Days of Treatment

FIGURE 6.3 Antimesothelioma effects of a-tocopheryl succinate. (A) Immunocompro-mised mice were injected intraperitoneally (i.p.) with human mesothelioma cells and peritoneal mesotheliomas allowed to established. On week 4 after the animals were injected with the cells, treatment was initiated consisting of i.p. administration of 200 |ll of 200 ||M a-TOS (in DMSO) every third day for more than 20 weeks. Survival was used as a marker for the effect of a-TOS. (Adapted from Reference 16.) (B) Immunocompromised mice were injected subcutaneously with human mesothelioma cells and tumors allowed to reach 100 mm3 before treatment onset. The mice were then injected i.p. with 200 |ll of 200 mM a-TOS (in DMSO) every second day for up to 2 weeks. Tumor size was estimated and volume calculated. (Adapted from Reference 96.)

Recently, Kline's group demonstrated anticancer activity of a novel VE analog against breast cancer and lung metastases alone or in combination with celo-coxib.4344 These data demonstrate the therapeutic promise of a-TOS and are likely to result in clinical application of the agent and design of novel anticancer agents.

A major reason for the anticancer efficacy of VE analogs is their high apo-ptogenic activity. We observed that while a-TOS significantly suppressed experimental colon cancer, a-TOH showed only marginal, nonsignificant effect.37 Analysis of the tumor sections revealed that both agents inhibited proliferation, but only a-TOS induced apoptosis.45,46 Apoptosis as a major mechanism for antitumor activity of VE analogs has also been proposed for its antimelanoma effect39 and may be expected also in mesotheliomas.41 Although multiple modes of action may be expected for VE analogs, induction of apoptosis is the major determinant of their anticancer efficacy.

6.3.3 Selectivity of VE Analogs Increases Their Clinical Application

A paradigm rendering VE analogs clinically applicable is their selectivity for neoplastic cells,1 as shown in many cultured cells.28 45 47-49 The reasons for the selectivity are not fully understood. Some types of normal cells have the propensity to hydrolyze a-TOS into its redox-active counterpart.1 Selective hydrolysis of a-TOS may, at least in some cases, explain the selective toxicity of the agent, since the proapoptotic species a-TOS would then accumulate in nonmalignant cells at levels below the toxicity threshold.

Hydrolysis of a-TOS cannot always explain its selectivity. For example, a-TOS is highly toxic to mesothelioma cells but not to nonmalignant mesothelial cells.4150 However, in this case, the resistant cells do not hydrolyze a-TOS. It is possible that the selectivity is given here by the resistance of the nonmalignant cells to oxidative stress. It has been published that a-TOS provokes generation of ROS in cancer cells.51-53 We observed that mesothelioma cells generated ROS as a fast response to a-TOS while nonmalignant mesothelial cells showed very little ROS accumulation (J. Neuzil, unpublished data). It is possible that anti-oxidant enzymes are more expressed in nonmalignant cells, whereby affording protection from ROS-induced apoptosis. In support of this, it has been published that cells depleted of their mtDNA are resistant to apoptosis,51 53 54 and a recent paper showed that a reason for this was adaptive upregulation of the mitochondrial superoxide dismutase.55 It remains to be shown whether this is a mechanism of resistance of nonmalignant cells to apoptosis induced by a-TOS, although there is a report indicating the importance of lack of efficient antioxidant systems to render cancer cells susceptible to the VE analog.56 A recent report documented a direct correlation between susceptibility of cancer cells to a-TOS and their propensity to respond to this agent by generation of ROS.57 In support for low ROS accumulation as a mode of resistance to a-TOS, we have observed relatively low accumulation of ROS in a-TOS-resistant differentiated neuroblastoma cells when compared to the a-TOS-susceptible parental cells (J. Neuzil, unpublished data).

There is yet another plausible explanation for selectivity of VE analogs for malignant cells. This is based on the physicochemical nature of these compounds that are weak acids and that are deprotonated at physiological pH but largely protonated at the acidic pH of the tumor interstitium. This allows selective faster diffusion of the drug across the plasma membrane of malignant cells. Thus, there are several alternative or parallel mechanisms underlying the selectivity of VE analogs for cancer cells. Because this is one of the most important features of VE analogs, it is important to understand these mechanisms and, consequently, design and synthesize novel agents with higher proapoptotic activity while retaining selectivity.

We have recently studied the effect of a-TOS on neuroblastoma cells and their differentiated counterparts mimicking nonmalignant neurons. While the former were highly susceptible to the VE analog, the latter were relatively resis-tant.58 We found two lines of defense against a-TOS in the differentiated cells. First, the cells, unlike the parental neuroblastomas, did not accumulate ROS. Second, their levels of antiapoptotic Bcl-2 family proteins were elevated, in particular that of Mcl-1. These data clearly suggest that mitochondria are important not only in induction of apoptosis, but also in the selectivity of importance VE analogs for malignant cells.

6.3.4 VE Analogs Overcome Resistance of Mutant Cancer Cells to Apoptosis, Induce the Mitochondrial Apoptotic Pathway, and Cooperate with Immunological Apoptogens

Many cancer cells avoid established therapy by constantly mutating the relevant genes. This is a complicating factor, compromising many successful treatments. Therefore, it is imperative to design novel agents that would overcome these complications. Many anticancer drugs act via induction of apoptosis of malignant cells by causing damage to their genomic DNA, which results in activation of p53 and inhibition of proliferation accompanied by apoptosis. VE analogs show promise for treatment of cancers where such genes are mutated, most likely because they use the mitochondrial apoptogenic route.

It was reported by Coffey's laboratory that Trolox, a water-soluble analog of VE, inhibited proliferation and induced apoptosis in human colon cancer cells by increasing the expression of the cell cycle protein p21 Cip1/Waf1 in a p53-inde-pendent manner.59 This paper also showed that the agent could efficiently inhibit growth of tumors in athymic mice derived from p53- but not p21Cip1/Waf1 -deficient colon cancer cells. It was later observed that a-TOS caused efficient apoptosis in both p53- and p21Cip1/Waf1 -deficient colon cancer cells.38 These findings place VE analogs among potential anticancer drugs capable of being used instead of or as adjuvants to other drugs whose application may be compromised by mutations in the above genes.

Antiapoptotic/pro-survival consequences of other mutations can also be overcome by VE analogs. For example, overexpression of the receptor tyrosine kinase erbB2/HER2 complicates breast cancer treatment.60 The reason is that the auto-activated erbB2 activates Akt, a protein kinase phosphorylating multiple substrates, including IkB kinase (IKK), caspase-9, and Bad, resulting in elevated expression of pro-survival genes and inhibition of proapoptotic proteins.6162 It has been suggested that VE analogs overcome the erbB2-Akt antiapoptotic signaling. Akazawa et al.63 showed that a-tocopheryloxybutyric acid suppressed auto-phosphorylation of erbB2, shutting down the whole signaling pathway, although the mechanism is not clear. We have observed that a-TOS caused comparable apoptosis in both erbB2-low and erbB2-high breast cancer cells by a two-tier mechanism64 that includes cytosolic mobilization of cytochrome c, activating the downstream caspases, as well as that of Smac/Diablo, a protein antagonizing the caspase-inhibitory activity of the inhibition of apoptosis proteins (IAPs) that are elevated due to Akt-dependent activation of nuclear factor-KB (NF-kB).65 66 a-TOS thus induces apoptosis in cells over-expressing erbB2 on at least three levels (Figure 6.4). We are currently investigating the anticancer activity of VE analogs using transgenic mice overexpressing erbB2 in the mammary epithelial cells, resulting in spontaneous formation of breast carcinomas.67

The major apoptogenic pathway induced by VE analogs is linked to mito-chondrial destabilization. This is compatible with mitochondria as a novel target for anticancer drugs.6869 Mitochondrial proapoptotic signaling has been documented in several papers, and involves activation of the sphingomyelinase pathways, generation of ROS, and mitochondrial translocation of Bax.51 52 70-73 Conceivably, the ratio between the mitochondrial pro- and antiapoptotic proteins may determine the overall susceptibility of the cells to VE analogs.

Perhaps more importantly, the mode of proapoptotic signaling of VE analogs makes them candidates for adjuvant therapy, that is, synergizing with apoptogens using a different mode of action. a-TOS has been investigated for sensitization of cancer cell to apoptosis induced by the Fas ligand (FasL) and the TNF-related apoptosis-inducing ligand (TRAIL). Kline's group has shown that the VE analog sensitized cancer cells to FasL by mobilizing the latent cytosolic Fas to the plasma membrane,7475 as also observed for gastric cancer cells.76 77 This may suggest a role of a-TOS in cancer surveillance by boosting the immune anticancer/proap-optotic mechanism.

We have explored the possibility that VE analogs synergize/cooperate with TRAIL. In colon cancer cells, a-TOS synergized with TRAIL in apoptosis induction, by utilizing different, convergent pathways. Cooperation between aTOS and TRAIL was observed in experimental colon cancer.38 In mesothelioma cells, a-TOS synergized with TRAIL by upregulating the TRAIL death receptor-4 (DR4) and DR5.50 This report as well as our recent finding that a-TOS extends survival of mice with experimental mesothelioma41 is important because

Apo Trail Dr4 Apoptosis

FIGURE 6.4 Possible mechanism of apoptosis induction by a-TOS in erbB2/HER2 over-expressing cells. a-TOS causes cytosolic mobilization of cytochrome c (Cyt c) and Smac/Diablo. Cyt c forms a ternary complex with Apaf-1 and pro-caspase-9, resulting in activation of the initiator caspase-9 that, in turn, leads to activation of the effector caspases. Smac/Diablo amplifies this process by suppressing the IAP family proteins that are elevated due to Akt-dependent activation of NF-kB. This suggests that a-TOS induces apoptosis in cells overexpressing erbB2 on at least three levels: inhibition of erbB2 activation, induction of the mitochondrial-linked apoptotic pathway, and relocalization of Smac/Diablo, thereby suppressing the caspase-inhibitory IAP activity. Mechanistically, aTOS induces mitochondrial generation of ROS as well as mitochondrial translocation of Bax. Additional effects of a-TOS include: inhibition of erbB2 and NF-kB activation and suppression of Akt-dependent phosphorylation of Bad (rendering it inactive due to association with the protein 14-3-3) and pro-caspase-9 (suppressing its activity normally leading to activation of effector caspases). These effects of a-TOS not only induce apop-tosis in erbB2-overexpressing cells, but also sensitize them to other apoptogens, as shown here for TRAIL.

mesotheliomas are refractory to treatment, largely due to resistance to apoptosis by established drugs.78 Another mode by which a-TOS can sensitize cancer cells to TRAIL killing is its interference with activation of NF-kB, as shown for Jurkat cells.79 A possible mechanism of inhibition of the pro-survival transcription factor may be caspase-dependent cleavage of its subunit p65 due to activation of the apoptosis machinery.8081

6.3.5 Vitamin E Analogs as Antitumor Agents: Beyond Mitochondria

Although the mitochondrial pathway is central to the apoptogenic action of VE analogs, there are other pathways that may play an important role in the effects of the agents. Kline's group reported regulation of the AP-1 and mitogen-activated protein kinase/extracellular-regulated protein kinase pathways as additional signaling routes for apoptosis induced by a-TOS.82-86 Some but not all papers suggested that a-TOS induces apoptosis by interfering with the tumor necrosis factor-P (TGF-P) signaling, compromising the expression of pro-survival factors.87-89 These findings may be related to the effect of the VE analog on transition of cell through the cell cycle. Several reports showed that the agent caused arrest in G1 or G2. Turley et al.90 presented evidence that a-TOS inhibited proliferation of breast cancer cells by interfering with the cyclin A-E2F restriction point machinery. Yeh's group reported that a-TOS inhibited proliferation of cancer cells by modulation of the cell cycle transition91 as well as cell invasiveness due to inhibition of the activity of matrix metalloproteinase-9.92 These effects may be more specific for prostate cancer cells, as a-TOS has been reported to inhibit the function of the prostate-specific antigen.93

Our results also show inhibitory effects of a-TOS on cell cycle transition, with G1 and/or G2 arrest, depending on the cell type.94-96 The mode of cell cycle inhibition may be related to the effect of a-TOS on its modulators. The G1 arrest of the osteosarcoma cells may be linked to inhibition of the activity of the cyclin A/cyclin-dependent kinase-2 complex, while the levels of the transcription factor E2F1 were enhanced and were followed by phosphorylation of p53.94

Mesothelioma cells undergo a G2 arrest when exposed to low levels of a-TOS.95 96 This is related to disruption of the FGF-FGFR autocrine proliferation signaling loop by selective downregulation of both FRF2 and its receptor FGFR1 in the mesothelioma but not the nonmalignant mesothelial cells.95,96 a-TOS exerts its effect on the transcriptional level, downregulating FGFR1 by inhibiting the activity of E2F1,95 while FGF2 is downregulated via modulating the transcriptional activity of the early-response growth factor-1.96 The selectivity appears related to the low level of ROS generation by the nonmalignant mesothelial cells while their malignant counterparts respond to a-TOS by early generation of high levels of ROS.96

There are reports suggesting the possibility that VE analogs inhibit angio-genesis, which indicates an effect of the agents on tumorigenesis and the meta-static potential. We have observed a reduction in the number of blood vessels in experimental colon cancer xenografts in mice treated with a-TOS (J. Neuzil, unpublished data). Preliminary results also indicate an effect of a-TOS on pro-angiogenic cytokines in endothelial cells, suggesting a proliferation-suppressive activity of the VE analog. This can be reconciled with findings that a-TOS caused downregulation of VEGF.36 Another possibility follows from studies indicating that proliferating endothelial cells are highly susceptible to a-TOS while the confluent arrested cells are resistant.80 This highly intriguing paradigm is supported by comparable results from Hogg's group using a different inducer of apoptosis.97 Thus, a-TOS may specifically target angiogenic endothelial cells while being nonapoptotic toward normal endothelium. Resistance of endothelial cells suspended in G0 can be explained by high levels of expression of the checkpoint proteins p21 WafllC^' and p27Kip1 that prevent reentry of the cells into the cell cycle98,99 and that inhibit caspase activity.100

By virtue of inhibiting angiogenesis, VE analogs would be efficient against cancers irrespective of the frequent mutations in various genes. This area is also worth exploring for novel VE analogs. A recent paper showed a potential anti-angiogenic effect of y-TOH by inhibiting the activity of cyclooxygenase-2,101 thereby suppressing formation of pro-angiogenic eicosanoids.102 It is expected that y-TOS combines an antiangiogenic effect with apoptogenic activity (see Table 6.1).

6.3.6 Pharmacokinetics of VE Analogs — A Potential Secondary Beneficial Bioactivity

A most intriguing aspect of the potential use of VE analogs as anticancer agents follows from their pharmacokinetics. These agents are esters of VE and, therefore, hydrolyzed upon intestinal intake after ingestion.103 To overcome the intestinal hydrolysis step, agents such as a-TOS need to be administered intraperi-toneally. After reaching the circulation, they associate with lipoproteins104 105 that carry them to the neoplastic microvasculature. Once in the tumor blood vessels, a-TOS migrates to the malignant tissue where it induces apoptosis, thereby suppressing growth of the tumor. Because the blood components and the peripheral tissue are a dynamic system, there is constant exchange of hydrophobic molecules. a-TOS is thus gradually moved from the tumor and cleared, bound to remnant lipoproteins, via the liver. Here, a-TOS is hydrolyzed by nonspecific esterases. It is then partially disposed of within the bile, partially resecreted into circulation depending on the level of the saturable a-tocopherol-binding protein (a-TTP).105-108

The paradigm described above is shown in Figure 6.5. It is clear that, based on this scheme, supported by theoretical considerations and experimental data,109110 esters of VE are hydrolyzed in the liver into the redox-active VE that is, in part, returned into circulation. From this, it can be deduced that a-TOS and similar compounds possess at least two bioactivities. In the pro-vitamin form, aTOS suppresses cancer. After conversion to its vitamin form, it acts as a redox-active compound and as an anti-inflammatory agent.111115 Thus, we believe that the novel VE analogs represent agents with thus far unrecognized dual beneficial bioactivity relevant to a variety of highly deleterious pathologies, including cancer and inflammatory diseases.


VE accumulates in circulating lipoproteins, thus enhancing the anti-oxidant/anti-inflammatory defences a-TOS —► (circuí

Mechanism Vitamin Myopathy


Lipoprotein-associated VES exerts its anti neoplastic effect within tumor microcirculation

FIGURE 6.5 Proposed molecular mechanism for the "double-edge" activity of a-toco-pheryl succinate. Following entry into the bloodstream, the pro-vitamin a-TOS vitamin E succinate (VES) associates with circulating lipoproteins (LP) that carry the agent to the microvasculature of the neoplastic tissue. Here, VES exerts its antiproliferative/proapop-totic activity toward malignant cells that translates into inhibition of tumor growth. Since there is a constant exchange of hydrophobic molecules between the peripheral tissues and the circulation, a-TOS is gradually removed by virtue of remnant lipoproteins that are endocytosed by hepatocytes that possess high levels of nonspecific esterases (NE). Here, the remnants are dissembled and nascent VLDL formed. a-TOH (VE), both the original and that formed by hydrolysis of VES, is partially shuttled to nascent VLDL bound to the saturable tocopherol-transfer protein (TTP), partially excreted in the bile. Nascent VLDL enriched with VE is then resecreted into circulation, endowing the system with additional VE that promotes the antioxidant and anti-inflammatory defenses.


The above discussion reveals the exceptional promise of VE analogs as therapeutic agents. There are several features that make these compounds unique: (1) VE analogs induce apoptosis selectively in malignant cells and inhibit tumor growth in experimental models; (2) they overcome resistance to established anticancer drugs due to bypassing mutations in or deletions of critical genes; (3) they synergize with anticancer agents and/or sensitize resistant cells toward them; (4) they cause apoptosis in proliferating endothelial cells, suggesting their anti-angiogenic activity; and (5) they are metabolized into the redox-active VE with secondary beneficial bioactivity.

At this stage, we need more data to understand the exact mechanisms by which these compounds exert their proapoptotic/anticancer activity and, in particular, what makes them selective for malignant cells. Importantly, too, we need to obtain more data from preclinical studies using several experimental models. Thus far, the majority of these data comes from work with athymic mice. Transgenic mice predisposed to develop tumors need to be used because in such animals the role of the immune system, essential for tumor surveillance, is not impaired. It is hoped that, with better understanding of the molecular mechanism underlying the activity of VE analogs, they will be approved for clinical testing. Should they prove successful, the very cheap a-TOS or its derivatives may become drugs of choice against multiple malignancies with a secondary beneficial activity.


  1. Neuzil J, Tomasetti M, Mellick AS, Alleva R, Salvatore BA, Birringer B, Fariss MW. Vitamin E analogues: a new class of inducers of apoptosis with selective anti-cancer effect. Curr Cancer Drug Targets 2004; 4:267-284.
  2. Jiang Q, Christen S, Shigenaga MK, Ames BN. y-Tocopherol, the major form of vitamin E in the US diet, deserves more attention. Am J Clin Nutr 2001; 74:714-722.
  3. Woodson K, Tangrea JA, Barrett MJ, Virtamo J, Taylor PR, Albanes D. Serum a-tocopherol and subsequent risk of lung cancer among male smokers. J Natl Cancer Inst 1999; 91:1738-1743.
  4. Heinonen OP, Albanes D, Virtamo J, Taylor PR, Huttunen JK, Hartman AM, Haapakoski J, Malila N, Rautalahti M, Ripatti S, Maenpaa H, Teerenhovi L, Koss L, Virolainen M, Edwards BK. Prostate cancer and supplementation with a-toco-pherol and ß-carotene: incidence and mortality in a controlled trial. J Natl Cancer Inst 1998; 90:440-446.
  5. Malila N, Taylor PR, Virtanen MJ, Korhonen P, Huttunen JK, Albanes D, Virtamo J. Effects of a-tocopherol and ß-carotene supplementation on gastric cancer incidence in male smokers (ATBC Study, Finland). Cancer Causes Control 2002; 13:617-623.
  6. Rautalahti MT, Virtamo JR, Taylor PR, Heinonen OP, Albanes D, Haukka JK, Edwards BK, Karkkainen PA, Stolzenberg-Solomon RZ, Huttunen J. The effects of supplementation with a-tocopherol and ß-carotene on the incidence and mortality of carcinoma of the pancreas in a randomized, controlled trial. Cancer 1999; 86:37-42.
  7. Malila N, Virtamo J, Virtanen M, Albanes D, Tangrea JA, Huttunen JK. The effect of a-tocopherol and ß-carotene supplementation on colorectal adenomas in middle-aged male smokers. Cancer Epidemiol Biomarkers Prev 1999; 8:489-493.
  8. Blot WJ, Li JY, Taylor PR, Guo W, Dawsey S, Wang GQ, Yang CS, Zheng SF, Gail M, Li GY. Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. J Natl Cancer Inst 1993; 85:1483-1492.

Klein EA, Thompson IM, Lippman SM, Goodman PJ, Albanes D, Taylor PR, Coltman C. SELECT: the next prostate cancer prevention trial. Selenium and Vitamin E Cancer Prevention Trial. J Urol 2001; 166:1311-1315. Menkes MS, Comstock GW, Vuilleumier JP, Helsing KJ, Rider AA, Brookmeyer R. Serum ß-carotene, vitamins A and E, selenium, and the risk of lung cancer. NEngl J Med 1986; 13:1250-1254.

Wald NJ, Thompson SG, Densem JW, Boreham J, Bailey A. Serum vitamin E

and subsequent risk of cancer. Br J Cancer 1987; 56:69-72.

Knekt P. Vitamin E and cancer: epidemiology. Ann NY Acad Sci 1992;


Moorman PG, Ricciuti MF, Millikan RC, Newman B. Vitamin supplement use and breast cancer in a North Carolina population. Public Health Nutr 2001; 4:821-827.

Jacobs EJ, Connell CJ, McCullough ML, Chao A, Jonas CR, Rodriguez C, Calle EE, Thun MJ. Vitamin C, vitamin E, and multivitamin supplement use and stomach cancer mortality in the cancer prevention study II cohort. Cancer Epidemiol Biomarkers Prev 2002; 11:35-41.

Satia-About AJ, Galanko JA, Martin CF, Potter JD, Ammerman A, Sandler RS. Associations of micronutrients with colon cancer risk in African Americans and Whites: results from the North Carolina colon cancer study. Cancer Epidemiol Biomarkers Prev 2003; 12:747-754.

Schuurman AAG, Goldbohm RA, Brants HA, van den Brandt PA. A prospective cohort study on intake of retinol, vitamins C and E, and carotenoids and prostate cancer risk (Netherlands). Cancer Causes Control 2002; 13:573-582. Fleshner N, Fair WR, Huryk R, Heston WDW. Vitamin E inhibits the high-fat diet promoted growth of established human prostate LNCaP tumors in nude mice. J Urol 2002; 168:1578-1582.

Moriguchi S, Muraga M. Vitamin E and immunity. Vitam Horm 2000; 59:305-336. Meydani M, Lipman RD, Han SN, Wu D, Beharka A, Martin KR, Bronson R, Cao G, Smith D, Meydani SN. The effect of long-term dietary supplementation with antioxidants. Ann NY Acad Sci 1998; 854:352-360.

Venkateswaran V, Fleshner NE, Sugar LM, Klotz LH. Antioxidants block prostate cancer in LADY transgenic mice. Cancer Res 2004; 64:5891-5896. Hartman TJ, Dorgan JF, Woodson K, Virtamo J, Tangrea JA, Heinonen OP, Taylor PR, Barrett MJ, Albanes D. Effects of longer a-tocopherol supplementation on serum hormones in older men. Prostate 2001; 46:33-38.

Kline K, Yu W, Sanders BG. Vitamin E: Mechanisms of action as tumor cell growth inhibitors. In: KN Prasad, WC Cole, eds. Cancer and Nutrition. IOS Press; 1998:37-53.

Schwartz J, Shklar G. The selective cytotoxic effect of carotenoids and a-toco-pherol on human cancer cell lines in vitro. J Oral Maxillofac Surg 1992; 50:367-373.

Wu K, Shan YJ, Zhao Y, Yu JW, Liu BH. Inhibitory effects of RRR-a-tocopheryl succinate on benzo(a)pyrene-induced forestomach carcinogenesis in female mice. World J Gastroenterol 2001; 7:60-65.

Birringer M, EyTina JH, Salvatore BA, Neuzil J. Vitamin E analogues as inducers of apoptosis: structure-function relationship. Br J Cancer 2003; 88:1948-1955.

  1. Yu W, Simmons-Menchaca M, Gapor A, Sanders BG, Kline K. Induction of apoptosis in human breast cancer cells by tocopherols and tocotrienols. Nutr Cancer. 1999; 33:26-32.
  2. Mo H, Elson CE. Studies of the isoprenoid-mediated inhibition of mevalonate synthesis applied to cancer chemotherapy and chemoprevention. Exp Biol Med 2004; 229:567-585.
  3. Neuzil J, Weber T, Gellert N, Weber C. Selective cancer cell killing by a-toco-pheryl succinate. Br J Cancer 2001; 84:87-89.
  4. Neuzil J, Zhao M, Ostermann G, Sticha M, Gellert N, Weber C, Eaton JW, Brunk UT. a-Tocopheryl succinate, an agent with in vivo anti-tumour activity, induces apoptosis by causing lysosomal instability. Biochem J 2002; 362:709-715.
  5. Kozin SV, Shkarin P, Gerweck LE. The cell transmembrane pH gradient in tumors enhances cytotoxicity of specific weak acid chemotherapeutics. Cancer Res 2001; 61:4740-4743.
  6. Neuzil J. Vitamin E succinate and cancer treatment: A vitamin E prototype for selective anti-tumour activity. Br J Cancer 2003; 89:1822-1826.
  7. Tomic-Vatic A, EyTina JH, Chapmann JM, Mahdavian E, Neuzil J, Salvatore BA. Vitamin E amides, a new class of vitamin E analogues with enhanced proapoptotic activity. Int J Cancer, in press.
  8. Fariss MW, Fortuna MB, Everett CK, Smith JD, Trent DF, Djuric Z. The selective cytotoxic effect of vitamin E succinate and cholesterol succinate on murine leukemia cells result from the action of the intact molecules. Cancer Res 1994; 54:3346-3351.
  9. Anderson K, Simmons-Menchaca M, Lawson KA, Atkinson J, Sanders BG, Kline K. Differential response of human ovarian cancer cells to induction of apoptosis by vitamin E succinate and vitamin E analogue, a-TEA. Cancer Res 2004; 64:4263-4269.
  10. Lawson KA, Anderson K, Simmons-Menchaca M, Atkinson J, Sun L, Saunders BG, Kline K. Comparison of vitamin E derivatives a-TEA and VES in reduction of mouse mammary tumor burden and metastasis. Exp Biol Med 2004; 229: 954-963.
  11. Malafa MP, Neitzel LT. Vitamin E succinate promotes breast cancer tumor dormancy. J Surg Res 2000; 93:163-170.
  12. Malafa MP, Fokum FD, Smith L, Louis A. Inhibition of angiogenesis and promotion of melanoma dormancy by vitamin E succinate. Ann Surg Oncol 2002; 9:1023-1032.
  13. Weber T, Lu M, Andera L, Lahm H, Gellert N, Fariss MW, Korinek V, Sattler W, Ucker DS, Terman A, Schröder A, Erl W, Brunk U, Coffey RJ, Weber C, Neuzil J. Vitamin E succinate is a potent novel anti-neoplastic agent with high tumor selectivity and cooperativity with tumor necrosis factor-related apoptosis-inducing ligand (Apo2 Ligand) in vivo. Clin Cancer Res 2002; 8:863-869.
  14. Malafa MP, Fokum FD, Mowlavi A, Abusief M, King M. Vitamin E inhibits melanoma growth in mice. Surgery 2002; 131:85-91.
  15. Kogure K, Manabe S, Hama S, Tokumura A, Fukuzawa K. Potentiation of anticancer effect by intravenous administration of vesiculated a-tocopheryl hemisuc-cinate on mouse melanoma in vivo. Cancer Lett 2003; 192:19-24.
  16. Tomasetti M, Gellert N, Procopio A, Neuzil J. A vitamin E analogue suppresses malignant mesothelioma in a pre-clinical model: a prototype of a future drug against a fatal neoplastic disease? Int J Cancer 2004; 109:641-642.

Barnett KT, Fokum FD, Malafa MP. Vitamin E succinate inhibits colon cancer liver metastases. J Surg Res 2002; 106:292-298.

Zhang S, Lawson KA, Simmons-Menchaca M, Sun L, Sanders BG, Kline K. Vitamin E analog a-TEA and celecoxib alone and together reduce human MDA-MB-435-FL-GFP breast cancer burden and metastasis in nude mice. Breast Cancer Res Treat 2004; 87:111-121.

Lawson KA, Anderson K, Snyder RM, Simmons-Menchaca M, Atkinson J, Sun LZ, Bandyopadhyay A, Knight V, Gilbert BE, Sanders BG, Kline K. Novel vitamin E analogue and 9-nitro-camptothecin administered as liposome aerosols decrease syngeneic mouse mammary tumor burden and inhibit metastasis. Cancer Chemother Pharmacol 2004; 54:421-431.

Neuzil J, Weber T, Schröder A, Lu M, Ostermann G, Gellert N, Mayne GC, Olejnicka B, Negre-Salvayre A, Sticha M, Coffey RJ, Weber C. Induction of apoptosis in cancer cells by a-tocopheryl succinate: molecular pathways and structural requirements. FASEB J 2001; 15:403-415.

Tasinato A, Boscoboinik D, Bartoli GM, Maroni P, Azzi A. d-a-Tocopherol inhibition of vascular smooth muscle cell proliferation occurs at physiological concentrations, correlates with protein kinase C inhibition, and is independent of its antioxidant properties. Proc Natl Acad Sci USA 1995; 92:12190-12194. Jha MN, Bedford JS, Cole WC, Edward-Prasad J, Prasad KN. Vitamin E (d-a-tocopheryl succinate) decreases mitotic accumulation in y-irradiated human tumor, but not in normal cells. Nutr Cancer 1999; 35:189-194.

Kumar B, Jha MN, Cole WC, Bedford JS, Prasad KN. D-a-Tocopheryl succinate (vitamin E) enhances radiation-induced chromosomal damage levels in human cancer cells, but reduces it in normal cells. J Am Coll Nutr 2002; 21:339-343. Prasad KN, Kumar B, Yan XD, Hanson AJ, Cole WC. a-Tocopheryl succinate, the most effective form of vitamin E for adjuvant cancer treatment: a review. J Am Coll Nutr 2003; 22:108-117.

Tomasetti M, Rippo MR, Alleva R, Moretti S, Andera L, Neuzil J, Procopio A. a-Tocopheryl succinate and TRAIL selectively synergise in apoptosis induction in human malignant mesothelioma cells. Br J Cancer 2004; 90:1644-1653. Weber T, Dalen H, Andera L, Negre-Salvayre A, Auge N, Sticha M, Loret A, Terman A, Witting PK, Higuchi M, Plasilova M, Zivny J, Gellert N, Weber C, Neuzil J. Mitochondria play a central role in apoptosis induced by a-tocopheryl succinate, an agent with anticancer activity. Comparison with receptor-mediated proapoptotic signaling. Biochemistry 2003; 42:4277-4291. Ottino P, Duncan JR. Effect of a-tocopherol succinate on free radical and lipid peroxidation levels in BL6 melanoma cells. Free Radical Biol Med 1997; 22:1145-1151.

Higuchi MB, Aggarwal BB, Yeh T. Activation of CPP32-like protease in tumor necrosis factor-induced apoptosis is dependent on mitochondrial function. J Clin Invest 1997; 99:1751-1758.

Dey R, Moraes CT. Lack of oxidative phosphorylation and low mitochondrial membrane potential decrease susceptibility to apoptosis and do not modulate the protective effect of Bcl-xL in osteosarcoma cells. J Biol Chem 2000; 275:7087-7094. L

Park SY, Chang I, Kim JY, Kang SW, Park SH, Singh K, Lee MS. mtDNA-depleted cells against cell death: role of mitochondrial superoxide dismutase. J Biol Chem 2004; 279:7512-7520.

  1. Kogure K, Hama S, Manabe S, Tokumura A, Fukuzawa K. High cytoxicity of a-tocopheryl hemisuccinate to cancer cells is due to failure of their antioxidative defence systems. Cancer Lett 2002; 186:151-156.
  2. Kang YH, Lee E, Choi MK, Ku JL, Kim SH, Park YG, Lin SJ. Role of reactive oxygen species in the induction of apoptosis by a-tocopheryl succinate. Int J Cancer 2004; 112:385-392.
  3. Swettenham E, Witting PK, Salvatore, BA, Neuzil J. a-Tocopheryl succinate selectively induces apoptosis in neuroblastoma cells: the role of oxidative stress and Mcl-1. J Neurochem, in press.
  4. Chinery R, Brockman JA, Peeler MO, Shyr Y, Beauchamp RD, Coffey RJ. Anti-oxidants enhance the cytotoxicity of chemotherapeutic agents in colorectal cancer: a p53-independent induction of p21WAF1/CIP1 via C/EBPp. Nat Med 1997; 3:1233-1241.
  5. Zhou BP, Hung MC. Dysregulation of cellular signaling by HER2/neu in breast cancer. Semin Oncol 2003; 30:38-48.
  6. Vivanco I, Sawyers CL. The phosphatidylinositol 3-kinase-Akt pathway in human cancer. Natl Rev Cancer 2002; 2:489-501.
  7. Datta SR, Brunet A, Greenberg ME. Cellular survival: a play in three Akts. Genes Dev 1999; 15:2905-2927.
  8. Akazawa A, Nishikawa K, Suzuki K, Asano R, Kumadaki I, Satoh H, Hagiwara K, Sin SJ. Yano T. Induction of apoptosis in a human breast cancer cell overex-pressing erbB2 receptor by a-tocopheryloxybutyric acid. Jpn J Pharmacol 2002; 89:417-421.
  9. Wang XF, Witting PK, Salvatore BA, Neuzil J. a-Tocopheryl succinate induces apoptosis in HER2/erbB2-overexpressing breast cancer cells by signalling via the mitochondrial pathway. Biochem Biophys Res Commun 2005; 326:282-289.
  10. LaCasse EC, Baird S, Korneluk RG, MacKenzie AE. The inhibitors of apoptosis (IAPs) and their emerging role in cancer. Oncogene 1998; 17:3247-3259.
  11. Karin M, Lin A. NF-kB at the crossroads of life and death. Nat Immunol 2002; 3:221-227.
  12. Guy CT, Webster MA, Schaller M, Parsons TJ, Cardiff RD, Muller WJ. Expression of the neu protooncogene in the mammary epithelium of transgenic mice induces metastatic disease. Proc Natl Acad Sci USA 1992; 89:10578-10582.
  13. Costantini P, Jacotot E, Decaudin D, Kroemer G. Mitochondrion as a novel target of anticancer chemotherapy. J Natl Cancer Inst 2000; 92:1042-1053.
  14. Don AS, Hogg PJ. Mitochondria as cancer drug targets. Trends Mol Med 2004; 10:372-378.
  15. Neuzil J, Svensson I, Weber T, Weber C, Brunk UT. a-Tocopheryl succinate-induced apoptosis in Jurkat T cells involves caspase-3 activation, and both lyso-somal and mitochondrial destabilisation. FEBS Lett 1999; 445:295-300.
  16. Kogure K, Morita M, Nakashima S, Hama S, Tokumura A, Fukuzawa K. Superoxide is responsible for apoptosis in rat vascular smooth muscle cells induced by a-tocopheryl hemisuccinate. Biochim Biophys Acta 2001; 1528:25-30.
  17. Yamamoto S, Tamai H, Ishisaka R, Kanno T, Arita K, Kobuchi H, Utsumi K. Mechanism of a-tocopheryl succinate-induced apoptosis of promyelocytic leukemia cells. Free Radical Res 2000; 33:407-418.
  18. Yu W, Sanders BG, Kline K. RRR-a-tocopheryl succinate-induced apoptosis of human breast cancer cells involves Bax translocation to mitochondria. Cancer Res 2003; 63:2483-2491.

Yu W, Israel K, Liao QY, Aldaz M, Sanders BG, Kline K. Vitamin E succinate (VES) induces Fas sensitivity in human breast cancer cells: Role for Mr 43,000 Fas in VES-triggered apoptosis. Cancer Res 1999; 59:953-961. Israel K, Yu W, Sanders BG, Kline K. Vitamin E succinate induces apoptosis in human prostate cancer cells: Role of Fas in vitamin E succinate-triggered apop-tosis. Nutr Cancer 2000; 36:90-100.

Wu K, Li Y, Zhao Y, Shan YJ, Xia W, Yu WP, Zhao L. Roles of Fas signaling pathway in vitamin E succinate-induced apoptosis in human gastric cancer SGC-7901 cells. World J Gastroenterol 2002; 8:982-986.

Wu K, Zhao L, Li Y, Shan YJ, Wu LJ. Effects of vitamin E succinate on the expression of Fas and PCNA proteins in human gastric carcinoma cells and its clinical significance. World J Gastroenterol 2004; 10:945-949.

Tomek S, Emri S, Krejcy K, Manegold C. Chemotherapy for malignant pleural mesothelioma: past results and recent developments. Br J Cancer 2003;


Dalen H, Neuzil J. a-Tocopheryl succinate sensitises T lymphoma cells to TRAIL killing by suppressing NF-kB activation. Br J Cancer 2003; 88:153-158. Neuzil J, Schröder A, von Hundelshausen P, Zernecke A, Weber T, Gellert N, Weber C. Inhibition of inflammatory endothelial responses by a pathway involving caspase activation and p65 cleavage. Biochemistry 2001; 40:4686-4692. Levkau B, Scatena M, Giachelli CM, Ross R, Raines EW. Apoptosis overrides survival signals through a caspase-mediated dominant-negative NF-kB loop. Nat Cell Biol 1999; 1:227-233.

Qian M, Kralova J, Yu W, Bose HR, Dvorak M, Sanders BG, Kline K. c-Jun involvement in vitamin E succinate induced apoptosis of reticuloendotheliosis virus transformed avian lymphoid cells. Oncogene 1997; 15:223-230. Zhao B, Yu W, Qian M, Simmons-Menchaca M, Brown P, Birrer MJ, Sanders BG, Kline K. Involvement of activator protein-1 (AP-1) in induction of apoptosis by vitamin E succinate in human breast cancer cells. Mol Carcinogen 1997; 19:180-190.

Yu W, Simmons-Menchaca M, You H, Brown P, Birrer MJ, Sanders BG, Kline K. RRR-a-tocopheryl succinate induction of prolonged activation of c-jun amino-terminal kinase and c-jun during induction of apoptosis in human MDA-MB-435 breast cancer cells. Mol Carcinogen 1998; 22:247-257.

Yu W, Liao QY, Hantash FM, Sanders BG, Kline K. Activation of extracellular signal-regulated kinase and c-Jun-NH2-terminal kinase but not p38 mitogen-acti-vated protein kinases is required for RRR-a-tocopheryl succinate-induced apoptosis of human breast cancer cells. Cancer Res 2001; 61:6569-6576. Wu K, Zhao Y, Li GC, Yu WP. c-Jun N-terminal kinase is required for vitamin E succinate-induced apoptosis in human gastric cancer cells. World J Gastroenterol 2004; 10:1110-1114.

You H, Yu W, Munoz-Medellin D, Brown PH, Sanders BG, Kline K. Role of extracellular signal-regulated kinase pathway in RRR-a-tocopheryl succinate-induced differentiation of human MDA-MB-435 breast cancer cells. Mol Carcinogen 2002; 33:228-236.

Turley JM, Funakoshi S, Ruscetti FW, Kasper J, Murphy WJ, Longo DL, Birch-enall-Roberts MC. Growth inhibition and apoptosis of RL human B lymphoma cells by vitamin E succinate and retinoic acid: role for transforming growth factor-ß. Cell Growth Differ 1995; 6:655-663.

  1. Yu W, Sanders BG, Kline K. RRR-a-tocopheryl succinate induction of DNA synthesis arrest of human MDA-MB-435 cells involves TGF-ß-independent activation of p21Waf1/CiP1. Nutr Cancer 2002; 43:227-236.
  2. Turley JM, Ruscetti FW, Kim SJ, Fu T, Gou FV, Birchenall-Roberts MC. Vitamin E succinate inhibits proliferation of BT-20 human breast cancer cells: increased binding of cyclin A negatively regulates E2F transactivation activity. Cancer Res 1997; 57:2668-2675.
  3. Ni J, Chen M, Zhang Y, Li R, Huang J, Yeh S. Vitamin E succinate inhibits human prostate cancer cell growth via modulating cell cycle regulatory machinery. Bio-chem Biophys Res Commun 2003; 300:357-363.
  4. Zhang M, Altuwaijri S, Yeh S. RRR-a-tocopheryl succinate inhibits human prostate cancer cell invasiveness. Oncogene 2004; 23:3080-3088.
  5. Zhang Y, Ni J, Messing EM, Chang E, Yang CR, Yeh S. Vitamin E succinate inhibits the function of androgen receptor and the expression of prostate-specific antigen in prostate cancer cells. Proc Natl Acad Sci USA 2002; 99:7408-7413.
  6. AllevaR, Benassi MS, Neuzil J, Tomasetti M, Gellert N, Borghi B, Procopio A, Picci P. a-Tocopheryl succinate controls cell growth and apoptosis of osteosarcoma cells by modulation of E2F1 independent of p53. Biochem Biophys Res Commun 2005; 331:1515-1521.
  7. Stapelberg M, Tomasetti M, Gellert, N, Alleva R, Procopio A, Neuzil J. a-Toco-pheryl succinate inhibits proliferation of mesothelioma cells by differential down-regulation of fibroblast growth factor receptors. Biochem Biophys Res Commun 2004; 318:636-641.
  8. Stapelberg M, Gellert N, Swettenham E, Tomasetti M, Witting KP, Procopio A, Neuzil J. a-Tocopheryl succinate inhibits malignant mesothelioma by disruption of the fibroblast growth factor autocrine signaling loop. J Biol Chem, in press.
  9. Don AS, Kisker O, Dilda P, Donoghue N, Zhao X, Decollogne S, Creighton B, Flynn E, Folkman J, Hogg PJ. A peptide trivalent arsenical inhibits tumor angio-genesis by perturbing mitochondrial function in angiogenic endothelial cells. Cancer Cell 2003; 3:497-509.
  10. Artwohl M, Roden M, Waldhausl W, Freudenthaler A, Baumgartner-Parzer SM. Free fatty acids trigger apoptosis and inhibit cell cycle progression in human vascular endothelial cells. FASEB J 2004; 18:146-148.
  11. Chen D, Walsh K, Wang J. Regulation of cdk2 activity in endothelial cells that are inhibited from growth by cell contact. Arterioscler Thromb Vasc Biol 2000; 20:629-635.
  12. Coqueret O. New roles for p21 and p27 cell-cycle inhibitors: a function for each cell compartment? Trends Cell Biol 2003; 13:65-70.
  13. Jiang Q, Elson-Schwab I, Courtemanche C, Ames BN. y-Tocopherol and its major metabolite, in contrast to alpha-tocopherol, inhibit cyclooxygenase activity in macrophages and epithelial cells. Proc Natl Acad Sci USA 2000; 97:11494-11499.
  14. Jiang Q, Ames BN. y-tocopherol, but not a-tocopherol, decreases proinflammatory eicosanoids and inflammation damage in rats. FASEB J 2003; 17:816-822.
  15. Borel P, Pasquier B, Armand M, Tyssandier V, Grolier P, Alexandre-Gouabau MC, Andre M, Senft M, Peyrot J, Jaussan V, Lairon D, Azais-Braesco V. Processing of vitamin A and E in the human gastrointestinal tract. Am J Physiol 2001; 280:G95-G103.

Pussinen PJ, Lindner H, Glatter O, Reicher H, Kostner GM, Wintersperger A, Malle E, Sattler W. Lipoprotein-associated a-tocopheryl-succinate inhibits cell growth and induces apoptosis in human MCF-7 and HBL-100 breast cancer cells. Biochim Biophys Acta 2000; 1485:129-144.

Hrzenjak A, Reicher H, Wintersperger A, Steinecker-Frohnwieser B, Sedlmayr P, Schmidt H, Nakamura T, Malle E, Sattler W. Inhibition of lung carcinoma cell growth by high density lipoprotein-associated alpha-tocopheryl-succinate. Cell Mol Life Sci 2004; 61:1520-1531.

Kayden HJ, Traber MG. Absorption, lipoprotein transport, and regulation of plasma concentrations of vitamin E in humans. J Lipid Res 1993; 34:343-358. Traber MG, Ramakrishnan R, Kayden HJ. Human plasma vitamin E kinetics demonstrate rapid recycling of plasma RRR-a-tocopherol. Proc Natl Acad Sci USA 1994; 91:10005-10008.

Kaempf-Rotzoll DE, Traber MG, Arai H. Vitamin E and transfer proteins. Curr Opin Lipidol 2003; 14:249-254.

Neuzil J. a-Tocopheryl succinate epitomizes a compound with a shift in biological activity due to pro-vitamin-to-vitamin conversion. Biochem Biophys Res Commun 2002; 293:1309-1313.

Neuzil J, Massa H. Hepatic processing determines dual activity of vitamin E succinate. Biochem Biophys Res Commun 2005; 327:1024-1027. Brigelius-Flohe R, Kelly FJ, Salonen JT, Neuzil J, Zingg JM, Azzi A. The European perspective on vitamin E: current knowledge and future research. Am J Clin Nutr 2002; 76:703-716.

Neuzil J, Thomas SR, Stocker R. Requirement for, promotion, or inhibition by a-tocopherol of radical-induced initiation of plasma lipoprotein lipid peroxidation. Free Radical Biol Med 1997; 22:57-71.

Neuzil J, Kontush A, Weber C. Vitamin E in atherosclerosis: Linking the chemical, biological and clinical aspects of the disease. Atherosclerosis 2001; 157:257-283. Li-Weber M, Weigand MA, Giaisi M, Suss D, Treiber MK, Baumann S, Ritsou E, Breitkreutz R, Krammer PH. Vitamin E inhibits CD95 ligand expression and protects T cells from activation-induced cell death. J Clin Invest 2002; 110:681-690.

Li-Weber M, Giaisi M, Treiber MK, Krammer PH. Vitamin E inhibits IL-4 gene expression in peripheral blood T cells. Eur J Immunol 2002; 32:2401-2408. Kristal AR, Stanford JL, Cohen JH, Wicklund K, Patterson RE. Vitamin and mineral supplement use is associated with reduced risk of prostate cancer. Cancer Epidemiol Biomarkers Prev 1999; 8:887-892.

Jacobs EJ, Connell CJ, Patel AV, Chao A, Rodriguez C, Seymour J, McCullough ML, Calle EE, Thun MJ. Vitamin C and vitamin E supplement use and colorectal cancer mortality in a large American cancer society cohort. Cancer Epidemiol Biomarkers Prev 2000; 10:17-23.

Murtaugh MA, Ma KN, Benson J, Curtin K, Caan B, Slattery ML. Antioxidants, carotenoids, and risk of rectal cancer. Am J Epidemiol 2004; 159:32-41. Bidoli E, Bosetti C, La Vecchia C, Levi F, Parpinel M, Talamini R, Negri E, Maso LD, Franceschi S. Micronutrients and laryngeal cancer risk in Italy and Switzerland: a case-control study. Cancer Causes Control 2003; 14:477-484.

  1. Weiser H, Vecchi M, Schlachter M. Stereoisomers of a-tocopheryl acetate. IV. USP units and a-tocopherol equivalents of all-rac-, 2-ambo- and RRR-a-toco-pherol evaluated by simultaneous determination of resorption-gestation, myopathy and liver storage capacity in rats. Int J Vitamin Nutr Res 1986; 56:45-56.
  2. Leth T, Sondergaard H. Biological activity of vitamin E compounds and natural materials by the resorption-gestation test, and chemical determination of vitamin E activity in foods and feeds. J Nutr 1977; 107:2236-2243.
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