Triptolide enhances the tumoricidal activity of TRAIL against renal cell carcinoma.

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.

• Authors: Erik L Brincks, Tamara A Kucaba, Britnie R James, Katherine A Murphy, Kathryn L Schwertfeger, Veena Sangwan, Sulagna Banerjee, Ashok K Saluja, Thomas S Griffith
• Journal: The FEBS journal (FEBS J) Vol. 282 Issue 24 Pg. 4747-4765 (Dec 2015) ISSN: 1742-4658 [Electronic] England
• PMID: 26426449 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 FEBS.

Chemical References

• Antibodies, Monoclonal
• Antineoplastic Agents
• Antineoplastic Agents, Phytogenic
• Diterpenes
• Epoxy Compounds
• Organophosphates
• Phenanthrenes
• Prodrugs
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• Recombinant Proteins
• TNF-Related Apoptosis-Inducing Ligand
• TNFSF10 protein, human
• Tnfrsf10b protein, mouse
• triptolide
• 14-O-phosphonooxymethyltriptolide disodium salt

Topics

• Animals
• Antibodies, Monoclonal (chemistry, pharmacology, therapeutic use)
• Antineoplastic Agents (chemistry, pharmacology, therapeutic use)
• Antineoplastic Agents, Phytogenic (pharmacology, therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (chemistry, pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Carcinoma, Renal Cell (drug therapy, metabolism, pathology)
• Cell Line, Tumor
• Diterpenes (pharmacology, therapeutic use)
• Drug Synergism
• Epoxy Compounds (pharmacology, therapeutic use)
• Female
• Humans
• Kidney Neoplasms (drug therapy, metabolism, pathology)
• Mice
• Mice, Inbred BALB C
• Neoplasm Transplantation
• Organophosphates (pharmacology, therapeutic use)
• Phenanthrenes (pharmacology, therapeutic use)
• Prodrugs (pharmacology, therapeutic use)
• Receptors, TNF-Related Apoptosis-Inducing Ligand (agonists, metabolism)
• Recombinant Proteins (chemistry, pharmacology, therapeutic use)
• Specific Pathogen-Free Organisms
• Survival Analysis
• TNF-Related Apoptosis-Inducing Ligand (agonists, genetics, pharmacology, therapeutic use)
• Tumor Burden (drug effects)