Triptolide induces pancreatic cancer cell death via inhibition of heat shock protein 70

Phoebe A. Phillips, Vikas Dudeja, Joshua A. McCarroll, Daniel Borja-Cacho, Rajinder Dawra, William E. Grizzle, Selwyn M. Vickers, Ashok Saluja

Research output: Contribution to journalArticle

213 Citations (Scopus)

Abstract

Pancreatic cancer is highly resistant to current chemotherapy agents. We therefore examined the effects of triptolide (a diterpenoid triepoxide) on pancreatic cancer growth and local-regional tumor spread using an orthotopic model of pancreatic cancer. We have recently shown that an increased level of HSP70 in pancreatic cancer cells confers resistance to apoptosis and that inhibiting HSP70 induces apoptosis in these cells. In addition, triptolide was recently identified as part of a small molecule screen, as a regulator of the human heat shock response. Therefore, our aims were to examine the effects of triptolide on (a) pancreatic cancer cells by assessing viability and apoptosis, (b) pancreatic cancer growth and local invasion in vivo, and (c) HSP70 levels in pancreatic cancer cells. Incubation of PANC-1 and MiaPaCa-2 cells with triptolide (50-200 nmol/L) significantly reduced cell viability, but had no effect on the viability of normal pancreatic ductal cells. Triptolide induced apoptosis (assessed by Annexin V, caspase-3, and terminal nucleotidyl transferase-mediated nick end labeling) and decreased HSP70 mRNA and protein levels in both cell lines. Triptolide (0.2 mg/kg/d for 60 days) administered in vivo decreased pancreatic cancer growth and significantly decreased local-regional tumor spread. The control group of mice had extensive local invasion into adjacent organs, including the spleen, liver, kidney, and small intestine. Triptolide causes pancreatic cancer cell death in vitro and in vivo by induction of apoptosis and its mechanism of action is mediated via the inhibition of HSP70. Triptolide is a potential therapeutic agent that can be used to prevent the progression and metastases of pancreatic cancer.

Original languageEnglish (US)
Pages (from-to)9407-9416
Number of pages10
JournalCancer Research
Volume67
Issue number19
DOIs
StatePublished - Oct 1 2007
Externally publishedYes

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HSP70 Heat-Shock Proteins
Pancreatic Neoplasms
Cell Death
Apoptosis
Cell Survival
Growth
triptolide
Heat-Shock Response
Diterpenes
Annexin A5
Transferases
Caspase 3
Small Intestine
Neoplasms
Spleen
Neoplasm Metastasis
Kidney
Drug Therapy
Cell Line
Control Groups

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Triptolide induces pancreatic cancer cell death via inhibition of heat shock protein 70. / Phillips, Phoebe A.; Dudeja, Vikas; McCarroll, Joshua A.; Borja-Cacho, Daniel; Dawra, Rajinder; Grizzle, William E.; Vickers, Selwyn M.; Saluja, Ashok.

In: Cancer Research, Vol. 67, No. 19, 01.10.2007, p. 9407-9416.

Research output: Contribution to journalArticle

Phillips, Phoebe A. ; Dudeja, Vikas ; McCarroll, Joshua A. ; Borja-Cacho, Daniel ; Dawra, Rajinder ; Grizzle, William E. ; Vickers, Selwyn M. ; Saluja, Ashok. / Triptolide induces pancreatic cancer cell death via inhibition of heat shock protein 70. In: Cancer Research. 2007 ; Vol. 67, No. 19. pp. 9407-9416.
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