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Research Articles: Therapeutics, Targets, and Development

Targeting the apoptotic machinery in pancreatic cancers using small-molecule antagonists of the X-linked inhibitor of apoptosis protein

Departments of ¹ Pathology, ² Oncology, and ³ Radiation Oncology and Molecular Radiation Sciences, The Sol Goldman Pancreatic Cancer Research Center and ⁴ McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; ⁵ Torrey Pines Institute of Molecular Studies, San Diego, California; ⁶ Burnham Institute for Medical Research, La Jolla, California; and ⁷ Department of Pathology, Children's Medical Center, University of Texas Southwestern Medical Center, Dallas, Texas

Requests for reprints: Anirban Maitra, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, CRB2 Room 345, 1550 Orleans Street, Baltimore, MD 21231. Phone: 410-955-3511; Fax: 410-614-0671. E-mail: Amaitra1{at}jhmi.edu

Abstract

Resistance to apoptosis is a hallmark of many solid tumors, including pancreatic cancers, and may be the underlying basis for the suboptimal response to chemoradiation therapies. Overexpression of a family of inhibitor of apoptosis proteins (IAP) is commonly observed in pancreatic malignancies. We determined the therapeutic efficacy of recently described small-molecule antagonists of the X-linked IAP (XIAP) in preclinical models of pancreatic cancer. Primary pancreatic cancers were assessed for XIAP expression by immunohistochemistry, using a pancreatic cancer tissue microarray. XIAP small-molecule antagonists ("XAntag"; compounds 1396-11 and 1396-12) and the related compound 1396-28 were tested in vitro in a panel of human pancreatic cancer cell lines (Panc1, Capan1, and BxPC3) and in vivo in s.c. xenograft models for their ability to induce apoptosis and impede neoplastic growth. In addition, pancreatic cancer cell lines were treated with XAntags in conjunction with either tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) or with radiation to determine potential synergy for such dual targeting of the apoptotic machinery. XIAP was overexpressed in 14 of 18 (77%) of primary pancreatic cancers. The XAntags1396-11 and 1396-12, but not the inactive isomer 1396-28, induced profound apoptosis in multiple pancreatic cancer cell lines tested in vitro, with a IC₅₀ in the range of 2 to 5 µmol/L. Mechanistic specificity of the XAntags for the baculoviral IAP repeat-2 domain of XIAP was shown by preferential activation of downstream "effector" caspases (caspase-3 and caspase-7) versus the upstream "initiator" caspase-9. S.c. BxPC3 xenograft growth in athymic mice was significantly inhibited by monotherapy with XAntags; treated xenografts showed marked apoptosis and increased cleavage of caspase-3. Notably, striking synergy was demonstrable when XAntags were combined with either TRAIL or radiation therapy, as measured by growth inhibition in vitro and reduced colony formation in soft agar of pancreatic cancer cell lines, at dosages where these therapeutic modalities had minimal to modest effects when used alone. Finally, XAntags in combination with the standard-of-care agent for advanced pancreatic cancer, gemcitabine, resulted in significantly greater inhibition of in vitro growth than gemcitabine alone. Our results confirm that pharmacologic inhibition of XIAP is a potent therapeutic modality in pancreatic cancers. These antagonists are independently capable of inducing pancreatic cancer cell death and also show synergy when combined with proapoptotic ligands (TRAIL), with radiation, and with a conventional antimetabolite, gemcitabine. These preclinical results suggest that targeting of the apoptotic machinery in pancreatic cancers with XAntags is a promising therapeutic option that warrants further evaluation. [Mol Cancer Ther 2007;6(3):957–66]

Grant support: R01CA113669, R21DK072532, AACR-PanCAN Career Development Award, the Sol Goldman Pancreatic Cancer Research Center and the Lustgarten Foundation for Pancreatic Cancer Research (A. Maitra). U19 CA113318 and the California Tobacco-Related Disease Program (J.C. Reed).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: C.A. Karikari and I. Roy contributed equally to this work. Current address for I. Roy: Institute for Lasers, Photonics, and Biophotonics, University of Buffalo, Buffalo, NY.

Received 10/12/06; revised 12/12/06; accepted 2/ 1/07.

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