Micellar delivery of bicalutamide and embelin for treating prostate cancer.
OBJECTIVE
To examine the effect of bicalutamide and embelin on the growth of prostate cancer cells in vitro and in vivo


METHODS
Cell viability was determined by MTT assay. Micelles were fabricated with polyethylene glycol-b-polylactic acid (PEG-PLA) copolymer and characterized in terms of particle size, micellar solubilization and drug loading, followed by evaluation in nude mice bearing LNCaP xenografts.


RESULTS
Embelin induced caspase 3 and 9 activation in LNCaP and C4-2 cells by decreasing XIAP expression and was more potent than bicalutamide in killing prostate tumor cells irrespective of their androgen status. As analyzed by isobologram analysis the combination of bicalutamide and embelin was synergistic for C4-2 but additive and slightly antagonistic for LNCaP cells. Micellar formulation resulted in at least 60-fold increase in the aqueous solubility of bicalutamide and embelin. Tumor growth was effectively regressed upon treatment with bicalutamide, but the extent of tumor regression was significantly higher when bicalutamide was formulated in micelles. However, tumor response to bicalutamide stopped after prolonged treatment and began to grow. Sequential treatment with XIAP inhibitor embelin resulted in regression of these hormone refractory tumors.


CONCLUSIONS
Combined treatment with bicalutamide and embelin may be an effective strategy for treating hormone refractory prostate cancer.
Danquah
Michael
M
Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN 38103-3308, USA.
Li
Feng
F
Duke
Charles B
CB
Miller
Duane D
DD
Mahato
Ram I
RI
D000813:Anilides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D016227:Benzoquinones / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D017931:DNA Primers; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008823:Micelles; D009570:Nitriles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D014105:Tosyl Compounds / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D014183:Transplantation, Heterologous
D000813:Anilides; D000970:Antineoplastic Agents; D016227:Benzoquinones; D017931:DNA Primers; D008823:Micelles; D009570:Nitriles; D014105:Tosyl Compounds; C053541:bicalutamide; C010945:embelin