title: Sticky siRNAs targeting survivin and cyclin B1 exert an antitumoral effect on melanoma subcutaneous xenografts and lung metastases.
abstract: BACKGROUND
  Melanoma represents one of the most aggressive and therapeutically challenging malignancies as it often gives rise to metastases and develops resistance to classical chemotherapeutic agents. Although diverse therapies have been generated, no major improvement of the patient prognosis has been noticed. One promising alternative to the conventional therapeutic approaches currently available is the inactivation of proteins essential for survival and/or progression of melanomas by means of RNA interference. Survivin and cyclin B1, both involved in cell survival and proliferation and frequently deregulated in human cancers, are good candidate target genes for siRNA mediated therapeutics.
  
  
  METHODS
  We used our newly developed sticky siRNA-based technology delivered with linear polyethyleneimine (PEI) to inhibit the expression of survivin and cyclin B1 both in vitro and in vivo, and addressed the effect of this inhibition on B16-F10 murine melanoma tumor development.
  
  
  RESULTS
  We confirm that survivin and cyclin B1 downregulation through a RNA interference mechanism induces a blockage of the cell cycle as well as impaired proliferation of B16-F10 cells in vitro. Most importantly, PEI-mediated systemic delivery of sticky siRNAs against survivin and cyclin B1 efficiently blocks growth of established subcutaneaous B16-F10 tumors as well as formation and dissemination of melanoma lung metastases. In addition, we highlight that inhibition of survivin expression increases the effect of doxorubicin on lung B16-F10 metastasis growth inhibition.
  
  
  CONCLUSIONS
  PEI-mediated delivery of sticky siRNAs targeting genes involved in tumor progression such as survivin and cyclin B1, either alone or in combination with chemotherapeutic drugs, represents a promising strategy for melanoma treatment.
authors.affiliation: Polyplus-transfection SA, Bioparc, BP 90018, Boulevard Sébastien Brant, Illkirch, 67401, France. vkedinger@polyplus-transfection.com
authors.forename: Valerie
authors.initials: V
authors.lastname: Kedinger
authors.forename: Aline
authors.initials: A
authors.lastname: Meulle
authors.forename: Omar
authors.initials: O
authors.lastname: Zounib
authors.forename: Marie-Elise
authors.initials: ME
authors.lastname: Bonnet
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Gossart
authors.forename: Elodie
authors.initials: E
authors.lastname: Benoit
authors.forename: Melanie
authors.initials: M
authors.lastname: Messmer
authors.forename: Pattabhiraman
authors.initials: P
authors.lastname: Shankaranarayanan
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Behr
authors.forename: Patrick
authors.initials: P
authors.lastname: Erbacher
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Bolcato-Bellemin
mesh_terms: D000818:Animals; D015153:Blotting, Western; D056744:Cyclin B1 / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D008546:Melanoma, Experimental / Q000235:genetics / Q000378:metabolism* / Q000556:secondary; D051379:Mice; D008819:Mice, Nude; D011094:Polyethyleneimine; D034741:RNA, Small Interfering / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077022:Survivin; D023041:Xenograft Model Antitumor Assays
chemical_list: C117749:Birc5 protein, mouse; C534700:Ccnb1 protein, mouse; D056744:Cyclin B1; D051034:Inhibitor of Apoptosis Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D000077022:Survivin; D011094:Polyethyleneimine