Romidepsin enhances the cytotoxicity of fludarabine, clofarabine and busulfan combination in malignant T-cells.
Novel approaches to pre-transplant conditioning are needed to improve treatment of advanced T-cell malignancies. We investigated the synergism of fludarabine (Flu), clofarabine (Clo), busulfan (Bu), and romidepsin (Rom) in T-cell lines and patient-derived cell samples. [Flu+Clo+Bu+Rom] had combination indexes of 0.4-0.5 at ∼50% cytotoxicity in PEER and SUPT1 cells, suggesting synergism. Drug exposure resulted in histone modifications, DNA-damage response (DDR), increased reactive oxygen species (ROS), decreased glutathione (GSH) and mitochondrial membrane (MM) potential, and apoptosis. Similar activation of DDR and apoptosis was observed in patient samples. The PI3K-AKT-mTOR, NFκB, Raf-MEK-ERK, JAK-STAT and Wnt/β-catenin pro-survival pathways were inhibited by the 4-drug combination. The SAPK/JNK stress pathway was activated. A novel finding was the down-regulation of the drug transporter MRP1. We propose the following mechanisms of synergism: Flu, Clo and Rom induce histone modifications and chromatin remodeling, exposing DNA to Bu alkylation; the increased production of ROS, due to drug-mediated stress response and decreased GSH, damages the MM causing leakage of pro-apoptotic factors; down-regulation of MRP1 increases intracellular Bu concentration and exacerbates the DDR; and inhibition of multiple survival pathways. Our results provide the basis for a clinical trial to evaluate [Flu+Clo+Bu+Rom] as part of conditioning regimen for refractory T-cell malignancy patients undergoing stem cell transplantation.
Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: bvaldez@mdanderson.org.
Benigno C
BC
Valdez
Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Jonathan E
JE
Brammer
Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Yang
Y
Li
Department of Experimental Oncology, Cross Cancer Institute, Edmonton, Alberta, Canada.
David
D
Murray
Department of Hematology, Singapore General Hospital, Level 3 Academia, 20 College Road, Singapore, Singapore.
Esmeralda C
EC
Teo
Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Yan
Y
Liu
Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Chitra
C
Hosing
Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Yago
Y
Nieto
Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Richard E
RE
Champlin
Department of Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Borje S
BS
Andersson
D000227:Adenine Nucleotides; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001087:Arabinonucleosides; D002066:Busulfan; D042002:Chromatin Assembly and Disassembly; D000077866:Clofarabine; D004249:DNA Damage; D047630:Depsipeptides / Q000008:administration & dosage* / Q000494:pharmacology; D004357:Drug Synergism; D042421:Histone Code; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014740:Vidarabine / Q000031:analogs & derivatives
D000227:Adenine Nucleotides; D001087:Arabinonucleosides; D047630:Depsipeptides; D000077866:Clofarabine; C087123:romidepsin; D014740:Vidarabine; D002066:Busulfan; C024352:fludarabine
Apoptosis; Romidepsin/fludarabine/clofarabine/busulfan; Stem cell transplant; Synergism; T-cell malignancy