Because epigenetic alterations are believed to be involved in the repression of tumor suppressor genes and the promotion of tumorigenesis in cancers, novel compounds endowed with histone deacetylase (HDAC) inhibitory activity are an attractive therapeutic approach. Indeed, the potential of HDAC inhibitors for cancer therapy has been explored in preclinical models, and some agents approved for hematologic malignancies have reached the clinical setting. HDAC inhibitors are able to mediate the induction of both apoptosis and autophagy, which are related to anticancer activity in a variety of cancer cell lines. Given the inherent resistance to apoptosis that characterizes cancer, the targeting of alternative pathways is an attractive strategy to improve anti-tumor therapy. The activation of autophagy represents novel cancer treatment targets. This paper aims to critically discuss how the anticancer potential of HDAC inhibitors may elicit a response to human cancers through different cell pathways leading to cell death.

SummaryWe demonstrated in the present study that with bacterial stimulation, an increased number of a/g T cells proliferated in the liver of mice and that even T cells bearing self-reactive T cell receptor (TCR) (or forbidden T cell clones), as estimated by antiV(3 monoclonal antibodies in conjunction with immunofluorescence tests, appeared in the liver and, to some extent, in the periphery. The majority (>80%) of forbidden clones induced had double-negative CD4-8-phenotype. In a syngeneic mixed lymphocyte reaction, these T cells appear to be self-reactive . Such forbidden clones and normal T cells in the liver showed a two-peak pattern of TCR expression, which consisted of u/(3 TCR dull and bright positive cells, as seen in the thymus. A systematic analysis of TCR staining patterns in the various organs was then carried out . T cells from not only the thymus but also the liver had the two-peak pattern of a/a TCR, whereas all of the other peripheral lymphoid organs had a single-peak pattern of TCR . However, T cells in the liver were not comprised of double-positive CD4 *8+ cells, which predominantly reside in the thymus. The present results therefore suggest that T cell proliferation in the liver might reflect a major extrathymic pathway for T cell differentiation and that this hepatic pathway has the ability to produce T cells bearing self-reactive TCR under bacterial stimulation, probably due to the lack of a double-positive stage for negative selection.I t is generally accepted that T lymphocytes differentiate in the thymus and go through a process of positive or negative selection to form the repertoires of mature T cells (1-4) . In earlier studies, several investigators proposed the existence of an extrathymic differentiation pathway of T cells, especially in experiments using congenitally athymic nude mice and in vitro culture systems (5-8) . However, investigators have not reached a consensus, since there is no definite information yet as to where such T cells differentiate outside the thymus. In recent studies, we have shown that both a/(3 and y/b T cells with double-negative (DN) t CD4 -8 -phenotype proliferate in the liver of humans and mice, especially under conditions of autoimmune diseases (9), malignancies (10, 11), and aging (12). These results have led us to consider the possibility that the liver might be a major site for extrathymic differentiation of certain T cells.In the present study, we have applied a recently described ' Abbreviations used in this paper. DN, double negative; DP, double positive, MMC, mitomycin ; MNC, mononuclear cells. 417system for identification of oligoclonal T cells expressing particular VQ of cx/0 TCRs by using mAbs (13,14) to demonstrate the hepatic pathway for cell differentiation . The present results support the possibility that the liver is a major site of extrathymic T cell differentiation and reveal that the hepatic pathway has several unique properties distinct from the intrathymic pathway for T cell differentiation . Materials and MethodsMice and Bacterial ...

Converging data from epidemiological, ecological, and clinical studies have shown that selenium (Se) can decrease the risk for some types of human cancers. Induction of apoptosis is considered an important cellular event that can account for the cancer preventive effects of Se. Prior to occurrence of apoptosis, Se compounds alter the expression and/or activities of signaling molecules, mitochondria-associated factors, transcriptional factors, tumor suppressor genes, and cellular reduced glutathione. Mechanistic studies have demonstrated that the methylselenol metabolite pool has many desirable attributes of chemoprevention, whereas the hydrogen selenide pool with excess of selenoprotein synthesis can lead to DNA single-strand breaks. To elucidate the effects of Se on cytotoxic events, it should be remembered that the chemical forms and the dose of Se, and the experimental system used, are determinants of its biological activities. This mini-review focuses on elucidation of the molecular mechanisms of cancer prevention by Se with the apoptotic approach.

For several decades, apoptosis has taken center stage as the principal mechanism of programmed cell death (type I cell death) in mammalian tissues. Autophagic cell death (type II) is characterized by the massive accumulation of autophagic vacuoles in the cytoplasm of cells. The autophagic process is activated as an adaptive response to a variety of extracellular and intracellular stresses, including nutrient deprivation, hormonal or therapeutic treatment, pathogenic infection, aggregated and misfolded proteins, and damaged organelles. Increasing evidence indicates that autophagy is associated with a number of pathological processes, including cancer. The regulation of autophagy in cancer cells is complex since it can enhance cancer cell survival in response to certain stresses, while it can also act to suppress the initiation of cancer growth. This paper focused on recent advances regarding autophagy in cancer and the techniques currently available to manipulate autophagy.

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