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Triptolide enhances the tumoricidal activity of TRAIL against renal cell carcinoma
Author(s) -
Brincks Erik L.,
Kucaba Tamara A.,
James Britnie R.,
Murphy Katherine A.,
Schwertfeger Kathryn L.,
Sangwan Veena,
Banerjee Sulagna,
Saluja Ashok K.,
Griffith Thomas S.
Publication year - 2015
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.13532
Subject(s) - triptolide , medicine , in vivo , renal cell carcinoma , apoptosis , programmed cell death , pharmacology , cancer research , immunotherapy , tumor necrosis factor alpha , cancer , immunology , biology , biochemistry , microbiology and biotechnology
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 ( DR 5) 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‐ DR 5 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.