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

Collins A. Karikari, Indrajit Roy, Eric Tryggestad, Georg Feldmann, Clemencia Pinilla, Kate Welsh, John C. Reed, Elwood P. Armour, John Wong, Joseph Herman, Dinesh Rakheja, Anirban Maitra

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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.

Original languageEnglish (US)
Pages (from-to)957-966
Number of pages10
JournalMolecular Cancer Therapeutics
Volume6
Issue number3
DOIs
StatePublished - Mar 2007

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X-Linked Inhibitor of Apoptosis Protein
Pancreatic Neoplasms
gemcitabine
Apoptosis
Heterografts
Inhibitor of Apoptosis Proteins
Cell Line
Growth
Caspase 3
Initiator Caspases
Effector Caspases
Radiation
Ligands
Caspase 7
Therapeutics
Antimetabolites
Caspase 9
Standard of Care
Nude Mice

ASJC Scopus subject areas

  • Oncology
  • Drug Discovery
  • Pharmacology

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Targeting the apoptotic machinery in pancreatic cancers using small-molecule antagonists of the X-linked inhibitor of apoptosis protein. / Karikari, Collins A.; Roy, Indrajit; Tryggestad, Eric; Feldmann, Georg; Pinilla, Clemencia; Welsh, Kate; Reed, John C.; Armour, Elwood P.; Wong, John; Herman, Joseph; Rakheja, Dinesh; Maitra, Anirban.

In: Molecular Cancer Therapeutics, Vol. 6, No. 3, 03.2007, p. 957-966.

Research output: Contribution to journalArticle

Karikari, CA, Roy, I, Tryggestad, E, Feldmann, G, Pinilla, C, Welsh, K, Reed, JC, Armour, EP, Wong, J, Herman, J, Rakheja, D & Maitra, A 2007, 'Targeting the apoptotic machinery in pancreatic cancers using small-molecule antagonists of the X-linked inhibitor of apoptosis protein', Molecular Cancer Therapeutics, vol. 6, no. 3, pp. 957-966. https://doi.org/10.1158/1535-7163.MCT-06-0634
Karikari, Collins A. ; Roy, Indrajit ; Tryggestad, Eric ; Feldmann, Georg ; Pinilla, Clemencia ; Welsh, Kate ; Reed, John C. ; Armour, Elwood P. ; Wong, John ; Herman, Joseph ; Rakheja, Dinesh ; Maitra, Anirban. / Targeting the apoptotic machinery in pancreatic cancers using small-molecule antagonists of the X-linked inhibitor of apoptosis protein. In: Molecular Cancer Therapeutics. 2007 ; Vol. 6, No. 3. pp. 957-966.
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AU - Tryggestad, Eric

AU - Feldmann, Georg

AU - Pinilla, Clemencia

AU - Welsh, Kate

AU - Reed, John C.

AU - Armour, Elwood P.

AU - Wong, John

AU - Herman, Joseph

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AU - Maitra, Anirban

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N2 - 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.

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