Brucine, an alkaloid from seeds of Strychnos nux-vomica Linn., represses hepatocellular carcinoma cell migration and metastasis: the role of hypoxia inducible factor 1 pathway.
Brucine is an alkaloid derived from the seeds of Strychnos nux-vomica Linn. which have long been used as a traditional medicine for the treatment of hepatocellular carcinoma (HCC) in China. HCC prognosis can be greatly influenced by metastasis. There has thus far been little research into brucine as a source of anti-metastasis activity against HCC. In this study, we revealed that brucine dramatically repressed HepG2 and SMMC-7721 HCC cell migration with few cytotoxic effects. Hypoxia inducible factor 1 (HIF-1) is a key transcription factor mediating cell migration and invasion. Brucine suppressed HIF-1-dependent luciferase activity in HepG2 cells. The transcriptions of four known HIF-1 target genes involved in HCC metastasis, i.e., fibronectin, matrix metallopeptidase 2, lysyl oxidase, and cathepsin D, were also attenuated after brucine treatment. Experiments in vivo showed that an intraperitoneal injection of 5 and 15 mg/kg of brucine resulted in dose-dependent decreases in the lung metastasis of H22 ascitic hepatoma cells. Moreover, a dosage of brucine at 15 mg/kg exhibited very low toxic effects to tumor-bearing mice. Consistently, brucine downregulated expression levels of HIF-1 responsive genes in vivo. Our current study demonstrated the capacity of brucine in suppressing HCC cell migration in vitro and lung metastasis in vivo. The inhibition of the HIF-1 pathway is implicated in the anti-metastasis activity of brucine.
School of Pharmacy, South-Central University for Nationalities, Wuhan, PR China.
Guangwen
G
Shu
Xue
X
Mi
Jian
J
Cai
Xinlin
X
Zhang
Wu
W
Yin
Xinzhou
X
Yang
You
Y
Li
Lvyi
L
Chen
Xukun
X
Deng
D000818:Animals; D021461:Animals, Outbred Strains; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000556:secondary; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002681:China; D004305:Dose-Response Relationship, Drug; D020834:Ethnopharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy*; D008175:Lung Neoplasms / Q000517:prevention & control* / Q000556:secondary; D008297:Male; D051379:Mice; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011897:Random Allocation; D012639:Seeds / Q000737:chemistry; D013331:Strychnine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D031461:Strychnos nux-vomica / Q000737:chemistry*; D023041:Xenograft Model Antitumor Assays
D000972:Antineoplastic Agents, Phytogenic; D051793:Hypoxia-Inducible Factor 1; D009363:Neoplasm Proteins; C083806:brucine; D013331:Strychnine
ALT; AST; BUN; Brucine; CRE; Ctsd; FACS; GAPDH; HCC; HIF-1; Hb; Hepatocellular carcinoma; Hypoxia inducible factor 1; Lox; MS; MTT; Metastasis; Mmp2; NMR; OD; PCR; PHD; PLT; RBC; S. nux-blanda; S. nux-vomica; SPF; Strychnos nux-blanda Hill; Strychnos nux-vomica Linn; TASNB; TASNV; UA; WBC; alanine aminotransferase; aminotransferase; blood urea nitrogen; cathepsin D; creatinine; flow cytometry analysis; glyceraldehyde-3-phosphate dehydrogenase; hemoglobins; hepatocellular carcinoma; hypoxia inducible factor 1; lysyl oxidase; mass spectrum; matrix metallopeptidase 2; methyl thiazolyl tetrazolium; nuclear magnetic resonance; optical density; platelets; polymerase chain reaction; prolyl hydroxylase; red blood cells; specific pathogens free; total alkaloids from S. nux-blanda; total alkaloids from S. nux-vomica; uric acid; white blood cells