Triptolide enhances the tumoricidal activity of TRAIL against renal cell carcinoma

Erik L. Brincks, Tamara A. Kucaba, Britnie R. James, Katherine A Murphy, Kaylee Schwertfeger, Veena Sangwan, Sulagna Banerjee, Ashok K Saluja, Thomas S Griffith

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Abstract

Renal cell carcinoma (RCC) is resistant to traditional cancer therapies, and metastatic RCC (mRCC) is incurable. The shortcomings in current therapeutic options for patients with mRCC provide the rationale for the development of novel treatment protocols. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has proven to be a potent inducer of tumor cell death in vitro and in vivo, and a number of TRAIL death receptor agonists (recombinant TRAIL or TRAIL death receptor-specific mAb) have been developed and tested clinically. Unfortunately the clinical efficacy of TRAIL has been underwhelming and is likely due to a number of possible mechanisms that render tumors resistant to TRAIL, prompting the search for drugs that increase tumor cell susceptibility to TRAIL. The objective of this study was to determine the effectiveness of combining the diterpene triepoxide triptolide, or its water-soluble prodrug, Minnelide, with TRAIL receptor agonists against RCC in vitro or in vivo, respectively. TRAIL-induced apoptotic death of human RCC cells was increased in the presence of triptolide. The triptolide-induced sensitization was accompanied by increased TRAIL-R2 (DR5) and decreased heat shock protein 70 expression. In vivo treatment of mice bearing orthotopic RCC (Renca) tumors showed the combination of Minnelide and agonistic anti-DR5 mAb significantly decreased tumor burden and increased animal survival compared to either therapy alone. Our data suggest triptolide/Minnelide sensitizes RCC cells to TRAIL-induced apoptosis through altered TRAIL death receptor and heat shock protein expression. TRAIL induces tumor cell death, but many cancers, including renal cell carcinoma (RCC), are resistant to TRAIL. Treatment of human and mouse RCC cells with the diterpene triepoxide, triptolide, effectively sensitizes these cells to TRAIL receptor agonists in vitro and in vivo. Triptolide sensitizes RCC cells to TRAIL by decreasing HSP70 expression and increasing TRAIL death receptor expression.

Original languageEnglish (US)
Pages (from-to)4747-4765
Number of pages19
JournalFEBS Journal
Volume282
Issue number24
DOIs
StatePublished - Dec 1 2015

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Renal Cell Carcinoma
TNF-Related Apoptosis-Inducing Ligand Receptors
Tumors
Death Domain Receptors
Cells
Diterpenes
Cell death
Neoplasms
Bearings (structural)
Apoptosis
HSP70 Heat-Shock Proteins
Prodrugs
Cell Death
Heat-Shock Proteins
Therapeutics
triptolide
Animals
Tumor Necrosis Factor-alpha
Clinical Protocols
Helper-Inducer T-Lymphocytes

Keywords

  • TRAIL
  • apoptosis
  • death receptor
  • renal cell carcinoma
  • triptolide

Cite this

Triptolide enhances the tumoricidal activity of TRAIL against renal cell carcinoma. / Brincks, Erik L.; Kucaba, Tamara A.; James, Britnie R.; Murphy, Katherine A; Schwertfeger, Kaylee; Sangwan, Veena; Banerjee, Sulagna; Saluja, Ashok K; Griffith, Thomas S.

In: FEBS Journal, Vol. 282, No. 24, 01.12.2015, p. 4747-4765.

Research output: Contribution to journalArticle

Brincks, EL, Kucaba, TA, James, BR, Murphy, KA, Schwertfeger, K, Sangwan, V, Banerjee, S, Saluja, AK & Griffith, TS 2015, 'Triptolide enhances the tumoricidal activity of TRAIL against renal cell carcinoma', FEBS Journal, vol. 282, no. 24, pp. 4747-4765. https://doi.org/10.1111/febs.13532
Brincks, Erik L. ; Kucaba, Tamara A. ; James, Britnie R. ; Murphy, Katherine A ; Schwertfeger, Kaylee ; Sangwan, Veena ; Banerjee, Sulagna ; Saluja, Ashok K ; Griffith, Thomas S. / Triptolide enhances the tumoricidal activity of TRAIL against renal cell carcinoma. In: FEBS Journal. 2015 ; Vol. 282, No. 24. pp. 4747-4765.
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