Flavonol and imidazole derivatives block HPV16 E6 activities and reactivate apoptotic pathways in HPV⁺ cells

Cell Death & Disease
C-H YuanPenelope J Duerksen-Hughes

Abstract

High-risk human papillomaviruses (HR-HPVs) cause nearly all cases of cervical cancer, as well as approximately 30% of head and neck cancers. HPV 16 E6, one of two major viral oncogenes, protects cells from apoptosis by binding to and accelerating the degradation of several proteins important in apoptotic signaling, including caspase 8 and p53. We proposed that blocking the interactions between HPV E6 and its partners using small molecules had the potential to re-sensitize HPV(+) cells to apoptosis. To test this idea, we screened libraries of small molecules for candidates that could block E6/caspase 8 binding and identified several candidates from different chemical classes. We tested hits for dose-dependency and specificity in vitro and for toxicity in a cell-based assay and then used this information to select the two best candidates for further testing: myricetin, a flavonol, and spinacine, an imidazole amino-acid derivative of histidine. Both compounds clearly inhibited the ability of E6 to bind in vitro to both caspase 8 and E6AP, the protein that mediates p53 degradation. In addition, both compounds were able to increase the level of caspase 8 and p53 in SiHa cervical cancer cells, resulting in an increase of caspase 3/7 ...Continue Reading

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Citations

Sep 5, 2019·Scientific Reports·Anneleen SteelsJan Gettemans
Jun 3, 2020·Medicinal Research Reviews·Avinash KumarSuvarna G Kini
Aug 13, 2020·Cellular & Molecular Biology Letters·Shuangyang TangYimou Wu
Jun 3, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Lennox Chitsike, Penelope J Duerksen-Hughes
Jul 3, 2021·Cancers·Eugenia BezzecchiRoberto Mantovani
Dec 21, 2021·Expert Opinion on Investigational Drugs·Lorenzo Messa, Arianna Loregian

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Methods Mentioned

BETA
AlphaScreen
ELISA
Assay
electrophoresis
Infrared Imaging

Software Mentioned

MRX Revelation
TimTec

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