In recent years the discovery of cancer biomarkers has become a major focus of cancer research. The widespread use of prostate-specific antigen in prostate cancer screening has motivated researchers to identify suitable markers for screening different types of cancer. Biomarkers are also useful for diagnosis, monitoring disease progression, predicting disease recurrence and therapeutic treatment efficacy. With the advent of new and improved genomic and proteomic technologies such as DNA and tissue microarray, two-dimensional gel eletrophoresis, mass spectrometry and protein assays coupled with advanced bioinformatic tools, it is possible to develop biomarkers that are able to reliably and accurately predict outcomes during cancer management and treatment. In years to come, a serum or urine test for every phase of cancer may drive clinical decision making, supplementing or replacing currently existing invasive techniques.

Public-sector research has had a more immediate effect on improving public health than was previously realized.

Paclitaxel has emerged as a front line treatment for aggressive malignancies of the breast, lung, and ovary. Successful therapy of cancer is frequently undermined by the development of paclitaxel resistance. There is a growing need to find other therapeutic targets to facilitate treatment of drug-resistant cancers. Using a proteomics approach, elevated levels of Prohibitin1 (PHB1) and GSTπ were found associated with paclitaxel resistance in discrete subcellular fractions of two drug-resistant sublines relative to their sensitive sublines. Immunofluorescence staining and fractionation studies revealed increased levels of PHB1 on the surface of resistant cell lines. Transiently silencing either PHB1 or GSTπ gene expression using siRNA in the paclitaxel-resistant cancer cell sublines partially sensitized these cells toward paclitaxel. Intriguingly, silencing PHB1 but not GSTπ resulted in activation of the intrinsic apoptosis pathway in response to paclitaxel. Similarly, stably silencing either PHB1 or GSTπ significantly improved paclitaxel sensitivity in A549TR cells both in vitro and in vivo. Our results indicate that PHB1 is a mediator of paclitaxel resistance and that this resistance may depend on the cellular localization of the protein. We suggest PHB1 as a potential target for therapeutic strategies for the treatment of drug-resistant tumors.apoptosis | glutathione-S-transferase Pi | mitochondria | plasma membrane | protein translocation

[reaction: see text] This work describes the synthesis of two novel macrocyclic taxoid constructs by ring-closing olefin metathesis (RCM) and their biological evaluation. Computational studies examine conformational profiles of 1 and 2 for their fit to the beta-tubulin binding site determined by electron crystallography. The results support the hypothesis that paclitaxel binds to microtubules in a "T" conformation.

The female steroid hormone 3,17beta-estradiol (2) was selected as an agent to target taxol (1) to estrogen receptor (ER) positive breast cancer cells. Estradiol-taxol conjugates (ETC) were synthesized through linkages from the 11- or 16-position of estradiol to the 2'-, 7-, or 10-position of taxol. All conjugates were cytotoxic to the A2870 ovarian cancer cell line, although less so than taxol. The MCF-7 breast cancer cell line (ER-alpha positive) and MDA-MB-231 breast cancer cell line (ER-alpha negative) were also used to evaluate the selectivity and cytotoxicity of these conjugates. One conjugate showed some selectivity for ER positive cells, but it was less potent than taxol. Two ETC hemisuccinates were also prepared to improve the solubility of the conjugates. The corresponding Na and triethanolammonium salts were slightly more cytotoxic than the acid form but were much less cytotoxic than the corresponding ETC.

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Minimally modified low-density lipoprotein (MM-LDL) is regarded as a major risk factor for the development of atherosclerosis. In this report, we show that this lipoprotein complex can induce expression of an inflammatory protein, serum amyloid A (SAA), in monocyte/macrophage cells, a key cell type implicated in the pathogenesis of atherosclerosis. By promoter function analysis and site-directed mutagenesis, we have located promoter regions responsive to MM-LDL action. Using electrophoretic mobility shift, antibody ablation/supershift, and Western blot assays, we showed that induction of SAA by MM-LDL is mediated via activation of SAS binding factor (SAF) and C/EBP transcription factors. We further show that tamoxifen, a downregulator of CD36, one of the major scavenger receptors which binds MM-LDL, can inhibit MM-LDL-mediated SAA induction in THP-1 cells. This finding suggests that CD36 participates in the manifestation of the inflammatory effects of MM-LDL. Our experiments provide the first evidence for transcription factor activation by MM-LDL.

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