In vivo Evidence of γ-Tocotrienol as a Chemosensitizer in the Treatment of Hormone-Refractory Prostate Cancer

Abstract

γ-Tocotrienol (γT3) 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 γT3 and the in vivo cytotoxic response of androgen-independent prostate cancer (AIPCa) tumor following γT3 treatment were investigated. Here, we investigated these antitumor effects for PCa tumors in vivo. The pharmacokinetic and tissue distribution of γT3 after exogenous γT3 supplementation were examined. Meanwhile, the response of the tumor to γT3 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, γT3 rapidly disappeared from the serum and was selectively deposited in the AIPCa tumor cells. Administration of γT3 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 γT3 and DTX (p < 0.002). The in vivo cytotoxic antitumor effects induced by γT3 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 γT3, 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.

γ-Tocotrienol Inhibits Pancreatic Tumors and Sensitizes Them to Gemcitabine Treatment by Modulating the Inflammatory Microenvironment

“…Previously, it has been reported that γ-T3 can enhance the effect of gefitinib, docetaxel, celecoxib and statins against various human cancers (18–20, 27). Although different cancer has its own property and therapeutic strategy, the synergistic action of γ-T3 is partially confirmed.…”

“…Recent studies have shown that tocotrienols can suppress the proliferation of various human pancreatic cancer cells (17) and, when given orally to mice, significant levels accumulate in the pancreatic tissues. Another recent study indicate that γ-T3 can sensitize androgen-independent prostate cancer to docetaxel in vivo through downregulation of proliferating cell nuclear antigen (PCNA), Ki-67 and Id1; and upregulation of cleaved caspase-3 and PARP (27). …”

First Evidence That γ-Tocotrienol Inhibits the Growth of Human Gastric Cancer and Chemosensitizes It to Capecitabine in a Xenograft Mouse Model through the Modulation of NF-κB Pathway

“…For instance, g-tocotrienol has been reported to suppress the proliferation of a wide variety of tumor cells (15), including gastric (16)(17)(18)(19), hepatocellular carcinoma (20), melanoma (21), breast (22), colorectal (23), and prostate (24). In vivo mice studies have shown that g-tocotrienol can suppress the growth of breast tumor (25), prostate (26), lung cancer and melanoma (27) and also inhibit the growth of liver and pancreatic cancer either alone or in combination with chemotherapeutic drugs and radiation (28,29). How g-tocotrienol mediates its anticancer effects is not completely understood, but the roles of various signaling cascades/kinases/transcription factors such as mitogen-activated protein kinases (17), phosphoinositide 3-kinase (PI3K)/Akt (30), NF-kB (13), STAT3 (20), telomerase (31), PPAR-g (32), hypoxiainducible factor-1a (33), b-catenin (23), EGF (24), and inhibitor of differentiation family proteins (34) have been implicated.…”

Combination Effect of δ-Tocotrienol and γ-Tocopherol on Prostate Cancer Cell Growth

“…To date, of the T3s, d-T3 has demonstrated both in vitro and in vivo the most potent antiproliferative activities against various cancers, including prostate cancer (7). In addition, T3s were found to accumulate in pancreatic tissue after oral administration (8), and in xenografted prostate tumors after intraperitoneal injection (9).…”