alpha-Tocopheryl succinate (alpha-TOS) is a semisynthetic vitamin E analogue with high pro-apoptotic and anti-neoplastic activity [Weber, T et al. (2002) Clin. Cancer Res. 8, 863-869]. Previous studies suggested that it acts through destabilization of subcellular organelles, including mitochondria, but compelling evidence is missing. Cells treated with alpha-TOS showed altered mitochondrial structure, generation of free radicals, activation of the sphingomyelin cycle, relocalization of cytochrome c and Smac/Diablo, and activation of multiple caspases. A pan-caspase inhibitor suppressed caspase-3 and -6 activation and phosphatidyl serine externalization, but not decrease of mitochondrial membrane potential or generation of radicals. For alpha-TOS, but not Fas or TRAIL, apoptosis was suppressed by caspase-9 inhibition, while TRAIL- and Fas-resistant cells overexpressing cFLIP or CrmA were susceptible to alpha-TOS. The central role of mitochondria was confirmed by resistance of mtDNA-deficient cells to alpha-TOS, by regulation of alpha-TOS apoptosis by Bcl-2 family members, and by anti-apoptotic activity of mitochondrially targeted radical scavengers. Co-treatment with alpha-TOS and anti-Fas IgM showed their cooperative effect, probably by signaling via different, convergent pathways. These data provide an insight into the molecular mechanism, by which alpha-TOS kills malignant cells, and advocate its testing as a potential anticancer agent or adjuvant.

The vitamin E analog alpha-tocopheryl succinate (alpha-TOS) can induce apoptosis. We show that the proapoptotic activity of alpha-TOS in hematopoietic and cancer cell lines involves inhibition of protein kinase C (PKC), since phorbol myristyl acetate prevented alpha-TOS-triggered apoptosis. More selective effectors indicated that alpha-TOS reduced PKCalpha isotype activity by increasing protein phosphatase 2A (PP2A) activity. The role of PKCalpha inhibition in alpha-TOS-induced apoptosis was confirmed using antisense oligonucleotides or PKCalpha overexpression. Gain- or loss-of-function bcl-2 mutants implied modulation of bcl-2 activity by PKC/PP2A as a mitochondrial target of alpha-TOS-induced proapoptotic signals. Structural analogs revealed that alpha-tocopheryl and succinyl moieties are both required for maximizing these effects. In mice with colon cancer xenografts, alpha-TOS suppressed tumor growth by 80%. This epitomizes cancer cell killing by a pharmacologically relevant compound without known side effects.

We report that α-tocopheryl succinate, a vitamin E analogue with pro-apoptotic properties, selectively kills cells with a malignant or transformed phenotype, i.e. multiple haematopoietic and carcinoma cell lines, while being non-toxic to normal, i.e. primary and non-transformed cells. These findings strongly suggest a potential of this micronutrient in the therapy and/or prevention of cancer without significant side-effects. © 2001 Cancer Research Campaign http://www.bjcancer.com

Controlling strongly interacting many-body systems enables the creation of tailored quantum matter, with properties transcending those based solely on single particle physics. Atomic ensembles which are optically driven to a Rydberg state provide many examples of this, such as atom-atom entanglement [1,2], many-body Rabi oscillations [3], strong photon-photon interaction [4] and spatial pair correlations [5]. In its most basic form, Rydberg quantum matter consists of an isolated ensemble of strongly interacting atoms spatially confined to the blockade volume -a so-called superatom. Here we demonstrate the controlled creation and characterization of an isolated mesoscopic superatom by means of accurate density engineering and excitation to Rydberg p-states. Its variable size allows to investigate the transition from effective two-level physics for strong confinement to many-body phenomena in extended systems. By monitoring continuous laser-induced ionization we observe a strongly anti-bunched ion emission under blockade conditions and extremely bunched ion emission under off-resonant excitation. Our experimental setup enables in vivo measurements of the superatom, yielding insight into both excitation statistics and dynamics. We anticipate straightforward applications in quantum optics and quantum information as well as future experiments on many-body physics.Rydberg superatoms combine single and many-body quantum effects in a unique way and have been proposed as fundamental building blocks for quantum simulation and quantum information [6]. Due to the phenomenon of Rydberg blockade [7], the ensemble collectively forms a system with only two levels of excitation. Provided a range of interaction larger than the sample size, the presence of one excitation shifts all other atoms out of resonance and therefore only one excitation can be created at a time. Changing the size or the driving conditions revives the underlying many-body nature and the presence of several excited atoms with pronounced correlations becomes possible. This tunability and the possibility of multiple usage within a single experimental sequence make superatoms a promising complement to single-atom-based quantum technology. It is therefore important to understand the significance of the superatom concept, the implications of its finite spatial extent and its many-body level structure. We here investigate the latter by measuring the mean Rydberg excitation as well as its time-resolved two-particle correlations in an optically excited, mesoscopic superatom for varying excitation strength and under resonant and non-resonant conditions, revealing very different excitation dynamics.The realization of superatom-based quantum systems requires the implementation of arbitrary arrangements of isolated mesoscopic atomic ensembles in a scalable way. We here prepare an individual superatom by carefully shaping the density distribution of a Bose-Einstein condensate of 87 Rb atoms. We first load the condensate into a one-dimensional optical lattice with a spacin...

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Suppression of NF kappa B activation has been involved in the elimination of survival programs during endothelial cell (EC) apoptosis. We used alpha-tocopheryl succinate (alpha-TOS) to trigger apoptosome formation and the subsequent activation of executioner caspases. The level of bcl-2 was reduced by alpha-TOS, and its downregulation potentiated and its overexpression suppressed pro-apoptotic effects of alpha-TOS, indicating a mitochondrial role in alpha-TOS-induced apoptosis in EC. alpha-TOS treatment was associated with induction of TUNEL-positive apoptosis in EC with a high but not with a low proliferation index. The use of the pan-caspase inhibitor z-VAD.fmk suggested the involvement of caspases in cleavage of p65, and in inhibition of nuclear translocation of p65 and NF kappa B-dependent transactivation of a gene construct encoding the green fluorescence protein elicited by TNF alpha in contact-arrested EC. The suppression by alpha-TOS of inflammatory EC responses induced by TNF alpha such as VCAM-1 mRNA and surface protein expression and shear-resistant arrest of monocytic cells were also reversed by z-VAD.fmk. NF kappa B-dependent transactivation was preserved in alpha-TOS-treated EC stably transfected with a caspase-noncleavable p65 mutant but not with its truncated form, thus establishing a direct link between alpha-TOS-induced effects and p65 cleavage. Our data infer a pathway by which caspase activation in EC inhibits NF kappa B-dependent inflammatory activation and monocyte recruitment, and provide evidence for a relationship between pro-apoptotic and anti-inflammatory pathways.

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We have studied the associative ionization of a Rydberg atom and a ground state atom in an ultracold Rydberg gas. The measured scattering cross section is three orders of magnitude larger than the geometrical size of the produced molecule. This giant enhancement of the reaction kinetics is due to an efficient directed mass transport which is mediated by the Rydberg electron. We also find that the total inelastic scattering cross section is given by the geometrical size of the Rydberg electron's wavefunction.PACS numbers: 32.80. Rm, 34.50.Fa, 82.45.Jn Molecule formation in dilute gases or plasmas usually happens via two-body collisions and is relevant, e.g., for the production of molecules in interstellar space [1] or during the early stage of the universe [2]. One prominent class of such collisions is the associative ionization between a ground state atom and a (highly) excited atom. The latter can result from electron capture in a plasma or photon absorption. The formation of a bound molecule requires the release of binding energy which is realized by the ejection of an electron [3]. Associative ionization involving Rydberg atoms has been studied in detail in hot atomic beam experiments and cross sections on the order of the geometrical size of the formed molecules have been found [4][5][6].Ultracold Rydberg gases allow to extend the study of this fundamental chemical reaction to the low-energy limit, where a new interaction mechanism [7] has drawn researchers' attention in the last years: The scattering between the electron in a Rydberg state and a ground state atom creates a potential for the atom that reaches far from the Rydberg atoms core. This potential gives rise to ultra long range Rydberg molecules [8], trilobite molecules [9] and was found to induce phonons inside of a Bose-Einstein-Condensate [10]. The understanding of this interaction and it's role in associative ionization is also important to fully exploit the potential of ultracold Rydberg systems to study many-body quantum phenomena [11][12][13] beyond the frozen gas approximation.Here, we study the associative ionization of a rubidium atom in a Rydberg p-state (principal quantum number n = 30 − 60) and a ground state atom at ultracold temperatures. The measured scattering cross section is three orders of magnitude larger than the geometrical size of the produced molecular ion. We attribute this enhancement to a directed mass transport of the ground state atom towards the ionic core of the Rydberg atom. This transport mechanism is mediated by the scattering between the Rydberg electron and the ground state atom. The formation of the molecular ion happens, when the two collision partners are close enough that the released binding energy suffices to eject the excited electron via resonant dipole interaction [3]. The appearance of a . .