Enhancement of TRAIL/Apo2L‐mediated apoptosis by adriamycin through inducing DR4 and DR5 in renal cell carcinoma cells

• Published in: International journal of cancer Vol. 104; no. 4; pp. 409 - 417
• Main Authors: Wu, Xiu‐Xian, Kakehi, Yoshiyuki, Mizutani, Youichi, Nishiyama, Hiroyuki, Kamoto, Toshiyuki, Megumi, Yuzuru, Ito, Noriyuki, Ogawa, Osamu
• Format: Journal Article
• Language: English
• Published: New York Wiley Subscription Services, Inc., A Wiley Company 20-04-2003; Wiley-Liss
• Subjects: ADR; Antineoplastic agents; apoptosis; Apoptosis - drug effects; Apoptosis Regulatory Proteins; Biological and medical sciences; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - pathology; Caspases - physiology; Doxorubicin - pharmacology; DR4; DR5; Drug Synergism; General aspects; Humans; Kidney Neoplasms - drug therapy; Kidney Neoplasms - pathology; Medical sciences; Membrane Glycoproteins - pharmacology; Pharmacology. Drug treatments; RCC; Receptors, TNF-Related Apoptosis-Inducing Ligand; Receptors, Tumor Necrosis Factor - biosynthesis; TNF-Related Apoptosis-Inducing Ligand; TRAIL; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha - pharmacology; Kidney disease; Antineoplastic agent; Human; Drug combination; Urinary system disease; Carcinoma; Cytokine; Malignant tumor; Doxorubicin; In vitro; Biological activity; Kidney; Antibiotic; Tumor necrosis factor; Cell death; Established cell line; Grawitz tumor; TNF related apoptosis inducing ligand; Anthracyclins; Drug interaction; Apoptosis; Biological receptor
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.10948

Renal cell carcinoma (RCC) is one of the most drug‐resistant malignancies in humans. We show that adriamycin (ADR) and TNF‐related apoptosis‐inducing ligand (TRAIL)/Apo2L have a synergistic cytotoxic effect against RCC cells. This synergistic cytotoxicity was obtained in ACHN, A704, Caki‐1 and Caki‐2 human RCC cell lines and freshly derived RCC cells from 6 patients. This synergistic effect, however, was not achieved in 5 samples of freshly isolated normal kidney cells. We further explored the mechanisms underlying this synergistic effect and found that the synergistic cytotoxicity of TRAIL/Apo2L and ADR was realized by inducing apoptosis. Sequential treatment with ADR followed by TRAIL/Apo2L induced significantly more cytotoxicity than the reverse treatment. ADR increased the expression of DR4 and DR5 in RCC cells, but not in the normal kidney cells. Furthermore, the synergistic cytotoxicity was significantly inhibited by DR4:Fc and DR5:Fc fusion proteins, which inhibit TRAIL/Apo2L‐mediated apoptosis. In addition, caspase activity assays and treatment of caspase inhibitors demonstrated that the combination treatment with ADR and TRAIL/Apo2L activated caspase cascade, including caspase‐9, ‐8, ‐6 and ‐3, which were the downstream molecules of death receptors. These findings indicate that ADR sensitizes RCC cells to TRAIL/Apo2L‐mediated apoptosis through induction of DR4 and DR5, suggesting that the combination therapy of TRAIL/Apo2L and ADR might be effective for RCC therapy. © 2003 Wiley‐Liss, Inc.