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Co-delivery Of Doxorubicin And Bcl-2 SiRNA By Mesoporous Silica Nanoparticles Enhances The Efficacy Of Chemotherapy In Multidrug-resistant Cancer Cells.
A. M. Chen, Min Zhang, Dongguang Wei, Dirk Stueber, O. Taratula, T. Minko, H. He
Published 2009 · Biology, Medicine
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Development of multidrug resistance in cancer cells and adverse side effects are the major obstacles for effective cancer chemotherapy.[1-3] Therapeutic strategies to overcome drug resistance and specific tumor targeting with minimal premature drug release should have a great impact on the treatment of cancer. The term multidrug resistance (MDR) is used to define a resistance phenotype where cancer cells become resistant simultaneously to multiple drugs with no obvious structural resemblance and with different molecular targets.[4, 5] The multidrug resistance can be divided into two distinct classes, pump and nonpump resistance. The pump resistance is caused by certain proteins that form membrane-bound ATP-dependent active drug efflux pumps, which significantly decrease the intracellular concentration of the drug and thereby the efficacy of the treatment. Membrane proteins, P-glycoprotein (Pgp) and multidrug resistance-associated protein (MRP) have been shown to be the main players for pump resistance to a broad range of structurally and functionally distinct cytotoxic agents. The main mechanism of nonpump resistance is an activation of cellular antiapoptotic defense, mainly by Bcl-2 protein. Most of the anticancer drugs trigger apoptosis and simultaneously activate both pump and nonpump cellular defense of multidrug resistance, which prevents cell death. Therefore, to effectively suppress the overall resistance to chemotherapy, it is essential to simultaneously inhibit both pump and nonpump mechanisms of cellular resistance by targeting all the intracellular molecular targets.[3, 7-9]
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PROOF COVER SHEET
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