Enhanced Anti-Tumor Efficacy of Lipid-Modified Platinum Derivatives in Combination with Survivin Silencing siRNA in Resistant Non-Small Cell Lung Cancer
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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 A549DDP cells 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 A549DDP cells. Pre-treatment of the A549DDP cells 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.
KEY WORDSchemoresistance lipid-modified platinates non-small cell lung cancer small interfering RNA survivin
Cis-diammine-dichloro-platinum (or cisplatin)
High pressure liquid chromatography
Inductively coupled plasma mass spectrometry
Nuclear magnetic resonance spetroscopy
Non-small cell lung cancer
Quantitative polymerase chain reaction
Small interfering RNA
ACKNOWLEDGMENTS AND DISCLOSURES
This study was supported by the National Cancer Institute’s (NCI) Alliance for Nanotechnology in Cancer Platform Partnership (CNPP) grant U01-CA151452 and by an NCI R21 grant CA-179652-01. We would like also to acknowledge Drs. Abhijit Kulkarni and Ganeshsingh Ganesh for their help on the LC-MS analysis of the platinum derivatives. ICP-MS platinum analysis in plasma and tissues was performed at the GLP Bioanalytical Laboratory, University of North Carolina (UNC) at Chapel Hill through a sub-contract agreement. We deeply appreciate the assistance of Professor William Zamboni, Dr. John Kagel, and others at the UNC with the analysis. The authors declare no conflicts of interest.
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