Browsing by Subject "Vitamin E--Therapeutic use"

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Investigation of the molecular mechanisms of apoptosis induced by a novel vitamin E derivative ([alpha]-TEA) in human breast and ovarian cancer using cell culture
(2005) Shun, Ming-chieh; Kline, Kimberly; Sanders, Bob G.
Previous studies from our lab have shown that the vitamin E derivative, RRR-α-tocopheryl succinate (vitamin E succinate, VES) induces MDA-MB-435 and MCF-7 human breast cancer cells to undergo DNA synthesis arrest, cellular differentiation, and apoptosis. Several studies have demonstrated VES to be a potent pro-apoptotic agent inducing apoptosis by restoring both transforming growth factor-β (TGF-β) and Fas (CD95) apoptotic signaling pathways that contribute to the activation of c-Jun N-terminal kinase (JNK)-mediated apoptosis. In an effort to develop a more clinically useful vitamin E-based chemotherapeutic agent, a non-hydrolyzable ether analog of RRR-α-tocopherol; namely, 2,5,7,8-tetramethyl-2R-(4R,8R,12-trimethyltridecyl)chroman-6-yloxyacetic acid (called RRR-α-tocopherol ether acetic acid analog; and abbreviated α-TEA) has been produced. Specific aim I studies investigated the individual effects of α-TEA and a naturally occurring from of vitamin E, δ-tocotrienol, as anticancer agents against breast cancer in vitro, and characterized signaling events involved in the pro-apoptotic and differentiation actions of α-TEA in human MDA-MB-435 and MCF-7 breast cancer cell lines. Data reported here showed that both α-TEA and δ-tocotrienol, like VES, induced estrogen-nonresponsive MDA-MB-435 and estrogen-responsive MCF-7 human breast cancer cells to undergo high levels of apoptosis in a concentration- and time-dependent fashion. Like VES, the two compounds induced either no or lower levels of apoptosis in normal human mammary epithelial cells (HMECs) and immortalized but nontumorigenic human MCF-10A cells. The pro-apoptotic mechanisms triggered by the structurally distinct α-TEA and δ-tocotrienol were identical to those previously reported for VES, that is α-TEA- and δ-tocotrienol-induced apoptosis involved sensitizing both cell lines to TGF-β and Fas apoptotic signaling, involving up-regulation of TGF-β receptor II protein expression and signaling apoptosis by TGF-β, and Fas converging on JNK signaling pathway. Specific aim II characterized the apoptotic effects of α-TEA on components of the Fas/CD95 apoptotic pathway in cisplatin-sensitive, A2780S, and cisplatin-resistant, A2780/cp70R human ovarian cancer cells. Both ovarian cancer cells were shown to undergo apoptosis in a dose-dependent manner following α-TEA treatment. α-TEA-induced apoptosis involved downregulation of Akt activation and c-FLIP and survivin expression. Data showed α-TEA to be an efficient inducer of cell death by decreasing constitutive active Akt in ovarian cancer cells. Downregulation of Flip and survivin expression were identified as key proapoptotic events regulated by Akt in α-TEA-induced apoptosis. Specific aim III studies showed α-TEA to induce MDA-MB-435 human breast cancer cells to undergo cellular differentiation. We use four markers to determine α-TEA induces differentiation including Oil red O staining of neutral lipids, downregulation of Her2/neu protein, upregulation of cytokeratin 18 and upregulation of p21. Studies showed α-TEA to induce human MDA-MB-435 cells to undergo cellular differentiation in a manner similar to, if not identical, to VES induced differentiation. Specific aim IV studies showed α-TEA to modulate ErbB family members and signaling. Studies showed α-TEA inhibited cell growth of both A2780S and A2780/CP70R cells and heregulin partially rescued both cell lines from α-TEA-induced apoptosis. α-TEA downregulated ErbB1, ErbB2, and ErbB3 message and protein levels, but not ErbB4, and reduced phosphorylated Akt and ERK1/2 in a time and dose dependent manner. Taken together, these findings demonstrated that α-TEA-induced apoptosis is by downregulation of c-FLIP and survivin through the activity of Akt and elimination of tumor cells through Fas-mediated apoptosis, and showed α-TEA to be a potent inducer of apoptosis in both human breast and ovarian cancer cells in culture.
Mechanisms of proliferation inhibition and apoptosis induced by vitamin E compounds and cyclooxygenase inhibitors in human breast cancer cells
(2004) Zhang, Shuo; Kline, Kimberly; Sanders, Bob G.
RRR-a-tocopheryl succinate (VES) and a-TEA [2, 5, 7, 8 - tetramethyl - 2R-(4R, 8R-12-trimethyltridecyl)chroman-6-yloxyacetic acid], a nonhydrolyzable ether analog of VES, induce growth inhibition in various human breast cancer cells. Cyclooxygenase 2 (COX-2) is up-regulated in human breast tumor tissues and cell lines, and has been shown to be associated with the process of neoplastic transformation and inhibition of apoptosis. Aims of this study were to investigate the individual and combined effects of vitamin E compounds (especially, a-TEA) and COX-2 selective inhibitors (especially, celecoxib) in protection against breast cancer in vitro and in vivo, and to determine their cellular and molecular signaling mechanisms. Using an MDA-MB-435-FL-GFP human breast cancer xenograft model, a-TEA and celecoxib separately or in combination significantly reduced tumor volume in comparison to control. The combination of a-TEA + celecoxib (1,250 mg/kg diet) significantly inhibited tumor volume in comparison to single treatments. Mean numbers of microscopic lung and lymph node metastases in all treatment groups were significantly lower than control. Furthermore, the mean number of microscopic lung metastases in the a-TEA + celecoxib (1,250) group was significantly lower in comparison to separate treatments. Analyses of 5 micron tumor sections showed that all treatments, with the exception of celecoxib (500) alone, to significantly enhance apoptosis and significantly decrease cell proliferation. Similarly, in vitro studies using MDA-MB-435-FL-GFP cells showed a-TEA or celecoxib to induce apoptosis and DNA synthesis arrest. Combination of a-TEA + celecoxib synergistically enhanced apoptosis and additively enhanced DNA synthesis arrest. Celecoxib coordinately mediated aTEA’s anticancer effects by enhancing the c-Jun-N-terminal kinase (JNK) and cJun apoptotic signaling pathway, reducing cell proliferation, reducing cell cycle regulators (cyclin A and E, Proliferation Cell Nuclear Antigen), and suppressing cell migration putatively via alternating integrin-mediated cell adhesion signaling pathways. In conclusion, simultaneous targeting of breast cancer cells in vitro or in vivo with a-TEA and celecoxib separately and together inhibited cancer growth by inducing cell death by apoptosis, G0/G1 cell cycle blockage, inhibiting proliferation, and suppressing cell migration more effectively than targeting with each compound alone. These data show promise for combinations of a-TEA + celecoxib for breast cancer chemotherapy
Studies of the antitumor activity of [alpha]-TEA in human breast cancer cells
(2006) Wang, Pei; Sanders, Bob G.
Breast cancer is the most common cancer among women and is the second leading cause of cancer deaths among women in the United States. An effective chemotherapeutic drug is greatly needed for breast cancer. In order to develop a stable and clinically useful vitamin E-based chemotherapeutic agent, a nonhydrolyzable ether linked acetic acid analogue of RRR-a-tocopherol, namely, a-TEA has been produced. a-TEA exhibits strong antitumor activity in tumor cells but has no effect on normal cells. Since a-TEA is hydrophobic, formulation into appropriate carrier systems to potentiate delivery is needed. The anticancer efficacy of a-TEA formulated into liposomes or nanoparticles has been assessed in this study. a-TEA formulated in either nanoparticles or liposomes at 5 mg/day was very effective in inhibiting tumor growth and visible lung metastases, as well as lung and lymph node micrometastatic lesions. a-TEA at 2.5 mg/day formulated in nanoparticles was more effective than a-TEA at 2.5 mg/day formulated in liposomes in reducing tumor burden and lymph node and lung micro-metastatic tumor foci; however, the difference could be attributed to a nanoparticle effect rather than an a-TEA effect since nanoparticles alone significantly reduced tumor burden and metastases. These studies show that oral delivery of a-TEA at an appropriate dosage formulated in either liposomes or nanoparticles to be effective, clinically relevant means for administrating this hydrophobic drug. In the mechanistic studies of a-TEA, over 400 potential targets have been identified in a-TEA treated MDA-MB-435 cells using microarray analyses. Thirty four genes were of interest for their possible involvement in the known biological activities of a-TEA. Three genes, Arg, TSP-1 and NOXA were further studied. The proapoptotic BH3 only protein NOXA was studied in detail. Data show that NOXA induction was involved in a-TEA-induced mitochondria-dependent apoptosis in human breast cancer cells and NOXA expression was mediated through JNK-p73 signaling pathway. From the data reported in this thesis, we now have a better understanding of how a-TEA functions as a promising anticancer drug, and more importantly, how to efficiently use it as a chemotherapeutic reagent.