Precision prostate cancer chemoprevention with gamma-tocotrienol

• Published in: Journal of clinical oncology Vol. 35; no. 15_suppl; p. e13043
• Main Authors: Moore, Christine Ann, Palau, Victoria, Lightner, Janet, Brannon, Marianne, Stone, William, Krishnan, Koyamangalath
• Format: Journal Article
• Language: English
• Published: 20.05.2017
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/JCO.2017.35.15_suppl.e13043

Abstract only e13043 Background:  A goal of precision chemoprevention is to prevent or delay cancer progression by using minimally toxic agents guided by knowledge of alterations in oncogenic molecular pathways and signaling cascades. Indolent prostate cancer can benefit from chemopreventive agents by delaying growth. Vitamin E is not a single compound and refers to four tocopherols and four tocotrienols. The use of all-racemic-alpha tocopheryl acetate in preventing cancer was studied in the SELECT clinical trial. This trial found it was not chemopreventive and could promote prostate cancer. We compared the abilities of RRR-alpha-tocopherol (AT), RRR-gamma-tocopherol (GT), and gamma-tocotrienol (GT3) in preventing growth of two prostate cancer cell lines (LNCaP and PC-3) and a control prostate cell line (RWPE-1) by quantifying their effects on two signaling pathways known to be pivotal in prostate carcinogenesis, AKT and MAP Kinase (pERK). Methods:  LNCaP, PC-3, and RWPE-1 cell lines were treated with increasing concentrations of AT, GT and GT3 in DMEM, and cytotoxicity determined by MTS cell culture experiments. We determined the effect of GT3 on signaling pathways by analyzing B-actin, P-AKT and p-ERK in combination with AKT and/or MEK inhibitors via Western immunoblot and PCR analysis. Results:  Initial experiments with LNCaP and PC-3 cells showed GT3 induced the expression of pERK and p-c-JUN, inhibited cell growth and promoted apoptotic cell death. Neither AT nor GT had these effects. AKT was not activated by AT, GT or GT3. Inhibition of AKT activation via MK-2206 did not block GT3 growth inhibition in LNCaP cells. No growth inhibition was found with RWPE-1 control cells in presence of AT, GT or GT3 yet GT3 induced pERK expression. AT did not interfere with cancer growth inhibition and did not block the anticancer effects of GT3. Conclusions: GT3 induces the activation of pERK but this effect is not sufficient to account for the in vitro chemopreventive effects of this form of vitamin E. The AKT pathway is not modulated by GT3 and does not appear to be relevant to GT3 killing of PC-3 or LNCaP. Of five signaling pathways implicated in prostate carcinogenesis, we explored AKT and pERK. Future research will explore B-catenin, mTOR and PI3K.