The mechanism of methylselenocysteine and docetaxel synergistic activity in prostate cancer cells.
The study was designed to evaluate the combination treatment of methylselenocysteine (MSeC) and docetaxel and to delineate the underlying mechanism associated with observed in vitro synergy between MSeC and docetaxel in prostate cancer cells. Cells were treated with different concentrations and schedules (concurrent or sequential) of MSeC and docetaxel alone or in combination. Cell growth/death was assessed with sulforhodamine B assay, trypan blue assay, and time-lapse video. Loewe synergism/antagonism model was used to determine whether the combination effect was additive, synergistic, or antagonistic. Apoptosis and caspase-3 activity were evaluated with cell death ELISA assay and caspase activity assay, respectively. Synergy between MSeC and docetaxel was further assessed in the presence and absence of z-VAD-fmk, a pan-caspase inhibitor. Effect of MSeC and docetaxel alone or in combination on the cellular expression of the antiapoptotic protein survivin was measured with Western blot analyses. Pretreatment with MSeC was crucial to enhance docetaxel antitumor activity. The enhanced antitumor activity of the sequential combination treatment of MSeC and docetaxel (MSeC/docetaxel) was highly synergistic. Apoptosis increased after MSeC/docetaxel, compared with each drug alone or concurrent treatment. Pretreatment with z-VAD-fmk converted the synergy into antagonism, suggesting that the synergy is caspase-dependent apoptosis. The survivin level was down-regulated following MSeC/docetaxel treatment when compared with each drug alone. In conclusion, pretreatment with MSeC was essential to markedly sensitize cells to docetaxel. The synergy between MSeC and docetaxel in C2G prostate cancer cells is associated with increased level of caspase-dependent apoptosis and decreased level of survivin.
Azrak
Rami G
RG
Department of Cancer Biology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA. azrak@roswellpark.org
Frank
Cheryl L
CL
Ling
Xiang
X
Slocum
Harry K
HK
Li
Fengzhi
F
Foster
Barbara A
BA
Rustum
Youcef M
YM
D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D003545:Cysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077143:Docetaxel; D015536:Down-Regulation; D004357:Drug Synergism; D004789:Enzyme Activation; D051034:Inhibitor of Apoptosis Proteins; D008297:Male; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis; D009363:Neoplasm Proteins / Q000096:biosynthesis; D016566:Organoselenium Compounds / Q000494:pharmacology*; D011471:Prostatic Neoplasms; D017279:Selenocysteine / Q000031:analogs & derivatives; D000077022:Survivin; D043823:Taxoids / Q000494:pharmacology*
D016588:Anticarcinogenic Agents; D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D016566:Organoselenium Compounds; D000077022:Survivin; D043823:Taxoids; D017279:Selenocysteine; D000077143:Docetaxel; D053148:Caspase 3; D003545:Cysteine; C002979:selenomethylselenocysteine