title: SM-1, a novel PAC-1 derivative, activates procaspase-3 and causes cancer cell apoptosis.
abstract: OBJECTIVE
  To develop more potent procaspase-3 activator, 7 novel derivatives of PAC-1 were synthesized and evaluated. Among them, SM-1 stood out for its promising activity and good pharmacokinetics properties. The purpose of this study is to elucidate the pharmacological mechanism of SM-1 and evaluate its efficacy and toxicity in-depth.
  
  
  METHODS
  To reveal the effects of SM-1 on caspase-3 activity, both in vitro activation assay and in cells fluorometric assay were tested. The protein levels and distributions of procaspase-3 and cleaved caspase-3 were also measured by western blot and immunostaining. MTT assay, apoptosis assay and mouse xenograft model were applied to evaluate the efficacy of SM-1. Preliminary safety assessments also tested the acute toxicity and tissue distribution of SM-1.
  
  
  RESULTS
  Compared to PAC-1, SM-1 showed higher cytotoxicity in cancer cells. Further investigation demonstrated that SM-1 relieved zinc-mediated inhibition of procaspase-3 and activated the caspase-3 activity both in tube test and in cells. Efficacy evaluation showed SM-1-induced cell apoptosis mainly via activation of caspase-3 and reduced tumor size in mouse xenograft model. Its apoptosis induction efficacy was higher than PAC-1. The preliminary safety assessment demonstrated that the overall LD50 of SM-1 lied between 500 and 1000 mg/kg and the distribution of SM-1 in brain was low.
  
  
  CONCLUSIONS
  We identified SM-1 as a promising antitumor candidate, which displayed enhanced procaspase-3 activating activity and potent cytotoxicity for cancer cells but low toxicity for normal cells.
authors.affiliation: The School of Pharmaceutical Sciences in Central South University, 172 Tongzipo Road, Yuelu District, Changsha, 410013, Hunan, China.
authors.forename: Yanfen
authors.initials: Y
authors.lastname: Chen
authors.affiliation: The School of Pharmaceutical Sciences in Central South University, 172 Tongzipo Road, Yuelu District, Changsha, 410013, Hunan, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Sun
authors.affiliation: The School of Pharmaceutical Sciences in Central South University, 172 Tongzipo Road, Yuelu District, Changsha, 410013, Hunan, China. dingjs0221@163.com.
authors.forename: Jingsong
authors.initials: J
authors.lastname: Ding
authors.affiliation: The School of Pharmaceutical Sciences in Central South University, 172 Tongzipo Road, Yuelu District, Changsha, 410013, Hunan, China. biqbz@hotmail.com.
authors.forename: Qubo
authors.initials: Q
authors.lastname: Zhu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects*; D001381:Azepines / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005260:Female; D005470:Fluorometry; D006801:Humans; D006835:Hydrazones / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: C514579:(4-benzylpiperazin-1-yl)acetic acid (3-allyl-2-hydroxybenzylidene)hydrazine; D000970:Antineoplastic Agents; D001381:Azepines; D006835:Hydrazones; D010879:Piperazines; C000619853:SM-1 compound; D053148:Caspase 3
keywords: Antitumor drug; Apoptosis; Caspase-3; PAC-1; SM-1