title: Enhanced Anti-Tumor Efficacy of Lipid-Modified Platinum Derivatives in Combination with Survivin Silencing siRNA in Resistant Non-Small Cell Lung Cancer.
abstract: Cisplatin, is recognized as a first line therapeutic for the treatment of non-small cell lung cancer (NSCLC). Cisplatin resistance is identified as the most detrimental complication during treatment and has been associated with upregulation of several genes, such as the anti-apoptotic gene survivin. In this study, we have evaluated the cytotoxic activity of lipid (C6 and C8)-modified platinum compounds in combination with a survivin-silencing siRNA against cisplatin resistant tumors.
  
  
  
  We synthesized and characterized several lipid-modified platinum compounds and evaluated their cytotoxic activity alone or in combination with survivin-silencing siRNA in vitro and in vivo against A549DDPcells and in vivo in tumor xenograft model.
  
  
  
  The lipid-modified compounds exhibited significantly stronger cytotoxic activity in vitro compared to cisplatin, with CDDP-C6 and CDDP-C8 producing the most pronounced effect, in both A549 and A549DDPcells. Pre-treatment of the A549DDPcells with survivin-silencing siRNA enhanced the cytotoxic activity of these compounds. In vivo, the co-treatment of the survivin-silencing siRNA and CDDP-C8 produced the strongest tumor growth inhibition effect (64.5%, p < 0.05) on a cancer mouse model of chemoresistant lung cancer. In contrast, cisplatin treatment exhibited no significant tumor growth inhibition (4.5%, no p).
  
  
  
  Co-treatment of lipid-modified compounds and survivin-silencing siRNA can constitute a reliable alternative to cisplatin treatment for cisplatin-resistant lung tumors that merit further evaluation.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, Boston, Massachusetts, USA.
authors.forename: George
authors.initials: G
authors.lastname: Mattheolabakis
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, Boston, Massachusetts, USA.
authors.forename: Dandan
authors.initials: D
authors.lastname: Ling
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, Boston, Massachusetts, USA.
authors.forename: Gulzar
authors.initials: G
authors.lastname: Ahmad
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, Boston, Massachusetts, USA. m.amiji@neu.edu.|Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia. m.amiji@neu.edu.
authors.forename: Mansoor
authors.initials: M
authors.lastname: Amiji
mesh_terms: D000072283:A549 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D049109:Cell Proliferation; D002945:Cisplatin / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D005260:Female; D020868:Gene Silencing; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics*; D008055:Lipids / Q000737:chemistry*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D011094:Polyethyleneimine / Q000737:chemistry; D034741:RNA, Small Interfering / Q000235:genetics*; D000077022:Survivin
chemical_list: D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008055:Lipids; D034741:RNA, Small Interfering; D000077022:Survivin; D011092:Polyethylene Glycols; D011094:Polyethyleneimine; D006820:Hyaluronic Acid; D002945:Cisplatin
keywords: chemoresistance; lipid-modified platinates; non-small cell lung cancer; small interfering RNA; survivin