Please use this identifier to cite or link to this item: http://hdl.handle.net/2381/15882
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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