Premium
Cytotoxic action of phorbol esters on human pancreatic cancer cells
Author(s) -
Bond Jane A.,
Gescher Andreas J.,
Verschoyle Richard D.,
Lemoine Nicholas R.,
Errington Rachel,
Wiltshire Marie,
Smith Paul J.,
WynfordThomas David
Publication year - 2007
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.22869
Subject(s) - pancreatic cancer , cytotoxic t cell , programmed cell death , cancer research , phorbol , apoptosis , cell culture , protein kinase c , cancer , cancer cell , pancreas , in vivo , medicine , biology , in vitro , microbiology and biotechnology , endocrinology , kinase , biochemistry , genetics
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. © 2007 Wiley‐Liss, Inc.