title: Peptide deformylase inhibitor actinonin reduces celastrol's HSP70 induction while synergizing proliferation inhibition in tumor cells.
abstract: BACKGROUND
  Celastrol is a promising anti-tumor agent, yet it also elevates heat shock proteins (HSPs), especially HSP70, this effect believed to reduce its anti-tumor effects. Concurrent use of siRNA to increase celastrol's anti-tumor effects through HSP70 interference has been reported, but because siRNA technology is difficult to clinically apply, an alternative way to curb unwanted HSP70 elevation caused by celastrol treatment is worth exploring.
  
  
  METHODS
  In this work, we explore three alternative strategies to control HSP70 elevation: (1) Searching for cancer cell types that show no HSP70 elevation in the presence of celastrol (thus recommending themselves as suitable targets); (2) Modifying HSP70-inducing chemical groups, i.e.: the carboxyl group in celastrol; and (3) Using signaling molecule inhibitors to specifically block HSP70 elevation while protecting and/or enhancing anti-tumor effects.
  
  
  RESULTS
  The first strategy was unsuccessful since celastrol treatment increased HSP70 in all 7 of the cancer cell types tested, this result related to HSF1 activation. The ubiquity of HSF1 expression in different cancer cells might explain why celastrol has no cell-type limitation for HSP70 induction. The second strategy revealed that modification of celastrol's carboxyl group abolished its ability to elevate HSP70, but also abolished celastrol's tumor inhibition effects. In the third strategy, 11 inhibitors for 10 signaling proteins reportedly related to celastrol action were tested, and five of these could reduce celastrol-caused HSP70 elevation. Among these, the peptide deformylase (PDF) inhibitor, actinonin, could synergize celastrol's proliferation inhibition.
  
  
  CONCLUSIONS
  Concurrent use of the chemical agent actinonin could reduce celastrol's HSP70 elevation and also enhance proliferation inhibition by celastrol. This combination presents a novel alternative to siRNA technology and is worth further investigation for its potentially effective anti-tumor action.
authors.forename: Bin
authors.initials: B
authors.lastname: Peng
authors.forename: Xue
authors.initials: X
authors.lastname: Zhang
authors.forename: Fanfan
authors.initials: F
authors.lastname: Cao
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Limin
authors.initials: L
authors.lastname: Xu
authors.forename: Lu
authors.initials: L
authors.lastname: Cao
authors.forename: Chunxin
authors.initials: C
authors.lastname: Yang
authors.forename: Maoquan
authors.initials: M
authors.lastname: Li
authors.forename: Georges
authors.initials: G
authors.lastname: Uzan
authors.affiliation: Sino-French Cooperative Central Lab, Shanghai Gongli Hospital, 207 Ju Ye Road, Pudong New District, Shanghai 200135, China. shanghai_zhang@hotmail.com.
authors.forename: Denghai
authors.initials: D
authors.lastname: Zhang
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D053978:Pentacyclic Triterpenes; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D014315:Triterpenes / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D018840:HSP70 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; D006877:Hydroxamic Acids; D053978:Pentacyclic Triterpenes; D014157:Transcription Factors; D014315:Triterpenes; D000581:Amidohydrolases; C084507:peptide deformylase; C050414:celastrol; C010531:actinonin