A new strategy in the treatment of chemoresistant lung adenocarcinoma via specific siRNA transfection of SRF, E2F1, Survivin, HIF and STAT3.

Abstract

OBJECTIVES:

According to the actual treatment strategies of lung cancer, the current therapeutic regimen is an individualized, multidisciplinary concept. The development of chemoresistance in the last decade represents the most important obstacle to an effective treatment. In our study, we examined a new therapeutic alternative in the treatment of multiresistant lung adenocarcinoma via siRNA-specific transfection of six crucial molecules involved in lung carcinogenesis [serum response factor(SFR), E2F1, Survivin, hypoxia inducible factor1 (HIF1), HIF2 and signal transducer and activator of transcription (STAT3)].

METHODS:

Three chemoresistant A549 adenocarcinoma cells were cultured under standard conditions at 37°C and 5% CO2. The chemoresistance against Vinflunine, Vinorelbine and Methotrexate was induced artificially. The A549 cells were transfected for 2 h at 37°C with specific siRNA targeting SRF, E2F1, Survivin, HIF1, HIF2 and STAT3 in a non-viral manner. The efficiency of siRNA silencing was evaluated via quantitative real-time polymerase chain reaction, whereas the surviving cells after siRNA transfection as predictor factor for tumoural growth were analysed with a CASY cell counter 3 days after transfection.

RESULTS:

The response of the chemotherapeutic resistant adenocarcinoma cells after siRNA transfection was concentration-dependent at both 25 and 100 nM. The CASY analysis showed a very effective suppression of adenocarcinoma cells in Vinorelbine, Vinflunine and Methotrexate groups, with significantly better results in comparison with the control group.

CONCLUSIONS:

In our study, we emphasized that siRNA interference might represent a productive platform for further research in order to investigate whether a new regimen in the treatment of multiresistant non-small-cell lung cancer could be established in vivo in the context of a multimodal cancer therapy.

• Authors: Mircea Gabriel Stoleriu, Volker Steger, Migdat Mustafi, Martin Michaelis, Jindrich Cinatl, Wilke Schneider, Andrea Nolte, Julia Kurz, Hans Peter Wendel, Christian Schlensak, Tobias Walker
• Journal: European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery (Eur J Cardiothorac Surg) Vol. 46 Issue 5 Pg. 877-86 (Nov 2014) ISSN: 1873-734X [Electronic] Germany
• PMID: 24627437 (Publication Type: Journal Article)
• Copyright: © The Author 2014. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

Chemical References

• Antineoplastic Agents
• BIRC5 protein, human
• Basic Helix-Loop-Helix Transcription Factors
• E2F1 Transcription Factor
• E2F1 protein, human
• Hypoxia-Inducible Factor 1
• Inhibitor of Apoptosis Proteins
• RNA, Small Interfering
• SRF protein, human
• STAT3 Transcription Factor
• STAT3 protein, human
• Serum Response Factor
• Survivin
• endothelial PAS domain-containing protein 1
• vinflunine
• Vinblastine
• Vinorelbine
• Methotrexate

Topics

• Adenocarcinoma (genetics, therapy)
• Adenocarcinoma of Lung
• Antineoplastic Agents (pharmacology)
• Basic Helix-Loop-Helix Transcription Factors (genetics)
• Cell Line, Tumor
• Drug Resistance, Neoplasm
• E2F1 Transcription Factor (genetics)
• Genetic Therapy (methods)
• Humans
• Hypoxia-Inducible Factor 1 (genetics)
• Inhibitor of Apoptosis Proteins (genetics)
• Lung Neoplasms (genetics, therapy)
• Methotrexate (pharmacology)
• RNA Interference
• RNA, Small Interfering (administration & dosage, genetics)
• STAT3 Transcription Factor (genetics)
• Serum Response Factor (genetics)
• Survivin
• Transfection (methods)
• Vinblastine (analogs & derivatives, pharmacology)
• Vinorelbine