Raedeh Saraei1,2,3, Heshu Sulaiman Rahman4,5, Masoud Soleimani6, Mohammad Asghari-Jafarabadi7,8, Adel Naimi9, Ali Hassanzadeh1,2, Saeed Solali10,11,12. 1. Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. 2. Division of Hematology, Faculty of Medicine, Department of Immunology, Tabriz University of Medical Sciences, Tabriz, Iran. 3. Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran. 4. College of Medicine, University of Sulaimani, Sulaimaniyah, Iraq. 5. Department of Medical Laboratory Sciences, Komar University of Science and Technology, Chaq-Chaq Qularaise, Sulaimaniyah, Iraq. 6. Hematology Department, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran. 7. Department of Statistics and Epidemiology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran. 8. Center for the Development of Interdisciplinary Research in Islamic Sciences and Heath Sciences, Tabriz University of Medical Sciences, Tabriz, Iran. 9. Cellular and Molecular Research Center, Sabzevar University of Medical Sciences, Sabzevar, Iran. 10. Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. ssolali@gmail.com. 11. Division of Hematology, Faculty of Medicine, Department of Immunology, Tabriz University of Medical Sciences, Tabriz, Iran. ssolali@gmail.com. 12. Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. ssolali@gmail.com.
Abstract
BACKGROUND: The tumor necrosis factor (TNF)-related apoptosis-inducing ligand, TRAIL, an apoptosis-inducing cytokine, has attracted much attention in the treatment of cancer for its selective toxicity to malignant rather than normal cells. However, the apoptosis-inducing ability of TRAIL is weaker than expected primarily due to cancer cell resistance. As one of the dietary flavonoids, kaempferol, has been shown to be antiproliferative and might have a protective effect against TRAIL resistance, particularly for hematologic malignancies. METHODS AND RESULTS: Here, we studied the potential of kaempferol to enhance the TRAIL-induced cytotoxicity and apoptosis in human chronic myelogenous leukemia (CML) cell line K-562, as well as the expression of specific genes with impact on TRAIL signal regulation. Analysis of flowcytometry data showed that treatment with kaempferol did enhance sensitivity of CML cells to pro-apoptotic effects of anti-TRAIL antibody. Although the gene expression levels were heterogeneous, cFLIP, cIAP1 and cIAP2 expression were generally downregulated where co-treatment of kaempferol and TRAIL was employed and these effects appeared to be dose-dependent. We further demonstrated that the expression of death receptors 4 and 5 tended to increase subsequent to the combination treatment. CONCLUSIONS: Consequently, it is reasonable to conclude that sensitization of chronic leukemia cells to TRAIL by kaempferol in vitro should be considered as a way of focusing clinical attention on leukemia therapy.
BACKGROUND: The tumor necrosis factor (TNF)-related apoptosis-inducing ligand, TRAIL, an apoptosis-inducing cytokine, has attracted much attention in the treatment of cancer for its selective toxicity to malignant rather than normal cells. However, the apoptosis-inducing ability of TRAIL is weaker than expected primarily due to cancer cell resistance. As one of the dietary flavonoids, kaempferol, has been shown to be antiproliferative and might have a protective effect against TRAIL resistance, particularly for hematologic malignancies. METHODS AND RESULTS: Here, we studied the potential of kaempferol to enhance the TRAIL-induced cytotoxicity and apoptosis in human chronic myelogenous leukemia (CML) cell line K-562, as well as the expression of specific genes with impact on TRAIL signal regulation. Analysis of flowcytometry data showed that treatment with kaempferol did enhance sensitivity of CML cells to pro-apoptotic effects of anti-TRAIL antibody. Although the gene expression levels were heterogeneous, cFLIP, cIAP1 and cIAP2 expression were generally downregulated where co-treatment of kaempferol and TRAIL was employed and these effects appeared to be dose-dependent. We further demonstrated that the expression of death receptors 4 and 5 tended to increase subsequent to the combination treatment. CONCLUSIONS: Consequently, it is reasonable to conclude that sensitization of chronic leukemia cells to TRAIL by kaempferol in vitro should be considered as a way of focusing clinical attention on leukemia therapy.
Authors: Jennifer Arrondeau; Hui K Gan; Albiruni R A Razak; Xavier Paoletti; Christophe Le Tourneau Journal: Discov Med Date: 2010-10 Impact factor: 2.970