Enhanced anti-tumor effects of combined MDR1 RNA interference and human sodium/iodide symporter (NIS) radioiodine gene therapy using an adenoviral system in a colon cancer model

Sohn Joo Ahn,Yong Jin Lee,Jeoung-Hee Ha,Jaetae Lee,You La Lee,Byeong-Cheol Ahn,Sang-Woo Lee,Yong Hyun Jeon

doi:10.1038/npre.2009.3307.1

Abstract

AbstractUsing an adenoviral system as a delivery mediator of therapeutic gene, we investigated the therapeutic effects of the use of combined MDR1 shRNA and human NIS (hNIS) radioiodine gene therapy in a mouse colon xenograft model. In vitro uptake of Tc-99m sestamibi was increased approximately two-fold in cells infected with an adenovirus vector that expressed MDR1 shRNA (Ad-shMDR) and I-125 uptake was 25-fold higher in cells infected with an adenovirus vector that expressed human NIS (Ad-hNIS) as compared to control cells. As compared with doxorubicin or I-131 treatment alone, the combination of doxorubicin and I-131 resulted in enhanced cytotoxicity for both Ad-shMDR and Ad-hNIS infected cells but not for control cells. In vivo uptake of Tc-99m sestamibi and Tc-99m pertechnetate was two-fold and 10-fold higher for Ad-shMDR and Ad-hNIS-infected tumors as compared to tumors infected with a control adenovirus construct that expressed [beta]-galactrosidase (Ad-LacZ), respectively. In mice treated with either doxorubicin or I-131 alone, there was a slight delay in tumor growth as compared to mice treated with Ad-LacZ. However, combination therapy with doxorubicin and I-131 induced further significant inhibition of tumor growth as compared with mice treated with Ad-LacZ. We have demonstrated successful therapeutic efficacy of combined MDR shRNA and hNIS radioiodine gene therapy using an adenoviral vector system in a mouse colon cancer model. Adenovirus-mediated cancer gene therapy using MDR1 shRNA and hNIS would be a useful tool for the treatment of cancer cells expressing multi-drug resistant genes.

Highlights

The human sodium/iodide symporter (NIS) protein is an active iodide transporter.[1]
Increased human NIS protein expression was observed in adenovirus vector that expressed human NIS (Ad-hNIS) infected cells, and decreased P-glycoprotein expression was found in Ad-shMDR infected cells as determined by Western blotting.[15]
RNA interference (RNAi) has currently been used as an valuable research tool to induce the suppression of specific genes of interest using small interference RNA or micro RNA, double strand RNA molecules of short fragments of 19–25 base pairs.[9]

Summary

Introduction

The human sodium/iodide symporter (NIS) protein is an active iodide transporter.[1] Since the transfer of the NIS gene and the subsequent functional expression of NIS protein induce cancer cells to accumulate therapeutic radionuclides (I-131 and 188Re) from plasma, NIS gene transfer represents a possible type of radionuclide gene therapy. Several investigators have reported that human sodium/iodide symporter (hNIS) mediated-radionuclide gene therapy would offer a potential means of cancer therapy.[2,3,4,5,6]. Classic MDR is characterized by cross resistance to antineoplastic drugs and is caused by overexpression of the MDR1 gene that encodes Pglycoprotein (Pgp), a member of the ATP-binding cassette (ABC) transporter superfamily.[7] Most efforts to reverse MDR during the past decades have focused on the use of compounds that modulate Pgp activity. Tumor cells can acquire resistance to the applied chemosensitizers, so-called tertiary resistance

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Conclusion