Synergistic Cytotoxicity of Sorafenib with Busulfan and Nucleoside Analogs in Human FMS-like Tyrosine Kinase 3 Internal Tandem Duplications–Positive Acute.

Slides:

Advertisements

Similar presentations

Improved FLT3 Internal Tandem Duplication PCR Assay Predicts Outcome after Allogeneic Transplant for Acute Myeloid Leukemia Michael R. Grunwald, Li-Hui.

Advertisements

The Combined Effects of Hematoporphyrin Monomethyl Ether-SDT and Doxorubicin on the Proliferation of QBC939 Cell Lines Lei Liang, Sheng Xie, Lin Jiang,

Up-Regulation of Activating Transcription Factor-5 Suppresses SAP Expression to Activate T Cells in Hemophagocytic Syndrome Associated with Epstein-Barr.

Anti-Apoptotic NF-κB and “Gain of Function” mutp53 in Concert Act Pro-Apoptotic in Response to UVB+IL-1 via Enhanced TNF Production Ines Müller, Stefan.

Rabbit Anti T-Lymphocyte Globulin Induces Apoptosis in Peripheral Blood Mononuclear Cell Compartments and Leukemia Cells, While Hematopoetic Stem Cells.

Curcumin (diferuloylmethane) down-regulates the constitutive activation of nuclear factor–κB and IκBα kinase in human multiple myeloma cells, leading to.

Xiang Li, Feng Xu, Ekapun Karoopongse, A

Constitutively activated phosphatidylinositol-3 kinase (PI-3K) is involved in the defect of apoptosis in B-CLL: association with protein kinase Cδ by Ingo.

Supplementary Figure 1 Oligomycin, 1µM FCCP,

by Kumudha Balakrishnan, William G. Wierda, Michael J

Droxinostat, a Histone Deacetylase Inhibitor, Induces Apoptosis in Hepatocellular Carcinoma Cell Lines via Activation of the Mitochondrial Pathway and.

Overexpression of survivin in primary ATL cells and sodium arsenite induces apoptosis by down-regulating survivin expression in ATL cell lines by Xiao-Fang.

Clofarabine ± Fludarabine with Once Daily i. v

Aurora kinase inhibitory VX-680 increases Bax/Bcl-2 ratio and induces apoptosis in Aurora-A-high acute myeloid leukemia by Xue-Fei Huang, Shao-Kai Luo,

by Daniel Sasca, Patricia S

Cord Blood–Derived and Peripheral Blood–Derived Cytokine-Induced Killer Cells Are Sensitive to Fas-Mediated Apoptosis Ludovic Durrieu, Mame Massar Dieng,

Apoptotic Donor Leukocytes Limit Mixed-Chimerism Induced by CD40-CD154 Blockade in Allogeneic Bone Marrow Transplantation Jian-ming Li, John Gorechlad,

Modification of Alternative Splicing of Mcl-1 Pre-mRNA Using Antisense Morpholino Oligonucleotides Induces Apoptosis in Basal Cell Carcinoma Cells Jeng-Jer.

Sustained signaling through the B-cell receptor induces Mcl-1 and promotes survival of chronic lymphocytic leukemia B cells by Aleksandar Petlickovski,

IL-12hi Rapamycin-Conditioned Dendritic Cells Mediate IFN-γ–Dependent Apoptosis of Alloreactive CD4+ T Cells In Vitro and Reduce Lethal Graft-Versus-Host.

by Susana Constantino Rosa Santos, and Sérgio Dias

Inhibition of glycogen synthase kinase-3 activity leads to epigenetic silencing of nuclear factor κB target genes and induction of apoptosis in chronic.

Acquired mutations in BCL2 family proteins conferring resistance to the BH3 mimetic ABT-199 in lymphoma by Vicente Fresquet, Melissa Rieger, Carlo Carolis,

The Farnesyl Transferase Inhibitor Lonafarnib Inhibits mTOR Signaling and Enforces Sorafenib-Induced Apoptosis in Melanoma Cells Heike Niessner, Daniela.

Histone deacetylase inhibitors suppress interleukin-1β-induced nitric oxide and prostaglandin E2 production in human chondrocytes N. Chabane, M.Sc.,

Mycophenolic Acid Inhibits Natural Killer Cell Proliferation and Cytotoxic Function: A Possible Disadvantage of Including Mycophenolate Mofetil in the.

Busulfan Triggers Intrinsic Mitochondrial-Dependent Platelet Apoptosis Independent of Platelet Activation Jianlin Qiao, Yulu Wu, Yun Liu, Xiaoqian Li,

by Jun Yuan, David B. Lovejoy, and Des R. Richardson

Volume 17, Issue 2, Pages (February 2010)

Enhancement of depsipeptide-mediated apoptosis of lung or esophageal cancer cells by flavopiridol: Activation of the mitochondria-dependent death-signaling.

Helium–Neon Laser Irradiation Stimulates Cell Proliferation through Photostimulatory Effects in Mitochondria Wan-Ping Hu, Jeh-Jeng Wang, Chia-Li Yu,

John F. Öhd, Katarina Wikström, Anita Sjölander Gastroenterology

AKT Delays the Early-Activated Apoptotic Pathway in UVB-Irradiated Keratinocytes Via BAD Translocation Sofie Claerhout, David Decraene, An Van Laethem,

Volume 141, Issue 2, Pages (August 2011)

The BH3-mimetic GX synergizes with bortezomib in mantle cell lymphoma by enhancing Noxa-mediated activation of Bak by Patricia Pérez-Galán, Gaël.

Small-molecule XIAP inhibitors derepress downstream effector caspases and induce apoptosis of acute myeloid leukemia cells by Bing Z. Carter, Marcela Gronda,

Generation of Highly Cytotoxic Natural Killer Cells for Treatment of Acute Myelogenous Leukemia Using a Feeder-Free, Particle-Based Approach Jeremiah.

by Sansana Sawasdikosol, Kristin M. Russo, and Steven J. Burakoff

Volume 122, Issue 5, Pages (May 2002)

Hematopoietic Cell Transplantation with and without Sorafenib Maintenance for Patients with FLT3-ITD Acute Myeloid Leukemia in CR1 Andrew M. Brunner,

Tie2-R849W Mutant in Venous Malformations Chronically Activates a Functional STAT1 to Modulate Gene Expression Hsiao-Tang Hu, Yi-Hsien Huang, Yi-Ann.

Volume 23, Issue 1, Pages (July 2006)

Volume 136, Issue 4, Pages (April 2009)

Endoplasmic reticulum stress is a target for therapy in Waldenstrom macroglobulinemia by Xavier Leleu, Lian Xu, Xiaoying Jia, Antonio Sacco, Mena Farag,

Akio Horiguchi, Mototsugu Oya, Ken Marumo, Masaru Murai

AT-101, a Pan-Bcl-2 Inhibitor, Leads to Radiosensitization of Non-small Cell Lung Cancer Luigi Moretti, MD, Bo Li, MD, Kwang Woon Kim, PhD, Heidi Chen,

Lysophosphatidic acid-induced proliferation in opossum kidney proximal tubular cells: Role of PI 3-kinase and ERK Richard J. Dixon, Nigel J. Brunskill

Bax Activation and Induction of Apoptosis in Human Keratinocytes by the Protein Kinase C δ Catalytic Domain Leonid A. Sitailo, Shalini S. Tibudan, Mitchell.

A JNK-Dependent Pathway Is Required for TNFα-Induced Apoptosis

Lisheng Ge, Ziqiu Wang, Meifang Wang, Siddhartha Kar, Brian I. Carr

Apoptosis Induction by SAHA in Cutaneous T-Cell Lymphoma Cells Is Related to Downregulation of c-FLIP and Enhanced TRAIL Signaling Nadya Al-Yacoub, Lothar.

Volume 16, Issue 24, Pages (December 2006)

Role and regulation of activation of caspases in cisplatin-induced injury to renal tubular epithelial cells Gur P. Kaushal, Varsha Kaushal, Ph.D., Xiaoman.

The Outcome of Allogeneic Hematopoietic Cell Transplantation for Children with FMS- Like Tyrosine Kinase 3 Internal Tandem Duplication–Positive Acute Myelogenous.

Clinical Application of the Dried Blood Spot Method in the Measurement of Blood Busulfan Concentration Kana Matsumoto, Naoyuki Uchida, Amane Sakurai,

Vorinostat Combined with High-Dose Gemcitabine, Busulfan, and Melphalan with Autologous Stem Cell Transplantation in Patients with Refractory Lymphomas

PPARδ Is a Type 1 IFN Target Gene and Inhibits Apoptosis in T Cells

Volume 25, Issue 4, Pages (April 2014)

Volume 18, Issue 4, Pages (April 2011)

Allogeneic Hematopoietic Stem Cell Transplantation in FLT3-ITD–Positive Acute Myelogenous Leukemia: The Role for FLT3 Tyrosine Kinase Inhibitors Post-

Curcumin Selectively Induces Apoptosis in Cutaneous T-Cell Lymphoma Cell Lines and Patients’ PBMCs: Potential Role for STAT-3 and NF-κB Signaling Chunlei.

Volume 14, Issue 10, Pages (October 2007)

Volume 18, Issue 3, Pages (March 2010)

Knocking down Wnt3 increases the cells' response to trastuzumab and reduces cells' invasiveness. Knocking down Wnt3 increases the cells' response to trastuzumab.

Mammen Chandy Biology of Blood and Marrow Transplantation

Volume 21, Issue 4, Pages (April 2013)

Ultraviolet-B-Induced G1 Arrest is Mediated by Downregulation of Cyclin-Dependent Kinase 4 in Transformed Keratinocytes Lacking Functional p53 Arianna.

Mary Eapen Biology of Blood and Marrow Transplantation

Futility of Relapsed Diffuse Large B Cell Lymphoma Transplantation?

by Dana S. Levy, Jason A. Kahana, and Rakesh Kumar

Presentation transcript:

Synergistic Cytotoxicity of Sorafenib with Busulfan and Nucleoside Analogs in Human FMS-like Tyrosine Kinase 3 Internal Tandem Duplications–Positive Acute Myeloid Leukemia Cells Guiyun Song, Benigno C. Valdez, Yang Li, Yan Liu, Richard E. Champlin, Borje S. Andersson Biology of Blood and Marrow Transplantation Volume 20, Issue 11, Pages 1687-1695 (November 2014) DOI: 10.1016/j.bbmt.2014.08.003 Copyright © 2014 American Society for Blood and Marrow Transplantation Terms and Conditions

Biology of Blood and Marrow Transplantation 2014 20, 1687-1695DOI: (10 Biology of Blood and Marrow Transplantation 2014 20, 1687-1695DOI: (10.1016/j.bbmt.2014.08.003) Copyright © 2014 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 1 Antiproliferative effects of Bu, Clo, Flu, and Sor in FLT3-ITD–positive (A,B) and FLT3-wild type (C,D) AML cell lines. Cells were exposed to drugs alone, or in combination, for 48 hours and analyzed by MTT and annexin V (Ann-V) assays. Results are expressed as the mean ± SD of 3 independent experiments. PCR analysis (E) shows the presence of mutated (FLT3-ITD) or wild type (WT-FLT3) FLT3 in the 4 cell lines. Bu or B, busulfan; Clo or C, clofarabine; Flu or F, fludarabine; Sor, sorafenib. Biology of Blood and Marrow Transplantation 2014 20, 1687-1695DOI: (10.1016/j.bbmt.2014.08.003) Copyright © 2014 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 2 Drug combinations activate the DNA damage response and induce apoptosis. MV-4-11 cells were exposed to Bu, Clo, Flu, and Sor alone, or in combination, for 48 hours and changes in the level and modification of proteins involved in DNA damage response pathway (A) and apoptosis (B) were analyzed by Western blot. Bu or B, busulfan; Clo or C, clofarabine; Flu or F, fludarabine; Sor, sorafenib. Biology of Blood and Marrow Transplantation 2014 20, 1687-1695DOI: (10.1016/j.bbmt.2014.08.003) Copyright © 2014 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 3 Drug exposures increase modifications of histones. MV-4-11 cells were exposed to Bu, Clo, Flu, and Sor alone, or in combination, for 48 hours and histone modifications were analyzed by Western blot. Bu or B, busulfan; Clo or C, clofarabine; Flu or F, fludarabine; Sor, sorafenib. Biology of Blood and Marrow Transplantation 2014 20, 1687-1695DOI: (10.1016/j.bbmt.2014.08.003) Copyright © 2014 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 4 Drug combinations inhibit tyrosine kinases and phosphorylation of their substrates. MV-4-11 cells were exposed to Bu, Clo, Flu, and Sor alone, or in combination, for 48 hours and the activation by phosphorylation of tyrosine kinases (A) and changes in the status of their downstream substrates (B) were analyzed by Western blot. Cyto, cytosolic fraction; Nuc, nuclear fraction; Bu or B, busulfan; Clo or C, clofarabine; Flu or F, fludarabine; Sor, sorafenib. Biology of Blood and Marrow Transplantation 2014 20, 1687-1695DOI: (10.1016/j.bbmt.2014.08.003) Copyright © 2014 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 5 Drug exposures decrease the mitochondrial membrane potential and induce release of death factors from isolated mitochondria. MV-4-11 cells (A) were exposed to 4.1 μM busulfan .01 μM, clofarabine, 2.5 μM fludarabine, ± 1 nM sorafenib (Sor) for 48 hours and analyzed for changes in mitochondrial membrane potential as described under Materials and Methods. Results are expressed as percentage of fluorescence changes relative to the control (mean ± SD of 3 independent experiments). §P < .05 relative to control. †P < .05 relative to BCF-treated group. Isolated mitochondria (B) from MV-4-11 cells were exposed to Sor alone or to BCF ± Sor for 30 minutes at the concentration indicated above. B, busulfan; C, clofarabine; F, fludarabine; Super, supernatant; Mito, mitochondria. Biology of Blood and Marrow Transplantation 2014 20, 1687-1695DOI: (10.1016/j.bbmt.2014.08.003) Copyright © 2014 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 6 Analysis of the BCL-2 family members involved in mitochondrial outer membrane permeabilization in MV-4-11 cells. Cells were exposed to 4.1 μM busulfan, .01 μM clofarabine, 2.5 μM fludarabine, ± 1 nM sorafenib (Sor) for 48 hours. Cell lysates for immunoprecipitation were analyzed by Western blot (A) and 450 μg was used to perform immunoprecipitation with antibody against MCL-1 (B) or PUMA (C). IgG was used as a negative control for the immunoprecipitation. The obtained immunoprecipitates were probed with antibodies against BIM and MCL-1 (B) or antibodies against BCL-2, MCL-1, and PUMA (C). The numbers at the bottom of each picture refer to the band density values. B, Busulfan; C, clofarabine; F, fludarabine. Biology of Blood and Marrow Transplantation 2014 20, 1687-1695DOI: (10.1016/j.bbmt.2014.08.003) Copyright © 2014 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 7 Analysis of mononuclear cells from the peripheral blood of 3 AML patients with FLT3-ITD mutations. FLT3-ITD mutations were confirmed by PCR with specific primers for FLT3-ITD (A). Mononuclear cells were exposed to the indicated concentrations of Sor, busulfan+clofarabine+fludarabine (BCF), or their combinations for 48 hours and analyzed for cell proliferation and apoptosis by the MTT and Annexin V assays, respectively (B). The levels of p-FLT3, p-P53, γ-H2AX, and PARP1 were determined by Western blot (C). Patient (Pt) number is indicated. BCF, busulfan+clofarabine+fludaribine; BCFS, BCF+Sor. 1X = 4.1 μM Bu, .01 μM Clo, 2.5 μM Flu, and 1 nM Sor. Biology of Blood and Marrow Transplantation 2014 20, 1687-1695DOI: (10.1016/j.bbmt.2014.08.003) Copyright © 2014 American Society for Blood and Marrow Transplantation Terms and Conditions