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¹ Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; ² Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario, Canada; and ³ Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio

Requests for reprints: David W. Hedley, Division of Experimental Therapeutics, Department of Medical Oncology and Hematology, Ontario Cancer Institute, Princess Margaret Hospital, 610 University Avenue, Toronto, Ontario, Canada M5G 2M9. Phone: 416-946-2262; Fax: 416-946-6546. E-mail: david.hedley{at}uhn.on.ca

Anticancer effects of the dietary isothiocyanate sulforaphane were investigated in the human pancreatic cancer cell lines MIA PaCa-2 and PANC-1. Sulforaphane-treated cells accumulated in metaphase as determined by flow cytometry [4C DNA content, cyclin A(–), cyclin B1(+), and phospho-histone H3 (Ser¹⁰)(+)]. In addition, treated cells showed nuclear apoptotic morphology that coincided with an activation of caspase-8, loss of mitochondrial membrane potential, and loss of plasma membrane integrity. The initial detection of caspase-3 cleavage occurring in G₂-M arrest was independent of a change in phospho-cdc2 (Tyr¹⁵) protein; consequently, sulforaphane treatment combined with UCN-01 had no significant impact on cellular toxicity. Incubations at higher sulforaphane doses (>10 µmol/L) resulted in cleavage of caspase-3 in the G₁ subpopulation, suggesting that the induction of apoptosis and the sulforaphane-induced mitosis delay at the lower dose are independently regulated. Cellular toxicity in MIA PaCa-2, and to a greater extent in PANC-1, was positively correlated with a decrease in cellular glutathione levels, whereas sustained increases in glutathione observed in MIA PaCa-2 cells or the simultaneous incubation with N-acetyl-L-cysteine in PANC-1 cells were associated with resistance to sulforaphane-induced apoptosis. Daily sulforaphane i.p. injections (375 µmol/kg/d for 3 weeks) in severe combined immunodeficient mice with PANC-1 s.c. tumors resulted in a decrease of mean tumor volume by 40% compared with vehicle-treated controls. Our findings suggest that, in addition to the known effects on cancer prevention, sulforaphane may have activity in established pancreatic cancer.

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Received 2/10/04; revised 8/11/04; accepted 8/20/04.

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