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Abstract: Neoxanthin and fucoxanthin, which have the characteristic structure of 5,6-monoepoxide and an allenic bond, were previously found to reduce the viability of human prostate cancer cells most intensively among 15 dietary carotenoids tested. In the present study, the induction of apoptosis in PC-3 cells by these two carotenoids was characterized by morphological changes, DNA fragmentation, an increased percentage of hypodiploid cells, and cleavages of caspase-3 and PARP. The ratio of apoptotic cells reached more than 30% after treatment for 48h with 20μM carotenoids. They reduced the expression of Bax and Bcl-2 proteins, but not Bcl-XL. Fucoxanthin accumulated in the cells at the same level as neoxanthin. Moreover, fucoxanthinol, a deacetylated product of fucoxanthin, formed in the cells treated with fucoxanthin and reached a level comparable to that of fucoxanthin after incubation for 24h. Treatment by fucoxanthinol alone also induced apoptosis in PC-3 cells. Thus, neoxanthin and fucoxanthin treatments were found to induce apoptosis through caspase-3 activation in PC-3 human prostate cancer cells. [Copyright &y& Elsevier]

Neoxanthin, a major carotenoid in green leafy vegetables, was reported to exhibit potent antiproliferative effect via apoptosis induction on human prostate cancer cells. However, the metabolic fate of dietary neoxanthin in mammals remains unknown. In the present study, we investigated the gastrointestinal metabolism of neoxanthin in mice and the in vitro digestion of spinach, and estimated the antiproliferative effect of neoxanthin metabolites on PC-3 human prostate cancer cells. Two hours after the oral administration to mice of purified neoxanthin, unchanged neoxanthin and stereoisomers of neochrome (8'-R/S) were detected in the plasma, liver, and small intestinal contents. To estimate the effect of intragastric acidity on the conversion of dietary neoxanthin into neochrome (epoxide-furanoid rearrangement), spinach was digested in vitro by incubating it with a pepsin-HCl solution at pH 2.0 or 3.0 (gastric phase) followed by a pancreatin-bile salt solution (intestinal phase). Spinach neoxanthin was largely converted into (R/S)-neochrome during the digestion when the gastric phase was set at pH 2.0, whereas the rearrangement was observed to a lesser extent at pH 3.0. (R/S)-neochrome dose-dependently inhibited the proliferation of PC-3 cells as well as neoxanthin at concentrations < or = 20 micromol/L. Although neoxanthin induced evident apoptotic cell death, (R/S)-neochrome inhibited the cell proliferation without obvious apoptosis induction. These results indicate that dietary neoxanthin is partially converted into (R/S)-neochrome by intragastric acidity before intestinal absorption and that (R/S)-neochrome exhibits an antiproliferative effect on PC-3 cells by the induction of cytostasis. [ABSTRACT FROM AUTHOR]

Bendamustine (BENDA), which bears the bis(2-chloroethyl)amino moiety, is an alkylating agent that stops the growth of cancer cells by binding to DNA and interfering with its replication. However, the mechanism of action underlying its excellent clinical efficacy remains unclear. In this work, we report that BENDA inhibits signal transducer and activator of transcription 3 (STAT3). In an AlphaScreen-based biochemical assay using recombinant human STAT3, binding of STAT3–Src homology 2 (SH2) to the phosphotyrosine (pTyr, pY) peptide was inhibited by BENDA but not by the inactive metabolite dihydroxy bendamustine (HP2). When a single point mutation of C550A or C712A was introduced into recombinant human STAT3, its sensitivity to BENDA was substantially reduced, suggesting that these cysteine residues are important for BENDA to inhibit STAT3. Furthermore, BENDA suppressed the function of cellular STAT3 as a transcriptional activator in a human breast cancer cell line, MDA-MB-468, with constitutively activated STAT3. A competitive pull-down assay using biotinylated BENDA (Bio-BENDA) revealed that BENDA bound tightly to cellular STAT3, presumably through covalent bonds. Therefore, our results suggest that the anticancer effects of BENDA may be associated, at least in part, with its inhibitory effect on the SH2 domain of STAT3. [ABSTRACT FROM AUTHOR]

Highlights: [•] Novel dynamin inhibitor, which decreases actin polymerization, was identified. [•] The compound strongly reduced dynamin GTPase activity, cell migration and invasion. [•] Potent anti cancer drug targeting for dynamin is proposed. [Copyright &y& Elsevier]

Abstract: Kynurenine (Kyn), a metabolite of tryptophan (Trp), is known to be a key regulator of human immune responses including cancer immune tolerance. Therefore, abrogation of Kyn production from cancer cells by small molecules may be a promising approach to anticancer therapy. Indeed, several small molecule inhibitors of indoleamine 2,3-dioxygenase (IDO), a rate-limiting enzyme in the catabolism of Trp to Kyn, exert antitumor effects in animal models. We screened our chemical libraries using a cell-based Kyn production assay to identify a new type of small molecules that regulate Kyn production, and for the first time identified a benzenesulfonamide derivative (compound 1) as a hit with the ability to inhibit Kyn production in interferon-γ (IFN-γ)-stimulated A431 and HeLa cells. Unlike the previously identified S-benzylisothiourea derivative, compound 2, compound 1 had little effect on the enzymatic activity of recombinant human IDO in vitro but suppressed the expression of IDO at the mRNA level in cells. Furthermore, compound 1 suppressed STAT1-dependent transcriptional activity and DNA binding, whereas no decrement in either the expression or phosphorylation level of STAT1 was observed. The inhibition of IDO expression by several benzenesulfonamide derivatives is associated with the suppression of STAT1. Thus, compound 1 and its analogs might be useful for analyzing the regulation of IDO activation, and STAT1-targeting could be an alternative to the IDO-directed approach for the regulation of Kyn levels by small molecules in the tumor microenvironment. [Copyright &y& Elsevier]

Abstract: Effect of CF3-STLC, a potent kinesin spindle protein (KSP) inhibitor, on K562 human CML cell line was investigated. Treatment with CF3-STLC induced mitotic arrest of the cell cycle with the appearance of characteristic monoastral spindles, subsequent apoptotic cell death and cleavage of PARP-1, caspase-3, and 4E-BP1. The wide ranging caspase inhibitor z-VAD fmk prevented the cleavage of caspase-3 and 4E-BP1, but failed to attenuate PARP-1 cleavage or cell death triggered by CF3-STLC. These results suggest that CF3-STLC can induce apoptotic cell death in a caspase-independent manner, and may work effectively as an anti-cancer agent for hematological malignancies. [ABSTRACT FROM AUTHOR]

Abstract: Recent studies have demonstrated that tocotrienol (T3) is superior to tocopherol (Toc) for cancer chemoprevention. However, there is little information on whether Toc influences the anticancer property of T3. In this study, we investigated the influence of Toc on the cytotoxic effects of δ-T3 in DLD-1 human colorectal adenocarcinoma cells. Toc, especially α-Toc, attenuated δ-T3-induced cytotoxicity and apoptosis in DLD-1 cells, whereas Toc alone did not exhibit any cytotoxic effect. δ-T3-induced cell cycle arrest and proapoptotic gene/protein expression (e.g., p21, p27, and caspases) were abrogated by α-Toc. Furthermore, coadministration of α-Toc decreased δ-T3 uptake into DLD-1 cells in a dose-dependent manner. These results indicate that α-Toc is not only less cytotoxic to cancer cells, but it also reduces the cytotoxicity of δ-T3 by inhibiting its cellular uptake. [Copyright &y& Elsevier]

The article evaluates the apoptotic effect of peridinin, one of the most abundant carotenoids found in nature, on DLD-1 human colorectal cancer cells. According to the authors, peridinin significantly reduced the cell viability in a dose-dependent manner and induced apoptosis by activating both caspase-8 and caspase-9. They suggest that the findings could be important for the high-performance utilization of marine bioproducts.

Abstract: Biochemical analysis of the cellular target of S-trityl-l-cysteine (STLC) derivatives was performed by using the newly synthesized STLC derivative-immobilized affinity beads (3d). The affinity beads efficiently captured KSP in HCT116 cytoplasmic cell lysate. The results obtained from pull-down and competition experiments using 3d with STLC derivatives provided the first evidence for direct interaction of these derivatives with KSP in cancer cells. Design, synthesis and application of 3d were reported. [Copyright &y& Elsevier]