Paclitaxel (Taxol)-induced cell death requires the intrinsic cell death pathway, but the specific participants and the precise mechanisms are poorly understood. Previous studies indicate that a BH3-only protein BIM (BCL-2 Interacting Mediator of cell death) plays a role in paclitaxel-induced apoptosis. We show here that BIM is dispensable in apoptosis with paclitaxel treatment using bim−/− MEFs (mouse embryonic fibroblasts), the bim−/− mouse breast tumor model, and shRNA-mediated down-regulation of BIM in human breast cancer cells. In contrast, both bak −/− MEFs and human breast cancer cells in which BAK was down-regulated by shRNA were more resistant to paclitaxel. However, paclitaxel sensitivity was not affected in bax−/− MEFs or in human breast cancer cells in which BAX was down-regulated, suggesting that paclitaxel-induced apoptosis is BAK-dependent, but BAX-independent. In human breast cancer cells, paclitaxel treatment resulted in MCL-1 degradation which was prevented by a proteasome inhibitor, MG132. A Cdk inhibitor, roscovitine, blocked paclitaxel-induced MCL-1 degradation and apoptosis, suggesting that Cdk activation at mitotic arrest could induce subsequent MCL-1 degradation in a proteasome-dependent manner. BAK was associated with MCL-1 in untreated cells and became activated in concert with loss of MCL-1 expression and its release from the complex. Our data suggest that BAK is the mediator of paclitaxel-induced apoptosis and could be an alternative target for overcoming paclitaxel resistance.

Accumulating evidence indicates that the chemokine receptor CCR5 and the chemokine CCL5 may be involved in the proliferation and metastasis of prostate cancer. Consequently, chemokine receptor CCR5 antagonists could potentially act as anti prostate cancer agents. As the first natural product CCR5 antagonist, anibamine provides a novel chemical structural skeleton compared with other known antagonists identified through high-throughput screening. Our studies demonstrate that anibamine produces significant inhibition of prostate cancer cell proliferation at micromolar to submicromolar concentrations as well as suppressing adhesion and invasion of the highly metastatic M12 prostate cancer cell line. Preliminary in vivo studies indicate that anibamine also inhibits prostate tumor growth in mice. These findings indicate that anibamine may prove to be a novel lead compound for the development of prostate cancer therapeutic agents. Keywordschemokine receptor CCR5; antagonist; anibamine; prostate cancer Prostate cancer is the most common non-cutaneous solid cancer occurring amongst men in the USA, and the second most common malignant cause of male death worldwide 1 . Current therapies remain limited to surgery, radiation, and/or androgen ablation 2 . Recent investigations indicate that there is a relationship between some inflammatory processes and cancer, specifically, prostate cancer development [3][4][5][6][7][8][9][10][11][12][13] . For example, the prostate cancer cell lines PC-3, DU145, and LNCaP express the chemokine CCL5 (RANTES) and the * Corresponding author: Department of Medicinal Chemistry, Virginia Commonwealth University, 800 East Leigh Street, P.O. Box 980540, Richmond, VA 23298-0540, USA. Tel: 01-804-828-0021; Fax: 01-804-828-7625; yzhang2@vcu.edu . # These two authors contribute equally to the manuscript.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Anibamine (Figure 1), a novel pyridine quaternary alkaloid recently isolated from Aniba sp., was found to bind to CCR5 with an IC 50 of 1 μM in competition with 125I-gp120, an HIV viral envelop protein 14 . Thus far, anibamine is the first known natural product acting as a CCR5 antagonist. While the chemokine receptor CCR5 has mainly been targeted in HIV therapies since it was first cloned more than a decade ago 15-21 , CCR5 antagonists could provide a novel therapeutic approach for prostate cancer treatment through the inhibition of CCL5 induced cell proliferation. NIH Public AccessAnibamine has a novel structural skeleton compared to other CCR5 antagonists identified through high-throughput screening. Con...

The use of kidneys from non-heart beating donors (NHBDs) presents a paradox; whilst they provide more organs for transplantation, there is an increased risk of poor graft outcome, particularly in the short term. This study has highlighted the difference in early graft function and late graft survival between NHBD kidneys with short (controlled) and long (uncontrolled) warm ischaemic times. Whilst it would seem that it is preferable to use controlled donors only, their numbers are small. By employing a rational approach to the use of each of these types of kidney, such as structured viability assessment and risk analysis, it may be that the results of uncontrolled NHBD can be improved.

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