Antagonistic effects of sodium butyrate and N-(4-hydroxyphenyl)-retinamide on prostate cancer.
Butyrates and retinoids are promising antineoplastic agents. Here we analyzed effects of sodium butyrate and N-(4-hydroxyphenyl)-retinamide (4-HPR) on prostate cancer cells as monotherapy or in combination in vitro and in vivo. Sodium butyrate and 4-HPR induced concentration-dependent growth inhibition in prostate cancer cells in vitro. The isobologram analysis revealed that sodium butyrate and 4-HPR administered together antagonize effects of each other. For the in vivo studies, a water-soluble complex (4-HPR with a cyclodextrin) was created. A single dose of sodium butyrate and 4-HPR showed a peak level in chicken plasma within 30 minutes. Both compounds induced inhibition of proliferation and apoptosis in xenografts of the chicken chorioallantoic membrane. Analysis of the cytotoxic effects of the drugs used in combination demonstrated an antagonistic effect on inhibition of proliferation and on induction of apoptosis. Prolonged jun N-terminal kinase phosphorylation induced by sodium butyrate and 4-HPR was strongly attenuated when both compounds were used in combination. Both compounds induced inhibition of NF-kappaB. This effect was strongly antagonized in LNCaP cells when the compounds were used in combination. These results indicate that combinational therapies have to be carefully investigated due to potential antagonistic effects in the clinical setting despite promising results of a monotherapy.
Kuefer
Rainer
R
Department of Urology and the Comprehensive Cancer Center Ulm, University of Ulm, 89075 Ulm, Germany. rainer.kuefer@uni-ulm.de
Genze
Felicitas
F
Zugmaier
Waltraud
W
Hautmann
Richard E
RE
Rinnab
Ludwig
L
Gschwend
Juergen E
JE
Angelmeier
Marina
M
Estrada
Aidee
A
Buechele
Berthold
B
D000818:Animals; D002087:Butyrates / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002645:Chickens; D049033:Chorioallantoic Membrane / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D017313:Fenretinide / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000502:physiology; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D014183:Transplantation, Heterologous
D002087:Butyrates; D017313:Fenretinide; D020928:Mitogen-Activated Protein Kinases