The novel anti-neuroblastoma agent PF403, inhibits proliferation and invasion in vitro and in brain xenografts.
Neuroblastoma is the most common cancer in infants and the fourth most common cancer in children. Our previous study showed that PF403 had a potent antitumor ability. In the present study, we evaluated the anti-neuroblastoma property of PF403 and investigated the underlying mechanisms. MTT assay, colony formation assay and flow cytometry assay were used to assess cytotoxicity of PF403 on SH-SY5Y cells. Transwell assay was chosen to estimate the anti-invasion ability of PF403 on neuroblastoma cells. The protein expression was detected by western blot analysis. The SH-SY5Y brain xenograft model was used to assess in vivo antitumor activity of PF403. PF403-mediated SH-SY5Y cell death was found to be dose- and time-dependent, and PF403 was able to limit invasion and metastasis of neuroblastoma cells. MRI and pathology analysis proved that the pro-drug of PF403, CAT3, inhibited SH-SY5Y cells in vivo. PF403 decreased expression of phosphorylated FAK, MMP-2 and MMP-9 proteins, and downregulated the activity of PI3K/AKT and Raf/ERK pathways, followed by regulation of the proteins expression of Bcl-2 family, activated caspase-3, -9 and PARP and initiation of apoptosis of neuroblastoma cells. PF403 exerted cytotoxicity against SH-SY5Y neuroblastoma cell both in vitro and in vivo, and inhibited its invasion ability, suggesting PF403 has potential as a new anticancer drug for the treatment of neuroblastoma.
Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P.R. China.
Chao
C
Li
Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P.R. China.
Yan
Y
Li
Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P.R. China.
Haining
H
Lv
Department of Neurosurgery, Capital Medical University Affiliated Beijing Tiantan Hospital; Beijing Neurosurgical Institute, Beijing 100050, P.R. China.
Shaowu
S
Li
Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P.R. China.
Ke
K
Tang
Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P.R. China.
Wanqi
W
Zhou
Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P.R. China.
Shishan
S
Yu
Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P.R. China.
Xiaoguang
X
Chen
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D001932:Brain Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D054836:Indolizidines / Q000008:administration & dosage* / Q000494:pharmacology; D007212:Indolizines / Q000008:administration & dosage* / Q000494:pharmacology; D051379:Mice; D009361:Neoplasm Invasiveness; D009447:Neuroblastoma / Q000188:drug therapy*; D010616:Phenanthrenes / Q000008:administration & dosage* / Q000494:pharmacology; D011355:Prodrugs / Q000008:administration & dosage* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
C000605938:3-O-desmethyl-13a-deoxytylophorinine; D000970:Antineoplastic Agents; D054836:Indolizidines; D007212:Indolizines; D010616:Phenanthrenes; D011355:Prodrugs; C559326:S-(+)-deoxytylophorinidine; C575993:tylophorinine