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Chemotherapy Augments TRAIL-induced Apoptosis in Breast Cell Lines

National Cancer Institute, Division of Clinical Sciences, Medicine Branch, National Naval Medical Center, Bethesda, Maryland 20889-5105

Expression and function of the TRAIL apoptotic pathway was investigated in normal and malignant breast epithelial cells. Glutathione-S-transferase (GST)-TRAIL extracellular domain fusion proteins were produced to analyze TRAIL-induced apoptosis. Only GST-TRAIL constructs containing regions homologous to the Fas self-association and ligand binding domains could induce apoptosis. GST-TRAIL induced significant (>90%) apoptosis in just one of eight normal and one of eight malignant breast cell lines. All other lines were relatively resistant to TRAIL-induced apoptosis. Activating TRAIL receptors DR4 and DR5 were expressed in all normal and malignant breast cell lines. The inhibitory receptor TRID was highly expressed in one of four normal and two of seven malignant breast cell lines. DR4, DR5, or TRID expression did not correlate with sensitivity to TRAIL-induced apoptosis. Incubation of cell lines with doxorubicin or 5-fluorouracil significantly augmented TRAIL-induced apoptosis in most breast cell lines. By fractional inhibition analysis, the toxicity of the combination of TRAIL and doxorubicin or 5-fluorouracil was synergistic compared with either agent alone. In contrast, melphalan and paclitaxel augmented TRAIL-induced apoptosis in few cell lines, and methotrexate did not augment it in any cell line. Augmentation of TRAIL-induced apoptosis by doxorubicin or 5-fluorouracil was mediated through caspase activation. This was evidenced by the fact that chemotherapy agents that synergized with TRAIL (e.g., doxorubicin) themselves caused cleavage of caspase-3 and poly(ADP-ribose) polymerase (PARP), and their toxicity was blocked by the caspase inhibitor Z-Val-Ala-Asp(OMe)-CH₂ (ZVAD-fmk). The combination of TRAIL and doxorubicin caused significantly greater caspase-3 and PARP cleavage, and the combined toxicity also was inhibited by ZVAD-fmk. In contrast, chemotherapy agents that did not augment TRAIL-induced apoptosis (e.g., methotrexate) caused minimal caspase-3 and PARP cleavage by themselves, and their toxicity was not inhibited by ZVAD-fmk. These drugs also did not increase caspase-3 or PARP cleavage when combined with TRAIL. In summary, few breast cell lines are sensitive to TRAIL-induced apoptosis, and no difference in sensitivity is found between normal and malignant cell lines. Treatment with chemotherapy provides an approach to sensitize breast cancer cells to TRAIL-induced apoptosis.

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				Y. Deng, Y. Lin, and X. Wu TRAIL-induced apoptosis requires Bax-dependent mitochondrial release of Smac/DIABLO Genes & Dev., January 1, 2002; 16(1): 33 - 45. [Abstract] [Full Text] [PDF]

				A. R. Jazirehi, C.-P. Ng, X.-H. Gan, G. Schiller, and B. Bonavida Adriamycin Sensitizes the Adriamycin-resistant 8226/Dox40 Human Multiple Myeloma Cells to Apo2L/Tumor Necrosis Factor-related Apoptosis-inducing Ligand-mediated (TRAIL) Apoptosis Clin. Cancer Res., December 1, 2001; 7(12): 3874 - 3883. [Abstract] [Full Text] [PDF]

				H. Thakkar, X. Chen, F. Tyan, S. Gim, H. Robinson, C. Lee, S. K. Pandey, C. Nwokorie, N. Onwudiwe, and R. K. Srivastava Pro-survival Function of Akt/Protein Kinase B in Prostate Cancer Cells. RELATIONSHIP WITH TRAIL RESISTANCE J. Biol. Chem., October 12, 2001; 276(42): 38361 - 38369. [Abstract] [Full Text] [PDF]

				P. Secchiero, A. Gonelli, C. Celeghini, P. Mirandola, L. Guidotti, G. Visani, S. Capitani, and G. Zauli Activation of the nitric oxide synthase pathway represents a key component of tumor necrosis factor-related apoptosis-inducing ligand-mediated cytotoxicity on hematologic malignancies Blood, October 1, 2001; 98(7): 2220 - 2228. [Abstract] [Full Text] [PDF]

				C. S. Mitsiades, S. P. Treon, N. Mitsiades, Y. Shima, P. Richardson, R. Schlossman, T. Hideshima, and K. C. Anderson TRAIL/Apo2L ligand selectively induces apoptosis and overcomes drug resistance in multiple myeloma: therapeutic applications Blood, August 1, 2001; 98(3): 795 - 804. [Abstract] [Full Text] [PDF]

				W. Liu, E. Bodle, J. Y. Chen, M. Gao, G. D. Rosen, and V. C. Broaddus Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand and Chemotherapy Cooperate to Induce Apoptosis in Mesothelioma Cell Lines Am. J. Respir. Cell Mol. Biol., July 1, 2001; 25(1): 111 - 118. [Abstract] [Full Text] [PDF]

				M. S. Shin, H. S. Kim, S. H. Lee, W. S. Park, S. Y. Kim, J. Y. Park, J. H. Lee, S. K. Lee, S. N. Lee, S. S. Jung, et al. Mutations of Tumor Necrosis Factor-related Apoptosis-inducing Ligand Receptor 1 (TRAIL-R1) and Receptor 2 (TRAIL-R2) Genes in Metastatic Breast Cancers Cancer Res., July 1, 2001; 61(13): 4942 - 4946. [Abstract] [Full Text] [PDF]

				M. Cuello, S. A. Ettenberg, A. S. Clark, M. M. Keane, R. H. Posner, M. M. Nau, P. A. Dennis, and S. Lipkowitz Down-Regulation of the erbB-2 Receptor by Trastuzumab (Herceptin) Enhances Tumor Necrosis Factor-related Apoptosis-inducing Ligand-mediated Apoptosis in Breast and Ovarian Cancer Cell Lines that Overexpress erbB-2 Cancer Res., June 1, 2001; 61(12): 4892 - 4900. [Abstract] [Full Text] [PDF]

				I. F. Pollack, M. Erff, and A. Ashkenazi Direct Stimulation of Apoptotic Signaling by Soluble Apo2L/Tumor Necrosis Factor-related Apoptosis-inducing Ligand Leads to Selective Killing of Glioma Cells Clin. Cancer Res., May 1, 2001; 7(5): 1362 - 1369. [Abstract] [Full Text]

				R. Di Pietro, P. Secchiero, R. Rana, D. Gibellini, G. Visani, K. Bemis, L. Zamai, S. Miscia, and G. Zauli Ionizing radiation sensitizes erythroleukemic cells but not normal erythroblasts to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated cytotoxicity by selective up-regulation of TRAIL-R1 Blood, May 1, 2001; 97(9): 2596 - 2603. [Abstract] [Full Text] [PDF]

				S. Kagawa, C. He, J. Gu, P. Koch, S.-J. Rha, J. A. Roth, S. A. Curley, L. C. Stephens, and B. Fang Antitumor Activity and Bystander Effects of the Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL) Gene Cancer Res., April 1, 2001; 61(8): 3330 - 3338. [Abstract] [Full Text]

				N. Mitsiades, V. Poulaki, C. Mitsiades, and M. Tsokos Ewing's Sarcoma Family Tumors Are Sensitive to Tumor Necrosis Factor-related Apoptosis-inducing Ligand and Express Death Receptor 4 and Death Receptor 5 Cancer Res., March 1, 2001; 61(6): 2704 - 2712. [Abstract] [Full Text]

				A. W. Tong, M. H. Papayoti, G. Netto, D. T. Armstrong, G. Ordonez, J. M. Lawson, and M. J. Stone Growth-inhibitory Effects of CD40 Ligand (CD154) and Its Endogenous Expression in Human Breast Cancer Clin. Cancer Res., March 1, 2001; 7(3): 691 - 703. [Abstract] [Full Text]

				S. Lacour, A. Hammann, A. Wotawa, L. Corcos, E. Solary, and M.-T. Dimanche-Boitrel Anticancer Agents Sensitize Tumor Cells to Tumor Necrosis Factor-related Apoptosis-inducing Ligand-mediated Caspase-8 Activation and Apoptosis Cancer Res., February 1, 2001; 61(4): 1645 - 1651. [Abstract] [Full Text]

				R. Nimmanapalli, M. Porosnicu, D. Nguyen, E. Worthington, E. O’Bryan, C. Perkins, and K. Bhalla Cotreatment with STI-571 Enhances Tumor Necrosis Factor {{alpha}}-related Apoptosis-inducing Ligand (TRAIL or Apo-2L)- induced Apoptosis of Bcr-Abl-positive Human Acute Leukemia Cells Clin. Cancer Res., February 1, 2001; 7(2): 350 - 357. [Abstract] [Full Text]

				R. Nimmanapalli, C. L. Perkins, M. Orlando, E. O’Bryan, D. Nguyen, and K. N. Bhalla Pretreatment with Paclitaxel Enhances Apo-2 Ligand/Tumor Necrosis Factor-related Apoptosis-inducing Ligand-induced Apoptosis of Prostate Cancer Cells by Inducing Death Receptors 4 and 5 Protein Levels Cancer Res., January 1, 2001; 61(2): 759 - 763. [Abstract] [Full Text]

				S.-Y. Sun, P. Yue, W. K. Hong, and R. Lotan Augmentation of Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL)-induced Apoptosis by the Synthetic Retinoid 6-[3-(1-Adamantyl)-4-hydroxyphenyl]-2-naphthalene Carboxylic Acid (CD437) through Up-Regulation of TRAIL Receptors in Human Lung Cancer Cells Cancer Res., December 1, 2000; 60(24): 7149 - 7155. [Abstract] [Full Text]

				J. Wen, N. Ramadevi, D. Nguyen, C. Perkins, E. Worthington, and K. Bhalla Antileukemic drugs increase death receptor 5 levels and enhance Apo-2L-induced apoptosis of human acute leukemia cells Blood, December 1, 2000; 96(12): 3900 - 3906. [Abstract] [Full Text] [PDF]

				B. Gong and A. Almasan Apo2 Ligand/TNF-related Apoptosis-inducing Ligand and Death Receptor 5 Mediate the Apoptotic Signaling Induced by Ionizing Radiation in Leukemic Cells Cancer Res., October 1, 2000; 60(20): 5754 - 5760. [Abstract] [Full Text]

				Y. Lin, A. Devin, A. Cook, M. M. Keane, M. Kelliher, S. Lipkowitz, and Z.-g. Liu The Death Domain Kinase RIP Is Essential for TRAIL (Apo2L)-Induced Activation of Ikappa B Kinase and c-Jun N-Terminal Kinase Mol. Cell. Biol., September 15, 2000; 20(18): 6638 - 6645. [Abstract] [Full Text]

				N. Mitsiades, V. Poulaki, S. Tseleni-Balafouta, D. A. Koutras, and I. Stamenkovic Thyroid Carcinoma Cells Are Resistant to FAS-mediated Apoptosis But Sensitive to Tumor Necrosis Factor-related Apoptosis-inducing Ligand Cancer Res., August 1, 2000; 60(15): 4122 - 4129. [Abstract] [Full Text]

				L. Zamai, P. Secchiero, S. Pierpaoli, A. Bassini, S. Papa, E. S. Alnemri, L. Guidotti, M. Vitale, and G. Zauli TNF-related apoptosis-inducing ligand (TRAIL) as a negative regulator of normal human erythropoiesis Blood, June 15, 2000; 95(12): 3716 - 3724. [Abstract] [Full Text] [PDF]

				M. Nagane, G. Pan, J. J. Weddle, V. M. Dixit, W. K. Cavenee, and H.-J. S. Huang Increased Death Receptor 5 Expression by Chemotherapeutic Agents in Human Gliomas Causes Synergistic Cytotoxicity with Tumor Necrosis Factor-related Apoptosis-inducing Ligand in Vitro and in Vivo Cancer Res., February 1, 2000; 60(4): 847 - 853. [Abstract] [Full Text]

				K. Kim, M. J. Fisher, S.-Q. Xu, and W. S. El-Deiry Molecular Determinants of Response to TRAIL in Killing of Normal and Cancer Cells Clin. Cancer Res., February 1, 2000; 6(2): 335 - 346. [Abstract] [Full Text]

				S. B. Gibson, R. Oyer, A. C. Spalding, S. M. Anderson, and G. L. Johnson Increased Expression of Death Receptors 4 and 5 Synergizes the Apoptosis Response to Combined Treatment with Etoposide and TRAIL Mol. Cell. Biol., January 1, 2000; 20(1): 205 - 212. [Abstract] [Full Text]

				B. Gliniak and T. Le Tumor Necrosis Factor-related Apoptosis-inducing Ligand's Antitumor Activity in Vivo Is Enhanced by the Chemotherapeutic Agent CPT-11 Cancer Res., December 1, 1999; 59(24): 6153 - 6158. [Abstract] [Full Text] [PDF]

				S. H. Lee, M. S. Shin, H. S. Kim, H. K. Lee, W. S. Park, S. Y. Kim, J. H. Lee, S. Y. Han, J. Y. Park, R. R. Oh, et al. Alterations of the DR5/TRAIL Receptor 2 Gene in Non-Small Cell Lung Cancers Cancer Res., November 1, 1999; 59(22): 5683 - 5686. [Abstract] [Full Text] [PDF]

				N. A. Fanger, C. R. Maliszewski, K. Schooley, and T. S. Griffith Human Dendritic Cells Mediate Cellular Apoptosis via Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (Trail) J. Exp. Med., October 18, 1999; 190(8): 1155 - 1164. [Abstract] [Full Text] [PDF]

				Y. Mizutani, O. Yoshida, T. Miki, and B. Bonavida Synergistic Cytotoxicity and Apoptosis by Apo-2 Ligand and Adriamycin against Bladder Cancer Cells Clin. Cancer Res., September 1, 1999; 5(9): 2605 - 2612. [Abstract] [Full Text] [PDF]

				A. Nesterov, X. Lu, M. Johnson, G. J. Miller, Y. Ivashchenko, and A. S. Kraft Elevated Akt Activity Protects the Prostate Cancer Cell Line LNCaP from TRAIL-induced Apoptosis J. Biol. Chem., March 30, 2001; 276(14): 10767 - 10774. [Abstract] [Full Text] [PDF]

				S. A. Ettenberg, A. Magnifico, M. Cuello, M. M. Nau, Y. R. Rubinstein, Y. Yarden, A. M. Weissman, and S. Lipkowitz Cbl-b-dependent Coordinated Degradation of the Epidermal Growth Factor Receptor Signaling Complex J. Biol. Chem., July 13, 2001; 276(29): 27677 - 27684. [Abstract] [Full Text] [PDF]