Lipoxygenase inhibitors inhibit growth of human pancreatic cancer xenografts and induce apoptosis



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.