1,2-dioleoyl-3-trimethylammonium-propane (DOTAP)-formulated, immune-stimulatory vascular endothelial growth factor a small interfering RNA (siRNA) increases antitumoral efficacy in murine orthotopic hepatocellular carcinoma with liver fibrosis.
Most experimental therapy studies are performed in mice that bear subcutaneous or orthotopic hepatoma but are otherwise healthy and nonfibrotic. The majority of hepatocellular carcinoma (HCC), however, develops in patients suffering from preexisting liver fibrosis. We investigated the efficacy of a standard experimental therapeutic approach to interrupt the vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) cascade via VEGF-A silencing, with or without 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP; cationic lipid) formulation, in HCC mice with preexisting liver fibrosis. The data show that intraperitoneal treatment with naked VEGF-A small interfering RNA (siRNA; 200 microg/kg) was inefficient to treat HCC implanted into fibrotic livers. VEGF-A siRNA containing an immunostimulatory motif in combination with DOTAP formulation significantly reduced hepatic VEGF-A expression and additionally activated the innate and adapted immune system as shown by an increased intrahepatic interferon type 1 response (68-fold increased beta-interferon expression). DOTAP-formulated VEGF-A siRNA markedly improved VEGF-A siRNA uptake and enhanced the antitumor response. This study shows for the first time the therapeutic feasibility of using synergistic effects (gene silencing and activation of the immune system) united in one siRNA sequence to reduce HCC growth and metastasis in mice with preexisting liver fibrosis. We expect that these results will help to direct and improve future experimental gene-silencing approaches and establish more efficient antitumoral therapies against HCC.
Kornek
Miroslaw
M
Department of Internal Medicine I, University Hospital Bonn, Germany. miroslawkornek@web.de
Lukacs-Kornek
Veronika
V
Limmer
Andreas
A
Raskopf
Esther
E
Becker
Ursula
U
Klöckner
Maren
M
Sauerbruch
Tilman
T
Schmitz
Volker
V
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D006528:Carcinoma, Hepatocellular / Q000150:complications / Q000473:pathology / Q000628:therapy*; D049109:Cell Proliferation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D005229:Fatty Acids, Monounsaturated / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D015316:Genetic Therapy; D018796:Immunoconjugates / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D008103:Liver Cirrhosis / Q000150:complications*; D008113:Liver Neoplasms / Q000150:complications / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008809:Mice, Inbred C3H; D008954:Models, Biological; D009368:Neoplasm Transplantation; D000644:Quaternary Ammonium Compounds / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D016042:Transplantation, Heterotopic; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000235:genetics
D000970:Antineoplastic Agents; D005229:Fatty Acids, Monounsaturated; D018796:Immunoconjugates; D000644:Quaternary Ammonium Compounds; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C070046:1,2-dioleoyloxy-3-(trimethylammonium)propane