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Published on: March 8, 2012
Flavonol and imidazole derivatives block HPV16 E6 activities and reactivate apoptotic pathways in HPV⁺ cells
C-H Yuan1, M Filippova1, J L Krstenansky2
1Department of Basic Sciences, Loma Linda University School of Medicine, 11021 Campus Street, 101 Alumni Hall, Loma Linda, CA 92354, USA.
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 activity. Finally, both myricetin and spinacine sensitized HPV(+) cervical and oral cancer cells, but not HPV(-) cervical and oral cancer cells, to apoptosis induced by the cancer-specific ligand TRAIL, as well as the chemotherapeutic agents doxorubicin and cisplatin. New therapies based on this work may improve treatment for HPV(+) cancer patients.
Insights
Small molecules like myricetin and spinacine can block high-risk human papillomavirus (HR-HPV) oncoprotein E6 interactions, restoring apoptosis in cancer cells. This research offers potential new therapies for HR-HPV-positive cancers.
Area of Science:
- Oncology
- Virology
- Molecular Biology
Background:
- High-risk human papillomaviruses (HR-HPVs) are linked to cervical and head and neck cancers.
- The HPV 16 E6 oncoprotein promotes cancer by inhibiting apoptosis, a programmed cell death process.
- Targeting E6-protein interactions could restore apoptosis in HPV-positive cancer cells.
Purpose of the Study:
- To identify small molecules that disrupt the interaction between HPV E6 and its cellular partners.
- To evaluate the potential of these molecules to re-sensitize cancer cells to apoptosis.
Main Methods:
- Screening of small molecule libraries to find inhibitors of E6/caspase 8 binding.
- In vitro testing for dose-dependency, specificity, and toxicity of candidate compounds.
- Assessing the effect of selected compounds (myricetin and spinacine) on apoptosis signaling pathways in cancer cells.
- Evaluating the sensitization of HPV-positive cancer cells to apoptosis-inducing agents.
Main Results:
- Myricetin and spinacine inhibited in vitro binding of HPV E6 to caspase 8 and E6AP.
- These compounds increased levels of caspase 8 and p53 in SiHa cervical cancer cells, enhancing caspase 3/7 activity.
- Myricetin and spinacine sensitized HPV-positive cervical and oral cancer cells, but not HPV-negative cells, to TRAIL, doxorubicin, and cisplatin-induced apoptosis.
Conclusions:
- Myricetin and spinacine effectively disrupt HPV E6 interactions and restore apoptosis in cancer cells.
- These compounds show promise as novel therapeutic agents for treating HR-HPV-associated cancers.
- Further development of these small molecules could lead to improved treatment outcomes for patients with HPV-positive malignancies.
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