In vivo evidence of gamma-tocotrienol as a chemosensitizer in the treatment of hormone-refractory prostate cancer.
gamma-Tocotrienol (gammaT3) is known to selectively kill prostate cancer (PCa) cells and to sensitize the cells to docetaxel (DTX)-induced apoptosis. In the present study, the pharmacokinetics of gammaT3 and the in vivo cytotoxic response of androgen-independent prostate cancer (AIPCa) tumor following gammaT3 treatment were investigated. Here, we investigated these antitumor effects for PCa tumors in vivo. The pharmacokinetic and tissue distribution of gammaT3 after exogenous gammaT3 supplementation were examined. Meanwhile, the response of the tumor to gammaT3 alone or in combination with DTX were studied by real-time in vivo bioluminescent imaging and by examination of biomarkers associated with cell proliferation and apoptosis. After intraperitoneal injection, gammaT3 rapidly disappeared from the serum and was selectively deposited in the AIPCa tumor cells. Administration of gammaT3 alone for 2 weeks resulted in a significant shrinkage of the AIPCa tumors. Meanwhile, further inhibition of the AIPCa tumor growth was achieved by combined treatment of gammaT3 and DTX (p < 0.002). The in vivo cytotoxic antitumor effects induced by gammaT3 seem to be associated with a decrease in expression of cell proliferation markers (proliferating cell nuclear antigen, Ki-67 and Id1) and an increase in the rate of cancer cell apoptosis [cleaved caspase 3 and poly(ADP-ribose) polymerase]. Additionally, the combined agents may be more effective at suppressing the invasiveness of AIPCa. Overall, our results indicate that gammaT3, either alone or in combination with DTX, may provide a treatment strategy that can improve therapeutic efficacy against AIPCa while reducing the toxicity often seen in patients treated with DTX.
Yap
W N
WN
Davos Life Science, Cancer Research Laboratory, Singapore, Singapore.
Zaiden
N
N
Luk
S Y
SY
Lee
D T W
DT
Ling
M T
MT
Wong
Y C
YC
Yap
Y L
YL
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015820:Cadherins / Q000096:biosynthesis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002839:Chromans / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D014018:Tissue Distribution; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use
D000970:Antineoplastic Agents; D015820:Cadherins; D002839:Chromans; D014810:Vitamin E; C013649:plastochromanol 8