Methylseleninic acid enhances taxane drug efficacy against human prostate cancer and down-regulates antiapoptotic proteins Bcl-XL and survivin.
OBJECTIVE
Our previous work has shown that methylseleninic acid (MSeA) sensitized hormone refractory prostate cancer (HRPCa) cells to apoptosis induced by paclitaxel (Taxol) through enhancing multiple caspases. This study aimed to (a) determine the general applicability of the sensitization effect for taxane drugs in vitro, (b) establish the enhancement of paclitaxel efficacy by MSeA in vivo, and (c) investigate Bcl-XL and survivin as molecular targets of MSeA to augment apoptosis.


METHODS
DU145 and PC-3 HRPCa cell lines were used to evaluate the in vitro apoptosis effects of paclitaxel, docetaxel and their combination with MSeA, and the molecular mechanisms. DU145 xenograft growth in athymic nude mice was used to evaluate the in vivo efficacy of paclitaxel and its combination with MSeA. The tumor samples were used to examine Bcl-XL and survivin protein abundance.


RESULTS
MSeA combination with paclitaxel or docetaxel exerted a greater than additive apoptosis effect on DU145 and PC-3 cells. In nude mice, paclitaxel and MSeA combination inhibited growth of DU145 subcutaneous xenograft with the equivalent efficacy of a four-time higher dose of paclitaxel alone. MSeA decreased the basal and paclitaxel-induced expression of Bcl-XL and survivin in vitro and in vivo. Ectopic expression of Bcl-XL or survivin attenuated MSeA/paclitaxel-induced apoptosis.


CONCLUSIONS
MSeA enhanced the efficacy of paclitaxel against HRPCa in vitro and in vivo, at least in part, by down-regulating the basal and paclitaxel-induced expression of both Bcl-XL and survivin to increase caspase-mediated apoptosis. MSeA may be a novel agent to improve taxane combination therapy.
Hu
Hongbo
H
The Hormel Institute, University of Minnesota, Austin, Minnesota 55912, USA.
Li
Guang-Xun
GX
Wang
Lei
L
Watts
Jennifer
J
Combs
Gerald F
GF
Lü
Junxuan
J
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D000077143:Docetaxel; D015536:Down-Regulation; D004357:Drug Synergism; D006801:Humans; D015151:Immunoblotting; D051034:Inhibitor of Apoptosis Proteins; D008297:Male; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000187:drug effects* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000187:drug effects* / Q000378:metabolism; D016566:Organoselenium Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics; D017239:Paclitaxel / Q000008:administration & dosage / Q000493:pharmacokinetics; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077022:Survivin; D043823:Taxoids / Q000008:administration & dosage / Q000493:pharmacokinetics; D023041:Xenograft Model Antitumor Assays; D051020:bcl-X Protein / Q000187:drug effects* / Q000378:metabolism
C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D016566:Organoselenium Compounds; D000077022:Survivin; D043823:Taxoids; D051020:bcl-X Protein; D000077143:Docetaxel; C008493:methylselenic acid; D017239:Paclitaxel