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
References
Nov 1, 1991·Cell·T CrookK H Vousden
Dec 21, 1990·Cell·M ScheffnerP M Howley
Feb 1, 1989·Gynecologic Oncology·J T ThigpenK D Hatch
Aug 1, 1985·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·P BonomiF J Major
Aug 15, 1981·Cancer·T ThigpenJ Blessing
Jul 1, 1994·Journal of Virology·M S Lechner, L A Laimins
Nov 5, 1993·Cell·M ScheffnerP M Howley
Jan 6, 1999·Antiviral Chemistry & Chemotherapy·W C PhelpsD C Lobe
Aug 29, 2000·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·S TanakaJ R Wands
Apr 6, 2001·The Journal of Immunology : Official Journal of the American Association of Immunologists·A ChuntharapaiK J Kim
Aug 2, 2001·Nature Medicine·K IchikawaT Zhou
Nov 15, 2001·Anti-cancer Drugs·D T Rein, C M Kurbacher
Sep 16, 2003·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Anas Younes, Marshall E Kadin
Apr 10, 2004·The Journal of Biological Chemistry·Maria FilippovaPenelope J Duerksen-Hughes
Jun 1, 2004·Pharmacological Reviews·Giorgio MinottiLuca Gianni
Jun 9, 2004·Biochemistry·Yuqi LiuJames D Baleja
Jan 11, 2005·BMC Cancer·Ahmed El-ZawahryChristina Voelkel-Johnson
Mar 11, 2006·Cell Death and Differentiation·T O GarnettP J Duerksen-Hughes
May 13, 2006·Antiviral Research·James D BalejaElliot J Androphy
Feb 3, 2007·Journal of Virology·Maria FilippovaPenelope J Duerksen-Hughes
Sep 28, 2007·Journal of Virology·Christy HebnerLaimonis A Laimins
Jul 18, 2008·Journal of Virology·Sandy S TungteakkhunPenelope J Duerksen-Hughes
Jan 20, 2009·Reviews on Recent Clinical Trials·Anita C BellailChunhai Hao
Aug 20, 2009·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Constantijne H MomStefan Sleijfer
Nov 13, 2009·Journal of Virology·Sandy S TungteakkhunPenelope J Duerksen-Hughes
Jul 20, 2011·The Open Virology Journal·C M D'Abramo, J Archambault
Oct 5, 2011·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Anil K ChaturvediMaura L Gillison
Feb 4, 2012·Bioorganic & Medicinal Chemistry Letters·Chung-Hsiang YuanJohn L Krstenansky
Dec 12, 2013·Obstetrics & Gynecology Science·Tae Yeon LeeWon Gyu Kim
Sep 17, 2014·Cancers·Allie K AdamsSusanne I Wells
Citations
Mar 16, 2019·PloS One·Joel Ricci-LópezSergio Aguila
Apr 18, 2018·Scientific Reports·Lorenzo MessaArianna Loregian
Sep 5, 2019·Scientific Reports·Anneleen SteelsJan Gettemans
Jun 3, 2020·Medicinal Research Reviews·Avinash KumarSuvarna G Kini
Aug 8, 2019·BMC Molecular and Cell Biology·Srikanth KolluruJohn L Krstenansky
May 14, 2016·International Journal of Oncology·Shuyu FengMingqiu Liu
Aug 13, 2020·Cellular & Molecular Biology Letters·Shuangyang TangYimou Wu
Apr 3, 2021·Oncotarget·Lennox ChitsikePenelope J Duerksen-Hughes
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