roger

Mol Cancer Ther. 2002 Sep;1(11):929-35.

Lipoxygenase inhibitors attenuate growth of human pancreatic cancer
xenografts and induce apoptosis through the mitochondrial pathway.

Tong WG, Ding XZ, Witt RC, Adrian TE.
Gastrointestinal Oncology Laboratories, Department of Surgery, Northwestern
University Medical School, Tarry 4-711, 303 East Chicago Avenue, Chicago, IL
60611, USA.

Several studies have suggested that high dietary fat intake, particularly
essential fatty acids, is associated with pancreatic cancer development and
growth. Our previous studies have demonstrated that blockade of either the
5-lipoxygenase (LOX) or 12-LOX pathway of arachidonic acid metabolism
inhibited pancreatic cancer cell proliferation and induced apoptosis. This
study investigated the underlying mechanisms for LOX inhibitor-induced
apoptosis and the potential of LOX inhibitors as antipancreatic cancer
agents using the athymic mice xenograft model. Apoptosis of pancreatic
cancer cells induced by LOX inhibitors (including the nonselective LOX
inhibitor nordihydroguaiaretic acid, the 5-LOX inhibitor Rev-5901, and the
12-LOX inhibitor baicalein) was confirmed by growth inhibition, annexin V
binding, and terminal deoxynucleotidyl transferase-mediated nick end
labeling assay in MiaPaCa-2 and AsPC-1 human pancreatic cancer cells.
Expression of the antiapoptotic proteins Bcl-2 and Mcl-1 was significantly
decreased after LOX inhibitor treatment while that of the proapoptotic
protein bax was increased. LOX inhibitors also markedly induced the release
of cytochrome c from mitochondria into the cytosol. Caspase-9, caspase-7,
and caspase-3 but not caspase-8 were activated after treatment, concomitant
with cleavage of the capase-3 substrate poly(ADP-ribose) polymerase. In vivo
studies in the athymic mice xenograft model also confirmed the growth
inhibitory effect and induction of apoptosis by these LOX inhibitors in
pancreatic cancer. In conclusion, LOX inhibitors block pancreatic cancer
cell proliferation and induce apoptosis through the mitochondrial pathway
both in vivo and in vitro. LOX inhibitors are likely to be valuable for the
treatment of human pancreatic cancer.