Authors: Piyanuch Wonganan, Woon-Gye Chung, Saijie Zhu, Kaoru Kiguchi, John DiGiovanni and Zhengrong Cui

Piyanuch Wonganan

Division of Pharmaceutics; College of Pharmacy; The University of Texas at Austin; Austin, TX USA

Woon-Gye Chung

Division of Pharmaceutics; College of Pharmacy; The University of Texas at Austin; Austin, TX USA

Saijie Zhu

Division of Pharmaceutics; College of Pharmacy; The University of Texas at Austin; Austin, TX USA

Kaoru Kiguchi

Division of Pharmacology and Toxicology; College of Pharmacy; The University of Texas at Austin; Austin, TX USA

John DiGiovanni

Division of Pharmacology and Toxicology; College of Pharmacy; The University of Texas at Austin; Austin, TX USA

Zhengrong Cui

Corresponding author: Zhengrong.cui@austin.utexas.edu
Division of Pharmaceutics; College of Pharmacy; The University of Texas at Austin; Austin, TX USA

Abstract:
Gemcitabine is a deoxycytidine analog used for the treatment of a wide range of solid tumors. Its efficacy is however often reduced due to the development of resistance. Ribonucleotide reductase M1 subunit (RRM1) is a key determinant of gemcitabine resistance, and tumor cells that overexpress RRM1 are resistant to the cytotoxicity of gemcitabine. In the present study, we showed that RRM1-specific small interfering RNA (siRNA), when complexed with polyethylenimine, effectively downregulated the expression of RRM1 protein in mouse tumor cells that overexpress RRM1, both in vitro and in vivo. More importantly, systemic administration of the RRM1-specific siRNA significantly inhibited the growth of RRM1-overexpressing tumors in mice and sensitized the tumors to gemcitabine treatment. These findings suggest that silencing RRM1 expression using siRNA could potentially be an effective strategy to overcome gemcitabine resistance.

Received: February 27, 2012; Accepted: May 22, 2012

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