Cationic polymer-mediated small interfering RNA delivery for P-glycoprotein down-regulation in tumor cells.
BACKGROUND
Among the treatment options that have been developed for cancer, chemotherapy remains 1 of the leading clinical approaches. Chemotherapy can usually control tumor growth at the onset of disease, but its effectiveness becomes limited by the overexpression of transporter proteins responsible for drug efflux, leading to multidrug resistance (MDR). To overcome this obstacle, the authors explored the feasibility of down-regulating the main drug transporter, P-glycoprotein (P-gp), by using nonviral small interfering RNA (siRNA) delivery as means to enhance the accumulation of chemotherapeutic agents in drug-resistant cancer cells.


METHODS
Several cationic carriers capable of siRNA complexation were investigated for P-gp down-regulation in the MDA435/LCC6 cell line and, consequently, increased cellular uptake of the chemotherapeutic agents doxorubicin and paclitaxel.


RESULTS
Efficient siRNA delivery into tumor cells was demonstrated particularly using a palmitic-acid substituted poly(L-lysine), with no apparent differences in siRNA delivery between the wild type (WT)-expressing and P-gp-expressing phenotype (MDR1) of the cells. Efficient siRNA delivery led to approximately 40% to 50% P-gp suppression (based on the average expression level of the protein), an approximately 3-fold increased DOX uptake, and increased cytotoxicity in MDR1 cells.


CONCLUSIONS
The authors concluded that effective siRNA delivery with nonviral carriers can reduce the level of P-gp on cell surfaces and enhance the efficiency of chemotherapeutic agents in vitro.
Abbasi
Meysam
M
Department of Biomedical Engineering, Faculty of Medicine, Cross Cancer Institute, Edmonton, Alberta, Canada.
Lavasanifar
Afsaneh
A
Berthiaume
Luc G
LG
Weinfeld
Michael
M
Uludağ
Hasan
H
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D002412:Cations; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000235:genetics*; D005240:Feasibility Studies; D018014:Gene Transfer Techniques; D006801:Humans; D008239:Lysine; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics*; D017239:Paclitaxel / Q000378:metabolism / Q000494:pharmacology; D011108:Polymers; D034741:RNA, Small Interfering / Q000008:administration & dosage*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002412:Cations; D011108:Polymers; D034741:RNA, Small Interfering; D004317:Doxorubicin; D008239:Lysine; D017239:Paclitaxel