Sparstolonin B, a novel plant derived compound, arrests cell cycle and induces apoptosis in N-myc amplified and N-myc nonamplified neuroblastoma cells.
Neuroblastoma is one of the most common solid tumors and accounts for ∼ 15% of all the cancer related deaths in the children. Despite the standard therapy for advanced disease including chemotherapy, surgery, and radiation, the mortality rate remains high for these patients. Hence, novel therapeutic agents are desperately needed. Here we examined the anticancer activity of a novel plant-derived compound, sparstolonin B (SsnB; 8,5'-dihydroxy-4-phenyl-5,2'-oxidoisocoumarin) using neuroblastoma cell lines of different genetics. SsnB was recently isolated from an aquatic Chinese herb, Sparganium stoloniferum, and tubers of this herb have been used in traditional Chinese medicine for the treatment of several inflammatory diseases and cancers. Our cell viability and morphological analysis indicated that SsnB at 10 µM concentration significantly inhibited the growth of both N-myc amplified (SK-N-BE(2), NGP, and IMR-32 cells) and N-myc nonamplified (SH-SY5Y and SKNF-1 cells) neuroblastoma cells. The flow cytometric analyses suggested that SsnB arrests the cell cycle progression at G2-M phase in all neuroblastoma cell lines tested. Exposure of SsnB inhibited the compact spheroid formation and reduced the tumorigenicity of SH-SY5Y cells and SK-N-BE(2) cells in in vitro 3-D cell culture assays (anchorage-independent colony formation assay and hanging drop assay). SsnB lowers the cellular level of glutathione (GSH), increases generation of reactive oxygen species and activates the cleavage of caspase-3 whereas co-incubation of a GSH precursor, N-acetylcysteine, along with SsnB attenuates the inhibitory effects of SsnB and increases the neuroblastoma cell viability. Our results for the first time demonstrate that SsnB possesses anticancer activity indicating that SsnB-induced reactive oxygen species generation promotes apoptotic cell death in neuroblastoma cells of different genetic background. Thus these data suggest that SsnB can be a promising drug candidate in neuroblastoma therapy.
Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, South Carolina, United States of America.
Ambrish
A
Kumar
Department of Cell Biology and Anatomy, School of Medicine, University of South Carolina, Columbia, South Carolina, United States of America.
Daping
D
Fan
Department of Internal Medicine, School of Medicine, University of South Carolina, Columbia, South Carolina, United States of America.
Donald J
DJ
Dipette
Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, South Carolina, United States of America.
Ugra S
US
Singh
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D006801:Humans; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics*; D015513:Oncogene Proteins / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism
D000970:Antineoplastic Agents; D006576:Heterocyclic Compounds, 4 or More Rings; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D017382:Reactive Oxygen Species; C561322:sparstolonin B; C505407:CASP3 protein, human; D053148:Caspase 3