Nifurtimox Is Effective Against Neural Tumor Cells and Is Synergistic with Buthionine Sulfoximine.
Children with aggressive neural tumors have poor survival rates and novel therapies are needed. Previous studies have identified nifurtimox and buthionine sulfoximine (BSO) as effective agents in children with neuroblastoma and medulloblastoma. We hypothesized that nifurtimox would be effective against other neural tumor cells and would be synergistic with BSO. We determined neural tumor cell viability before and after treatment with nifurtimox using MTT assays. Assays for DNA ladder formation and poly-ADP ribose polymerase (PARP) cleavage were performed to measure the induction of apoptosis after nifurtimox treatment. Inhibition of intracellular signaling was measured by Western blot analysis of treated and untreated cells. Tumor cells were then treated with combinations of nifurtimox and BSO and evaluated for viability using MTT assays. All neural tumor cell lines were sensitive to nifurtimox, and IC50 values ranged from approximately 20 to 210 μM. Nifurtimox treatment inhibited ERK phosphorylation and induced apoptosis in tumor cells. Furthermore, the combination of nifurtimox and BSO demonstrated significant synergistic efficacy in all tested cell lines. Additional preclinical and clinical studies of the combination of nifurtimox and BSO in patients with neural tumors are warranted.
Department of Pediatrics, Section of Hematology-Oncology, Texas Children's Cancer and Hematology Centers, Baylor College of Medicine, Houston, TX 77030, USA.
Michael
M
Du
Department of Pediatrics, Section of Hematology-Oncology, Texas Children's Cancer and Hematology Centers, Baylor College of Medicine, Houston, TX 77030, USA.
Linna
L
Zhang
Department of Pediatrics, Section of Hematology-Oncology, Texas Children's Cancer and Hematology Centers, Baylor College of Medicine, Houston, TX 77030, USA.
Kathleen A
KA
Scorsone
Department of Pediatrics, Section of Hematology-Oncology, Texas Children's Cancer and Hematology Centers, Baylor College of Medicine, Houston, TX 77030, USA.
Sarah E
SE
Woodfield
Department of Pediatrics, Section of Hematology-Oncology, Texas Children's Cancer and Hematology Centers, Baylor College of Medicine, Houston, TX 77030, USA.
Peter E
PE
Zage
D017209:Apoptosis / Q000187:drug effects; D019328:Buthionine Sulfoximine / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D009447:Neuroblastoma / Q000188:drug therapy*; D009547:Nifurtimox / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects
D019328:Buthionine Sulfoximine; D009547:Nifurtimox