Suppression of cFLIP by lupeol, a dietary triterpene, is sufficient to overcome resistance to TRAIL-mediated apoptosis in chemoresistant human pancreatic cancer cells

Imtiyaz Murtaza, Mohammad Saleem, Vaqar Mustafa Adhami, Bilal Hafeez, Hasan Mukhtar

Research output: Contribution to journalArticle

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Abstract

Overexpression of cellular FLICE-like inhibitory protein (cFLIP) is reported to confer chemoresistance in pancreatic cancer (PaC) cells. This study was designed to investigate the effect of lupeol, a dietary triterpene, on (a) apoptosis of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) therapy-resistant PaC cells overexpressing cFLIP and (b) growth of human pancreatic tumor xenografts in vivo. The effect of lupeol treatment on proliferation and TRAIL/caspase-8/cFLIP machinery in PaC cells was investigated. Next, cFLIP-overexpressing and cFLIP-suppressed cells were tested for sensitivity to recombinant TRAIL therapy in the presence of lupeol. Further, athymic nude mice implanted with AsPC-1 cells were treated with lupeol (40 mg/kg) thrice a week and surrogate biomarkers were evaluated in tumors. Lupeol alone treatment of cells caused (a) decrease in proliferation, (b) induction of caspase-8 and poly(ADP-ribose) polymerase cleavage, and (c) down-regulation of transcriptional activation and expression of cFLIP. Lupeol was observed to increase the TRAIL protein level in cells. Lupeol significantly decreased the viability of AsPC-1 cells both in cFLIP-suppressed cells and in cFLIP-overexpressing cells. Lupeol significantly sensitized chemoresistant PaC cells to undergo apoptosis by recombinant TRAIL. Finally, lupeol significantly reduced the growth of human PaC tumors propagated in athymic nude mice and caused modulation of cFLIP and TRAIL protein levels in tumors. Our findings showed the anticancer efficacy of lupeol with mechanistic rationale against highly chemoresistant human PaC cells. We suggest that lupeol, alone or as an adjuvant to current therapies, could be useful for the management of human PaC.

Original languageEnglish (US)
Pages (from-to)1156-1165
Number of pages10
JournalCancer Research
Volume69
Issue number3
DOIs
StatePublished - Feb 1 2009

Fingerprint

CASP8 and FADD-Like Apoptosis Regulating Protein
Triterpenes
Pancreatic Neoplasms
Apoptosis
Nude Mice
TNF-Related Apoptosis-Inducing Ligand
Caspase 8
lupeol
Neoplasms
Poly(ADP-ribose) Polymerases
Growth
Heterografts
Transcriptional Activation

All Science Journal Classification (ASJC) codes

  • Cancer Research
  • Oncology

Cite this

Suppression of cFLIP by lupeol, a dietary triterpene, is sufficient to overcome resistance to TRAIL-mediated apoptosis in chemoresistant human pancreatic cancer cells. / Murtaza, Imtiyaz; Saleem, Mohammad; Adhami, Vaqar Mustafa; Hafeez, Bilal; Mukhtar, Hasan.

In: Cancer Research, Vol. 69, No. 3, 01.02.2009, p. 1156-1165.

Research output: Contribution to journalArticle

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abstract = "Overexpression of cellular FLICE-like inhibitory protein (cFLIP) is reported to confer chemoresistance in pancreatic cancer (PaC) cells. This study was designed to investigate the effect of lupeol, a dietary triterpene, on (a) apoptosis of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) therapy-resistant PaC cells overexpressing cFLIP and (b) growth of human pancreatic tumor xenografts in vivo. The effect of lupeol treatment on proliferation and TRAIL/caspase-8/cFLIP machinery in PaC cells was investigated. Next, cFLIP-overexpressing and cFLIP-suppressed cells were tested for sensitivity to recombinant TRAIL therapy in the presence of lupeol. Further, athymic nude mice implanted with AsPC-1 cells were treated with lupeol (40 mg/kg) thrice a week and surrogate biomarkers were evaluated in tumors. Lupeol alone treatment of cells caused (a) decrease in proliferation, (b) induction of caspase-8 and poly(ADP-ribose) polymerase cleavage, and (c) down-regulation of transcriptional activation and expression of cFLIP. Lupeol was observed to increase the TRAIL protein level in cells. Lupeol significantly decreased the viability of AsPC-1 cells both in cFLIP-suppressed cells and in cFLIP-overexpressing cells. Lupeol significantly sensitized chemoresistant PaC cells to undergo apoptosis by recombinant TRAIL. Finally, lupeol significantly reduced the growth of human PaC tumors propagated in athymic nude mice and caused modulation of cFLIP and TRAIL protein levels in tumors. Our findings showed the anticancer efficacy of lupeol with mechanistic rationale against highly chemoresistant human PaC cells. We suggest that lupeol, alone or as an adjuvant to current therapies, could be useful for the management of human PaC.",
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