Abstract
BackgroundMultidrug resistance (MDR) generally leads to breast cancer treatment failure. The most common mechanism of MDR is the overexpression of ATP-binding cassette (ABC) efflux transporters such as P-glycoprotein (P-gp) that reduce the intracellular accumulation of various chemotherapeutic agents. Celecoxib (CXB), a selective COX-2 inhibitor, can dramatically enhance the cytotoxicity of doxorubicin (DOX) in breast cancer cells overexpressing P-gp. Thus it can be seen that the combination of DOX and CXB maybe obtain synergistic effects against breast cancer by overcoming drug resistance.ResultsIn this study, we designed a pH and redox dual-responsive nanocarrier system to combine synergistic effects of DOX and CXB against drug resistant breast cancer. This nanocarrier system denoted as HPPDC nanoparticles showed good in vitro stability and significantly accelerated drug releases under the acidic and redox conditions. In drug-resistant human breast cancer MCF-7/ADR cells, HPPDC nanoparticles significantly enhanced the cellular uptake of DOX through the endocytosis mediated by CD44/HA specific binding and the down-regulated P-gp expression induced by COX-2 inhibition, and thus notably increased the cytotoxicity and apoptosis-inducing activity of DOX. In MCF-7/ADR tumor-bearing nude mice, HPPDC nanoparticles showed excellent tumor-targeting ability, remarkably enhanced tumor chemosensitivity and reduced COX-2 and P-gp expressions in tumor tissues.ConclusionAll results demonstrated that HPPDC nanoparticles can efficiently overcome drug resistance in breast cancer both in vitro and in vivo by combining chemotherapy and COX-2 inhibitor. In a summary, HPPDC nanoparticles show a great potential for combination treatment of drug resistant breast cancer.
Highlights
Multidrug resistance (MDR) generally leads to breast cancer treatment failure
Preparation and characterization of HPPDC nanoparticles In this study, a novel therapeutic system (HPPDC nanoparticles) was designed for overcoming drug resistance in breast cancer by combining chemotherapy and Cyclooxygenase 2 (COX-2) inhibitor
HPPDC nanoparticles consisted of hydrophilic hyaluronic acid (HA) shells and hydrophobic PPDC nanocores co-loaded with a chemotherapeutic drug DOX and a COX-2 selective inhibitor CXB
Summary
Multidrug resistance (MDR) generally leads to breast cancer treatment failure. The most common mechanism of MDR is the overexpression of ATP-binding cassette (ABC) efflux transporters such as P-glycoprotein (P-gp) that reduce the intracellular accumulation of various chemotherapeutic agents. It can be seen that the combination of DOX and CXB maybe obtain synergistic effects against breast cancer by overcoming drug resistance. Multidrug resistance (MDR), characterized by a simultaneous resistance to diverse chemotherapeutic drugs, is a major impediment towards chemotherapy fighting breast cancer [3, 4]. Several mechanisms have been reported to be responsible for MDR, including ATP-binding cassette (ABC) transporters, anti-apoptotic proteins, DNA repair enzymes, etc. P-glycoprotein (P-gp), encoded by MDR1, is a well-characterized ABC-transporter and found to be over-expressed or constitutively active in 50% of breast cancers [7,8,9]. Much research has been devoted to exploring P-gp inhibitors for overcoming MDR, only limited success has been achieved in clinical practice [10]
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