Sticky siRNAs targeting survivin and cyclin B1 exert an antitumoral effect on melanoma subcutaneous xenografts and lung metastases
| Autor: | Patrick Erbacher, Omar Zounib, Valérie Kedinger, Jean-Paul Behr, Pattabhiraman Shankaranarayanan, Marie-Elise Bonnet, Mélanie Messmer, Aline Meulle, Jean-Baptiste Gossart, Elodie Benoit, Anne-Laure Bolcato-Bellemin |
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| Rok vydání: | 2013 |
| Předmět: |
Cancer Research
Small interfering RNA Lung Neoplasms Survivin Blotting Western Melanoma Experimental Down-Regulation Mice Nude Inhibitor of Apoptosis Proteins Mice Sticky siRNA RNA interference Genetics Medicine Animals Polyethyleneimine Doxorubicin Cyclin B1 RNA Small Interfering neoplasms Melanoma business.industry Reverse Transcriptase Polymerase Chain Reaction Gene Transfer Techniques Tumor inhibition Genetic Therapy Cell cycle medicine.disease Xenograft Model Antitumor Assays Repressor Proteins Disease Models Animal Oncology Tumor progression Cancer research Female business Delivery medicine.drug Research Article |
| Zdroj: | BMC Cancer |
| ISSN: | 1471-2407 |
| Popis: | 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. Conclusion 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. |
| Databáze: | OpenAIRE |
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