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Pharmaceutical Research

, Volume 33, Issue 12, pp 2943–2953 | Cite as

Enhanced Anti-Tumor Efficacy of Lipid-Modified Platinum Derivatives in Combination with Survivin Silencing siRNA in Resistant Non-Small Cell Lung Cancer

  • George Mattheolabakis
  • Dandan Ling
  • Gulzar Ahmad
  • Mansoor AmijiEmail author
Research Paper

Abstract

Purpose

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.

Methods

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.

Results

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).

Conclusions

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 WORDS

chemoresistance lipid-modified platinates non-small cell lung cancer small interfering RNA survivin 

ABBREVIATIONS

ALT

Alanine transaminase

AST

Aspartate transaminase

CDDP

Cis-diammine-dichloro-platinum (or cisplatin)

DAPI

4′,6-diamidino-2-phenylindole

DDP

Cisplatin resistant

DMF

Dimethylformamide

EDC

1-Ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride

HA

Hyaluronic acid

HPLC

High pressure liquid chromatography

ICP-MS

Inductively coupled plasma mass spectrometry

MTT

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

NMR

Nuclear magnetic resonance spetroscopy

NSCLC

Non-small cell lung cancer

PEG

Poly(ethylene glycol)

PEI

Poly(ethyleneimine)

qPCR

Quantitative polymerase chain reaction

RNA

Ribonucleic acid

RNAi

RNA interference

siRNA

Small interfering RNA

Wt

Wild-type

Notes

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.

Supplementary material

11095_2016_2016_MOESM1_ESM.pptx (726 kb)
ESM 1 (PPTX 726 kb)

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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • George Mattheolabakis
    • 1
  • Dandan Ling
    • 1
  • Gulzar Ahmad
    • 1
  • Mansoor Amiji
    • 1
    • 2
    Email author
  1. 1.Department of Pharmaceutical Sciences, School of PharmacyNortheastern UniversityBostonUSA
  2. 2.Faculty of PharmacyKing Abdulaziz UniversityJeddahSaudi Arabia

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