Published in Cancer Detection and Prevention 2000; 24(Supplement 1).

Inhibition of arachidonic acid remodeling reduces squamous cell carcinoma proliferation

FH Chilton PhD 1, H Tiano PhD 2, C Lee BS 2, AJ Trimboli PhD 1, R Langenbach PhD 2

1 Wake Forest University School of Medicine, Winston-Salem, NC, 2 National Institute of Environmental Health Sciences, Research Triangle Park, NC,

AIMS: Recent studies have demonstrated that arachidonic acid (AA) can serve as an important signal that controls cell proliferation of mammalian cells. We have shown that blocking AA movement between membrane phospholipids by inhibitors of the enzyme, CoA-independent transacylase (CoA-IT), attenuates the proliferation breast cancer and leukemia cells. This study examines the influence of a CoA-IT inhibitor, PLT 75183 on squamous cell carcinoma formation and growth. METHODS & RESULTS: PLT 75183 arrested the growth of several types of squamous cell carcinomas, A-431 (skin, IC50 = 28.7 µM), HEp-2 (larynx, IC50 = 28.7 µM), SK-MES-1 (lung, IC50 = 20.2 µM) and SiHa (cervix, IC50 = 24.0 µM). The growth inhibition in A-431 cells was accompanied by an accumulation of AA in triglycerides, a marker of intracellular AA stress within mammalian cells. Cell synchronization experiments revealed that PLT 75183 blocked SiHa cell replication in S phase of the cell cycle. The influence of PLT 75183 on tumor formation was also examined in a two stage mouse skin carcinogenesis model with DMBA and phorbol ester treatment. These chemical agents induced papilloma lesions that were dramatically reduced in both number and size by PLT 75183. CONCLUSIONS: Taken together, these experiments suggest that disruption of AA remodeling in a manner that increases intracellular AA represents a novel therapeutic strategy to reduce tumor formation.

KEY WORDS: Cancer, Apoptosis, Cell Proliferation.

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Paper presented at the International Symposium on Impact of Biotechnology on Cancer Diagnostic & Prognostic Indicators; Geneva, Switzerland; October 28 - 31, 2000; in the section on satellite symposium.