Small Molecule Inhibitors of HPV16 E6

<p>High-risk human papillomaviruses (HR-HPVs) cause nearly all cases of cervical cancer. HPV 16 E6, one of two viral oncogenes, protects cells from apoptosis by binding to and accelerating the degradation of several apoptotic proteins, 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 prediction, we screened libraries of small molecules for candidates that could block E6/caspase 8 binding, and identified several candidates from different chemical classes. Testing hits for dose-dependency and specificity in vitro and for toxicity in a cell-based assay allowed us to select the two best candidates, myricetin and 6,7-dihydro-1H-imidazo[4,5-c] pyridine-6-carboxylic acid (DIPC), for further testing. Both compounds significantly and specifically inhibited the ability of E6 to bind in vitro to both caspase 8 and to E6AP, the protein that mediates p53 degradation. In addition, both compounds were able to increase caspase 3/7 activity and to sensitize HPV+ SiHa cells, but not HPV- C33A cells, to apoptosis induced by TRAIL, a cancer-specific ligand, as well as the chemotherapeutic agents doxorubicin and cisplatin. New therapies based on this work may improve treatment for HPV+ cancer patients.</p>

Name thesis:degree_name

Doctor of Philosophy (Medical Science)

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Microbiology

Year

2013

Author dc:creator

• Yuan, Chung-Hsiang

Contributors dc:contributor

• Penelope J. Duerksen-Hughes
• Maria Filippova
• Daila S. Gridley
• John L. Krstenansky
• Ubaldo Soto
• Ron E. Swensen

• Medical Genetics
• Medical Microbiology
• Molecular Genetics
• Human papilloma virus; HPV E6

Statement dc:rights

• This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.

Language dc:language

English

Repository record dc:identifier

https://scholarsrepository.llu.edu/etd/1211

OAI identifier oai:identifier

oai:scholarsrepository.llu.edu:etd-2729