title: Norcantharidin enhances ABT-263-mediated anticancer activity in neuroblastoma cells by upregulation of Noxa.
abstract: Neuroblastoma is an aggressive childhood disease. Even with intensive conventional treatments, the long term survival rate for children with neuroblastoma remains less than 40%, highlighting the importance of finding new therapies. Bcl-2 family proteins play crucial roles in survival, proliferation and chemotherapeutic resistance of neuroblastoma cells. Therefore, targeting Bcl-2 with small molecule inhibitor ABT-263 could be a novel strategy for treatment of neuroblastoma. However, previous studies indicated that most neuroblastoma cell lines are resistant to ABT-263-mediated apoptosis. Thus, it is crucial to discover approaches that could overcome ABT-263 resistance. In this study, we examined the anticancer activity of ABT-263 in combination with norcantharidin (NCTD), a small-molecule anticancer drug derived from a traditional Chinese medicine, in human malignant neuroblastoma cells. We found that NCTD substantially enhanced ABT-263-mediated apoptosis induction, cell viability inhibition, and clonal formation inhibition in neuroblastoma SH-SY5Y and CHLA-119 cell lines. Moreover, the combination anticancer activity was accompanied by upregulation of Noxa, and was associated with characteristics of mitochondrial apoptosis signaling, such as cytosolic release of cytochrome c, activation of caspase-9,-3, and cleavage of PARP. Notably, we observed that knockdown of Noxa significantly attenuated cell death induction by cotreatment with ABT-263 and NCTD, indicating Noxa essentially contributes to the combination anticancer effect. Collectively, our study demonstrated that NCTD could overcome ABT-263-resistance in neuroblastoma cells, and suggested that combinational treatment of ABT-263 with NCTD might be a novel therapeutic option for children with neuroblastoma.
authors.affiliation: Department of Pediatric Surgery, People's Hospital of Zhengzhou University, Zhengzhou, Henan 450003, P.R. China.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Ophthalmology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450003, P.R. China.
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Gu
authors.affiliation: Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450003, P.R. China.
authors.forename: Gongquan
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Pediatric Surgery, People's Hospital of Zhengzhou University, Zhengzhou, Henan 450003, P.R. China.
authors.forename: Shufeng
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Pediatric Surgery, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450003, P.R. China.
authors.forename: Zhenjie
authors.initials: Z
authors.lastname: Cao
authors.affiliation: Department of Hepatobiliary Surgery, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450003, P.R. China.
authors.forename: Zhanfeng
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Obstetrics and Gynecology, People's Hospital of Zhengzhou University, Zhengzhou, Henan 450003, P.R. China.
authors.forename: Guangzhi
authors.initials: G
authors.lastname: Liu
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D008928:Mitochondria / Q000187:drug effects; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; C498702:PMAIP1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; C069741:norcantharidin; C528561:navitoclax