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Title: | Cytotoxic action of phorbol esters on human pancreatic cancer cells. |
Authors: | Bond, JA Gescher, AJ Verschoyle, RD Lemoine, NR Errington, R Wiltshire, M Smith, PJ Wynford-Thomas, D |
First Published: | 1-Oct-2007 |
Citation: | INT J CANCER, 2007, 121 (7), pp. 1445-1454 |
Abstract: | We previously showed that phorbol esters are cytotoxic to human thyroid epithelial cells expressing a mutant RAS oncogene. Here we explore the generality of this finding using cells derived from pancreatic cancer, which, like thyroid, shows a high frequency of RAS mutation, but is a much greater cause of cancer mortality. The response to phorbol myristate acetate (PMA) and related agents was assessed on a panel of 9 pancreatic cancer cell lines, using a range of assays for cell growth and death in vitro and in vivo. In most lines, PMA induced non-apoptotic cell death which was, surprisingly, independent of its "classic" target, protein kinase C. With 24 hr exposure, the IC(50) in the most sensitive line (Aspc-1) was <1 ng/ml (1.6 nM), with survival undetectable at concentrations >/=>/=16 nM, and after only 1 hr exposure the IC(50) was still </=</=16 nM. Interestingly, the efficacy of a second phorbol ester, phorbol dibutyrate, was much lower, and the PMA analogue bryostatin-1, which is in clinical trials against other tumour types, was totally inactive. Pre-treatment of Aspc-1 cells with PMA before subcutaneous inoculation into nude mice prevented, or greatly retarded, subsequent xenograft tumour growth. Furthermore, treatment of established tumours with a single peri-tumoral injection of PMA induced extensive cell death and arrested tumour development. Taken together with recent Phase 1 clinical studies, these data suggest that activity against pancreatic cancer will be attainable by systemic administration of PMA, and point to potential novel therapeutic targets for this highly aggressive cancer. |
DOI Link: | 10.1002/ijc.22869 |
ISSN: | 0020-7136 |
Links: | http://hdl.handle.net/2381/15882 |
Type: | Journal Article |
Appears in Collections: | Published Articles, Dept. of Cancer Studies and Molecular Medicine |
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