plastochromanol-8 and Prostatic-Neoplasms

Prostate cancer is the second most commonly diagnosed cancer in men, and metastatic prostate cancer is currently incurable. Prostate cancer frequently becomes resistant to standard of care treatments, and the administration of chemotherapeutic drugs is often accompanied by toxic side effects. Combination therapy is one tool that can be used to combat therapeutic resistance and drug toxicity. Vitamin E (VE) compounds and analogs have been proposed as potential non-toxic chemotherapeutics. Here we modeled combination therapy using mixture design response surface methodology (MDRSM), a statistical technique designed to optimize mixture compositions, to determine whether combinations of three chemotherapeutic agents: γ-tocotrienol (γ-T3), α-tocopherol ether acetate (α-TEA), and docetaxel (DOC), would prove more effective than docetaxel alone in the treatment of human prostate cancer cells. Response surfaces were generated for cell viability, and the optimal treatment combination for reducing cell viability was calculated. We found that a combination of 20 µM γ-T3, 30 µM α-TEA, and 25 nm DOC was most effective in the treatment of PC-3 cells. We also found that the combination of γ-T3 and α-TEA with DOC decreased the amount of DOC required to reduce cell viability in PC-3 cells and ameliorated therapeutic resistance in DOC-resistant PC-3 cells.

Topics: alpha-Tocopherol; Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Chromans; Docetaxel; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Drug Synergism; Ether; Humans; Male; Prostatic Neoplasms; Vitamin E

Emerging evidence suggests that gamma-tocotrienol (γ-T3), a vitamin E isomer, has potent anti-cancer properties against a wide-range of cancers. γ-T3 not only inhibited the growth and survival of cancer cells in vitro, but also suppressed angiogenesis and tumour metastasis under in vivo conditions. Recently, γ-T3 was found to target cancer stem cells (CSCs), leading to suppression of tumour formation and chemosensitisation. Despite its promising anti-cancer potential, the exact mechanisms responsible for the effects of γ-T3 are still largely unknown. Here, we report the identification of Ang-1 (Angiopoietin-1)/Tie-2 as a novel γ-T3 downstream target. In prostate cancer cells, γ-T3 treatment leads to the suppression of Ang-1 at both the mRNA transcript and protein levels. Supplementing the cells with Ang-1 was found to protect them against the anti-CSC effect of γ-T3. Intriguingly, inactivation of Tie-2, a member receptor that mediates the effect of Ang-1, was found to significantly enhance the cytotoxic effect of γ-T3 through activation of AMP-activated protein kinase (AMPK) and subsequent interruption of autophagy. Our results highlighted the therapeutic potential of using γ-T3 in combination with a Tie-2 inhibitor to treat advanced prostate cancer.

Topics: Angiopoietin-1; Autophagy; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chromans; Down-Regulation; Gene Expression Regulation, Neoplastic; Humans; Male; Prostatic Neoplasms; Receptor, TIE-2; Signal Transduction; Vitamin E

Tocotrienols (T3s) and tocopherols (Tocs) are both members of the vitamin E family. It is known that δ-tocotrienol (δ-T3) has displayed the most potent anti-cancer activity amongst the tocotrienols. On the other hand, γ-tocopherol (γ-Toc) is reported to have a protective effect against prostate cancer. Therefore, we investigated whether the combination of γ-Toc and δ-T3 could strengthen the inhibitory effect of δ-T3 on prostate cancer cell growth. In this study the effect of combined δ-T3 (annatto T3 oil) and γ-Toc (Tmix, γ-Toc-rich oil) therapy was assessed against human androgen-dependent prostate cancer cells (LNCaP). We found that combined treatment of δ-T3 (10 μM) and γ-Toc (5 μM) resulted in reinforced anti-prostate cancer activity. Specifically, cell cycle phase distribution analysis revealed that in addition to G1 arrest caused by the treatment with δ-T3, the combination of δ-T3 with γ-Toc induced G2/M arrest. Enhanced induction of apoptosis by the combined treatment was also observed. These findings indicate that combination of δ-T3 and γ-Toc significantly inhibits prostate cancer cell growth due to the simultaneous cell cycle arrest in the G1 phase and G2/M phase.

Topics: Anticarcinogenic Agents; Antineoplastic Agents, Phytogenic; Apoptosis; Bixaceae; Carotenoids; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chromans; G1 Phase; G2 Phase; Humans; Male; Osmolar Concentration; Plant Extracts; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Vitamin E

To investigate the roles of androgen receptor (AR) in epithelial- mesenchymal transition (EMT) in human prostate cancer stem progenitor (S/P) cells isolated from LNCaP cell line.. The S/P cells were obtained from LNCaP cell line through florescence-activated cell sorting (FACS). AR was overexpressed in S/P cells through lentivirus. Western blot assay was used to detect the EMT markers expression, such as E Cadherin, N Cadherin, Vimentin and Snail. MTT assay, soft agar colony formation assay, sphere formation assay and migration assay were used to investigate AR's roles in EMT of S/P cells. Cell signaling pathways associated with proliferation and apoptosis of S/P cells were detected simultaneously. And S/P cells were treated with in vitro combinatory use of LY 294002 (inhibitor of AKT signaling molecules) with γ-TT and/or 5-AZA.. Our data showed that S/P cells from LNCaP had high EMT markers expression, more tumorigenesis and strong migration ability. And in S/P cells overexpressed with AR, the expression of EMT markers decreased. In addition, these cells had less proliferation ability, tumorigenesis ability, self-renewal and migration ability. At the same time, targeting S/P cells with AKT signaling pathway inhibitor LY29004 and γ-TT and/or 5-AZA could inhibit S/P cell's proliferation and tumorigenesis.. Our data suggest that AR played a negative role in EMT of PCa S/P cells, by regulating AKT cell signaling pathway, which could be a new strategy to treat castration resistant prostate cancer (CRPC).

Topics: Azacitidine; Cell Line, Tumor; Cell Self Renewal; Chromans; Chromones; Decitabine; Drug Synergism; Epithelial-Mesenchymal Transition; Humans; Male; Morpholines; Neoplastic Stem Cells; Prostatic Neoplasms; Receptors, Androgen; Signal Transduction; Vitamin E

Prostate cancer (PCa) frequently relapses after hormone ablation therapy. Unfortunately, once progressed to the castration resistant stage, the disease is regarded as incurable as prostate cancer cells are highly resistant to conventional chemotherapy.. We recently reported that the two natural compounds polysaccharopeptide (PSP) and Gamma-tocotrienols (γ-T3) possessed potent anti-cancer activities through targeting of CSCs. In the present study, using both prostate cancer cell line and xenograft models, we seek to investigate the therapeutic potential of combining γ-T3 and PSP in the treatment of prostate cancer.. We showed that in the presence of PSP, γ-T3 treatment induce a drastic activation of AMP-activated protein kinase (AMPK). This was accompanied with inactivation of acetyl-CoA carboxylase (ACC), as evidenced by the increased phosphorylation levels at Ser 79. In addition, PSP treatment also sensitized cancer cells toward γ-T3-induced cytotoxicity. Furthermore, we demonstrated for the first time that combination of PSP and γ-T3 treaments significantly reduced the growth of prostate tumor in vivo.. Our results indicate that PSP and γ-T3 treaments may have synergistic anti-cancer effect in vitro and in vivo, which warrants further investigation as a potential combination therapy for the treatment of cancer.

Topics: AMP-Activated Protein Kinases; Animals; Antineoplastic Agents; Cell Line; Chromans; Drug Synergism; Enzyme Activation; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Phosphorylation; Prostatic Neoplasms; Proteoglycans; Vitamin E

Although cell-based studies have shown that γ-tocotrienol (γTE) exhibits stronger anticancer activities than other forms of vitamin E including γ-tocopherol (γT), the molecular bases underlying γTE-exerted effects remains to be elucidated. Here we showed that γTE treatment promoted apoptosis, necrosis and autophagy in human prostate PC-3 and LNCaP cancer cells. In search of potential mechanisms of γTE-provoked effects, we found that γTE treatment led to marked increase of intracellular dihydroceramide and dihydrosphingosine, the sphingolipid intermediates in de novo sphingolipid synthesis pathway but had no effects on ceramide or sphingosine. The elevation of these sphingolipids by γTE preceded or coincided with biochemical and morphological signs of cell death and was much more pronounced than that induced by γT, which accompanied with much higher cellular uptake of γTE than γT. The importance of sphingolipid accumulation in γTE-caused fatality was underscored by the observation that dihydrosphingosine and dihydroceramide potently reduced the viability of both prostate cell lines and LNCaP cells, respectively. In addition, myriosin, a specific inhibitor of de novo sphingolipid synthesis, counteracted γTE-induced cell death. In agreement with these cell-based studies, γTE inhibited LNCaP xenograft growth by 53% (p < 0.05), compared to 33% (p = 0.07) by γT, in nude mice. These findings provide a molecular basis of γTE-stimulated cancer cell death and support the notion that elevation of intracellular dihydroceramide and dihydrosphingosine is likely a novel anticancer mechanism.

Topics: Animals; Antineoplastic Agents; Apoptosis; Autophagy; Cell Line, Tumor; Cell Survival; Ceramides; Chromans; Humans; Intracellular Space; Male; Mevalonic Acid; Mice; Mice, Inbred BALB C; Mice, Nude; Phosphorylation; Prostatic Neoplasms; Proto-Oncogene Proteins c-akt; Sphingosine; Tumor Burden; Vitamin E

There is growing evidence showing that prostate cancer cells have perturbed cholesterol homoeostasis, accumulating cholesterol to promote cell growth. Consequently, cholesterol-lowering drugs such as statins are being evaluated in prostate cancer treatment. Furthermore, natural products such as betulin (from birch tree bark) and tocotrienol (a minor form of vitamin E) have been shown to lower cholesterol levels. Using these drugs and oxysterols, we have determined which aspects of cholesterol homoeostasis should be targeted in prostate cancer, e.g. cellular cholesterol levels are increased by the transcription factor SREBP-2 (sterol-regulatory-element-binding protein isoform 2), whereas LXR (liver X receptor) promotes cholesterol efflux. Whereas betulin exerted non-specific effects on cell viability, tocotrienols produced a strong direct correlation between SREBP-2 activity and cell viability. Mechanistically, tocotrienols lowered SREBP-2 activity by degrading mature SREBP-2 independently of the proteasome. In contrast, no correlation was seen between LXR activity and cell viability, implying that SREBP-2 is a better target than LXR for prostate cancer treatment. Lastly, androgen-dependent and -independent LNCaP cells were both sensitive to tocotrienols. Overall, this suggests that tocotrienols and other drugs targeting the SREBP-2 pathway are a potential therapeutic option for prostate cancer.

Topics: Animals; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Cell Survival; CHO Cells; Cholesterol; Chromans; Cricetinae; Cricetulus; Humans; Intracellular Signaling Peptides and Proteins; Liver X Receptors; Male; Membrane Proteins; Mutant Proteins; Neoplasm Proteins; Orphan Nuclear Receptors; Prostatic Neoplasms; Recombinant Proteins; Sterol Regulatory Element Binding Protein 2; Tocotrienols; Triterpenes; Vitamin E

Emerging evidence supports that prostate cancer originates from a rare subpopulation of cells, namely prostate cancer stem cells (CSCs). Conventional therapies for prostate cancer are believed to mainly target the majority of differentiated tumor cells but spare CSCs, which may account for the subsequent disease relapse after treatment. Therefore, successful elimination of CSCs may be an effective strategy to achieve complete remission from this disease. Gamma-tocotrienols (γ-T3) is one of the vitamin-E constituents, which have been shown to have anticancer effects against a wide range of human cancers. Recently, we have reported that γ-T3 treatment not only inhibits prostate cancer cell invasion but also sensitizes the cells to docetaxel-induced apoptosis, suggesting that γ-T3 may be an effective therapeutic agent against advanced stage prostate cancer. Here, we demonstrate for the first time that γ-T3 can downregulate the expression of prostate CSC markers (CD133/CD44) in androgen-independent prostate cancer cell lines (PC-3 and DU145), as evident from Western blotting analysis. Meanwhile, the spheroid formation ability of the prostate cancer cells was significantly hampered by γ-T3 treatment. In addition, pretreatment of PC-3 cells with γ-T3 was found to suppress tumor initiation ability of the cells. More importantly, although CD133-enriched PC-3 cells were highly resistant to docetaxel treatment, these cells were as sensitive to γ-T3 treatment as the CD133-depleted population. Our data suggest that γ-T3 may be an effective agent in targeting prostate CSCs, which may account for its anticancer and chemosensitizing effects reported in previous studies.

Topics: Animals; Antineoplastic Agents; Blotting, Western; Cell Line, Tumor; Chromans; Humans; Male; Mice; Mice, Nude; Neoplastic Stem Cells; Prostatic Neoplasms; Vitamin E; Xenograft Model Antitumor Assays

Regions along the Mediterranean and in southern Asia have lower prostate cancer incidence compared to the rest of the world. It has been hypothesized that one of the potential contributing factors for this low incidence includes a higher intake of tocotrienols. Here we examine the potential of γ-tocotrienol (GT3) to reduce prostate cancer proliferation and focus on elucidating pathways by which GT3 could exert a growth-inhibitory effect on prostate cancer cells. We find that the γ and δ isoforms of tocotrienol are more effective at inhibiting the growth of prostate cancer cell lines (PC-3 and LNCaP) compared with the γ and δ forms of tocopherol. Knockout of PPAR-γ and GT3 treatment show inhibition of prostate cancer cell growth, through a partially PPAR-γ-dependent mechanism. GT3 treatment increases the levels of the 15-lipoxygenase-2 enzyme, which is responsible for the conversion of arachidonic acid to the PPAR-γ-activating ligand 15-S-hydroxyeicosatrienoic acid. In addition, the latent precursor and the mature forms of TGFβ2 are down-regulated after treatment with GT3, with concomitant disruptions in TGFβ receptor I, SMAD-2, p38, and NF-κB signaling.

Topics: Antineoplastic Agents; Apoptosis; Cell Proliferation; Cell Survival; Chromans; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Male; Prostatic Neoplasms; Structure-Activity Relationship; Transforming Growth Factor beta2; Tumor Cells, Cultured; Vitamin E

Gamma-tocotrienol has demonstrated anti-proliferative effect on breast cancer (BCa) cells, but mechanisms involved are largely unknown. This study aimed at deciphering the molecular pathways responsible for its activity. Our results showed that treatment of BCa cells with gamma-tocotrienol resulted in induction of apoptosis as evidenced by activation of pro-caspases, accumulation of sub-G1 cells and DNA fragmentations. Examination of the pro-survival genes revealed that the gamma-tocotrienol-induced cell death was associated with suppression of Id1 and NF-kappaB through modulation of their upstream regulators (Src, Smad1/5/8, Fak and LOX). Meanwhile, gamma-tocotrienol treatment also resulted in the induction of JNK signaling pathway and inhibition of JNK activity by specific inhibitor partially blocked the effect of gamma-tocotrienol. Furthermore, synergistic effect was observed when cells were co-treated with gamma-tocotrienol and Docetaxel. Interestingly, in cells that treated with gamma-tocotrienol, alpha-tocopherol or beta-aminoproprionitrile were found to partially restore Id1 expression. Meanwhile, this restoration of Id1 was found to protect the cells from gamma-tocotrienol induced apoptosis. Consistent outcome was observed in cells ectopically transfected with the Id-1 gene. Our results suggested that the anti-proliferative and chemosensitization effect of gamma-tocotrienol on BCa cells may be mediated through downregulation of Id1 protein.

Topics: Androgens; Breast Neoplasms; Cell Death; Cell Differentiation; Cell Division; Chromans; Collagen; DNA Fragmentation; Down-Regulation; Drug Combinations; Estrogens; Female; Humans; In Situ Nick-End Labeling; Inhibitor of Differentiation Protein 1; Laminin; Male; Neoplasm Invasiveness; Prostatic Neoplasms; Proteoglycans; Reverse Transcriptase Polymerase Chain Reaction; Transfection; Tumor Cells, Cultured; Vitamin E

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.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cadherins; Cell Line, Tumor; Cell Proliferation; Chromans; Dose-Response Relationship, Drug; Gene Expression Regulation, Neoplastic; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Nude; Neoplasm Transplantation; Neoplasms, Experimental; Prostatic Neoplasms; Tissue Distribution; Vitamin E

Tocotrienol-rich fraction (TRF) has demonstrated antiproliferative effect on prostate cancer (PCa) cells. To elucidate this anticancer property in PCa cells, this study aimed, first, to identify the most potent isomer for eliminating PCa cells; and second, to decipher the molecular pathway responsible for its activity. Results showed that the inhibitory effect of gamma-tocotrienol was most potent, which resulted in induction of apoptosis as evidenced by activation of pro-caspases and the presence of sub-G(1) cell population. Examination of the pro-survival genes revealed that the gamma-tocotrienol-induced cell death was associated with suppression of NF-kappaB, EGF-R and Id family proteins (Id1 and Id3). Meanwhile, gamma-tocotrienol treatment also resulted in the induction of JNK-signalling pathway and inhibition of JNK activity by a specific inhibitor (SP600125) was able to partially block the effect of gamma-tocotrienol. Interestingly, gamma-tocotrienol treatment led to suppression of mesenchymal markers and the restoration of E-cadherin and gamma-catenin expression, which was associated with suppression of cell invasion capability. Furthermore, a synergistic effect was observed when cells were co-treated with gamma-tocotrienol and Docetaxel. Our results suggested that the antiproliferative effect of gamma-tocotrienol act through multiple-signalling pathways, and demonstrated for the first time the anti-invasion and chemosensitisation effect of gamma-tocotrienol against PCa cells.

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Movement; Cell Proliferation; Chromans; Flow Cytometry; Humans; Male; Neoplasm Invasiveness; Prostatic Neoplasms; Signal Transduction; Vitamin E

Gamma-tocotrienol (GT) is a member of the vitamin E family. Our preliminary studies indicated that it protected mice from lethal irradiation, so we hypothesized that GT might be a radiation sensitizing agent for tumors. To test this, we induced prostate tumors by injecting PC3 cells into nude BALB/c mice. When the tumors were about 5 mm in diameter, mice were injected subcutaneously with 400 mg/kg gamma-tocotrienol and irradiated 24 h later at the site of the tumor with a dose of 12 Gy (60)Cobalt. Tumor size was monitored for 24 days after radiation. Tumor tissues as well as normal tissues like rectum, kidney, and liver were monitored for lipid peroxidation on day 4 and day 24 after radiation. The results indicated that the size of the tumors was reduced by almost 40%, but only in GT-treated and irradiated mice. In unstimulated and Fe-stimulated lipid peroxidation groups, lipid peroxidation in the tumors from irradiated mice increased to 135% and 150%, respectively, four days after irradiation and 33% and 66% in the same groups, respectively, 24 days after irradiation. In general, lipid peroxidation in the rectum did not increase in GT-treated and irradiated mice, although there was a slight increase in Fe-stimulated lipid peroxidation (29%) four days after irradiation. Unexpectedly, the kidneys were as equally sensitized to lipid peroxidation as the tumors. Liver tissue was protected in the short-term from radiation-induced lipid peroxidation. These studies indicate that the radiotherapy efficacy of prostate cancer can be increased with GT and a pro-oxidant if the kidneys can be shielded.

Topics: Animals; Antioxidants; Chromans; Iron; Kidney; Lipid Peroxidation; Liver; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Prostatic Neoplasms; Radiation-Sensitizing Agents; Rectum; Tumor Cells, Cultured; Vitamin E

In this study, we evaluated the antiproliferative effect of tocotrienols (T3) and the presence of a specific vitamin E metabolism in PC3 and LNCaP prostate cancer cells. These cell lines are able to transform tocopherols (T) and T3 in the corresponding carboxyethyl-hydroxychromans metabolites (CEHCs). The extent of this metabolism and the inhibitory effect on cell growth followed the order of magnitude alpha-T

Topics: Cell Division; Chromans; Humans; Ketoconazole; Male; Prostatic Neoplasms; Tumor Cells, Cultured; Vitamin E