The present work gives the preliminary results of a systematic theoretical investigation of the relationship of structure and dynamics for a series of naturally occurring carbohydrate polymers as a function of the topological features, i.e., sugar composition and linkage type. Specifically, homopolymeric (1f3)-and (1f4)-linked Rand β-D-glucans and homopolymeric (1f4)-linked Rand β-D-galactans are considered. These polysaccharide chains cover a broad spectrum of macromolecular stiffness and extension. The theoretical calculations are developed within a diffusive approach that takes accurately into account the polymer connectivity and the corresponding conformational energy surface. This theoretical approach to the polymer dynamics, designated as the optimized Rouse Zimm local dynamics (ORZLD) theory, has been improved and implemented for applications to random coil polysaccharides in solution. The results show that correlation times, such as those obtainable from appropriate NMR, fluorescence, radiation scattering, and rheological relaxation experiments, are very sensitive to the details of the molecular structure and reveal patterns that are useful for characterizing the different chain topologies. Correlations are also illustrated among the dynamic chain pattern (i.e., the position and chain length dependence of the correlation times), equilibrium chain stiffness parameters, and the primary structure of the chain.
We previously reported that N-(4-hydroxyphenyl)retinamide (4HPR) inhibits retinoblastoma tumor growth in a murine model in vivo and kills Y79 retinoblastoma cells in vitro. In this work, we assayed different cell deathrelated parameters, including mitochondrial damage and caspase activation, in Y79 cells exposed to 4HPR. 4HPR induced cytochrome c release from mitochondria, caspase-3 activation, and oligonucleosomal DNA fragmentation. However, pharmacologic inactivation of caspases by the pan-caspase inhibitor BOC-D-fmk, or specific caspase-3 inhibition by Z-DEVD-fmk, was not sufficient to prevent cell death, as assessed by loss of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction, lactate dehydrogenase release, disruption of mitochondrial transmembrane potential (#y m ), and ATP depletion. We found that 4HPR causes lysosomal membrane permeabilization and cytosolic relocation of cathepsin D. Pepstatin A partially rescued cell viability and reduced DNA fragmentation and cytosolic cytochrome c. The antioxidant Nacetylcysteine attenuated cathepsin D relocation into the cytosol, suggesting that lysosomal destabilization is dependent on elevation of reactive oxygen species and precedes mitochondrial dysfunction. Activation of AKT, which regulates energy level in the cell, by the retinal survival factor insulin-like growth factor I was impaired and insulin-like growth factor I was ineffective against ATP and #y m loss in the presence of 4HPR. Lysosomal destabilization, associated with mitochondrial dysfunction, was induced by 4HPR also in other cancer cell lines, including PC3 prostate adenocarcinoma and the vascular tumor Kaposi sarcoma KS-Imm cells. The novel finding of a lysosome-mediated cell death pathway activated by 4HPR could have implications at clinical level for the development of combination chemoprevention and therapy of cancer. [Mol Cancer Ther 2007;6(1):286 -98]
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