Combination of proteasome and HDAC inhibitors for uterine cervical cancer treatment.
OBJECTIVE
Cervical cancer cells are addicted to the expression of the human papillomavirus (HPV) oncoproteins E6 and E7. The oncogencity of E6 is mediated in part by targeting p53 and PDZ-family tumor suppressor proteins for rapid proteasomal degradation, whereas the E7 oncoprotein acts in part by coopting histone deacetylases (HDAC)1/2. Here, we examine the hypothesis that inhibition of proteasome function and HDAC activity would synergistically and specifically trigger cervical cancer cell death by the interruption of E6 and E7 signaling.


METHODS
The sensitivity and molecular responses of keratinocytes and HPV-positive and HPV-negative cervical cancer cells and xenografts to combinations of proteasome and HDAC inhibitors were tested. The expression of HDAC1/HDAC2 in situ was examined in cervical cancer, its precursors, and normal epithelium.


RESULTS
Cervical cancer cell lines exhibit greater sensitivity to proteasome inhibitors than do HPV-negative cervical cancers or primary human keratinocytes. Treatment of cervical cancer cells with bortezomib elevated the level of p53 but not hDlg, hScribble or hMAGI. Immunohistochemical analysis revealed elevated HDAC1/HDAC2 expression in cervical dysplasia and cervical carcinoma versus normal cervical epithelium. The combination of bortezomib and HDAC inhibitor trichostatin A or vorinostat shows synergistic killing of HPV-positive, but not HPV-negative, cervical cancer cell lines. Similarly, treatment of HeLa xenografts with the combination of bortezomib and trichostatin A retarded tumor growth significantly more effectively than either agent alone.


CONCLUSIONS
A combination of proteasome and HDAC inhibitors, including bortezomib and vorinostat, respectively, warrants exploration for the treatment of cervical cancer.
Lin
Zhenhua
Z
Department of Pathology, The Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
Bazzaro
Martina
M
Wang
Mei-Cheng
MC
Chan
Kwun C
KC
Peng
Shiwen
S
Roden
Richard B S
RB
D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004848:Epithelium / Q000378:metabolism; D005260:Female; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D015603:Keratinocytes / Q000166:cytology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D015398:Signal Transduction; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000378:metabolism
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex