction dependency. Summary: Squalene derived from marine brown algae displays strong anti-cancer (RCC) activity, functionally targeting HIF-signaling pathway, and affects various cellular process. The significance of squalene effect for RCC is highlighted by its efficiency beyond VHL status, designating itself a promising drug candidate. Graphical abstract.
- Journal
- Cell Biol Toxicol
- Publish Year
- 2021
- Experiment Subject
- rat; vhl wild type and mutant cell lines; vhlmut rcc cells; vhlwt; vhlwt/mut cells
- Experiment Type
- Animal & Cell Experiment
- Phenotype Related
- Von Hippel-lindau Tumor; Renal Cell Carcinoma
- Paper Title Cn
- Paper Title En
- Squalene deters drivers of RCC disease progression beyond VHL status
- Bilingual Status
- semi_complete