The histone deacetylase inhibitor FK228 preferentially enhances adenovirus transgene expression in malignant cells.
OBJECTIVE
Efficient adenovirus infection requires coxsackie-adenovirus receptor (CAR) and alpha(v) integrin. Whereas many malignant cells express these proteins poorly, normal tissues, especially liver, express high levels and are susceptible to adenovirus infection. Our previous studies showed that treatment of cancer cell lines with low concentrations of the histone deacetylase inhibitor FK228 (FR901228, depsipeptide), a drug in Phase II clinical trials, before infection was associated with an increase in adenovirus transgene expression. The purpose of these studies was to analyze the effects of FK228 on cultured normal human cells before initiating animal studies.


METHODS
Cancer and normal cells from the corresponding tissue were treated with FK228 and analyzed for the proteins needed for infection and the infection efficiency.


RESULTS
Treatment of cancer cell lines with 1 ng/ml FK228 increased CAR RNA, alpha(v) integrin RNA, and histone H3 acetylation levels, and was associated with a 4-10-fold increase in the number of infected cells expressing the transgene. Similar treatment of normal human mammary epithelial cells, renal proximal tubule epithelial cells, and hepatocytes had little effect. The insensitivity of cultured normal cells may be explained, in part, by expression of the drug efflux pump P-glycoprotein, because addition of the P-glycoprotein inhibitor XR9576 (tariquidar) with FK228 resulted in increased histone acetylation and CAR expression.


CONCLUSIONS
These studies suggest that low concentrations of FK228 preferentially increase the efficiency of adenoviral transgene expression in cancer cells compared with cultured normal cells from the corresponding tissue and may increase the efficiency of adenovirus therapies in vivo.
Goldsmith
Merrill E
ME
Cancer Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
Kitazono
Masaki
M
Fok
Patrick
P
Aikou
Takashi
T
Bates
Susan
S
Fojo
Tito
T
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000107:Acetylation; D000260:Adenoviruses, Human / Q000235:genetics*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001940:Breast / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D047630:Depsipeptides; D004338:Drug Combinations; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004847:Epithelial Cells / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D022781:Hepatocytes / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D006801:Humans; D039564:Integrin alphaV / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000821:virology; D010456:Peptides, Cyclic / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism; D011991:Receptors, Virus / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019076:Transgenes / Q000187:drug effects*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; C568771:CLMP protein, human; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D047630:Depsipeptides; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D039564:Integrin alphaV; D010456:Peptides, Cyclic; D011804:Quinolines; D012333:RNA, Messenger; D012367:RNA, Viral; D011991:Receptors, Virus; C087123:romidepsin; C402343:tariquidar