Effective response of doxorubicin-sensitive and -resistant breast cancer cells to combinational siRNA therapy
Hamidreza Montazeri Aliabadi1, Robert Maranchuk2, Cezary Kucharski1
1Department of Chemical & Material Engineering, Faculty of Engineering, University of Alberta, Edmonton, AB T6G 2G6, Canada.
Abstract:
Chemotherapy is an effective approach to curb uncontrolled proliferation of malignant cells. However, most drugs rapidly lose their efficacy as a result of resistance development. We explored the potential of combinational siRNA silencing to prevent growth of drug-resistant breast cancer cells independent of chemotherapy. Resistance was induced in two breast cancer lines by chronic exposure to doxorubicin. Microarray analysis of apoptosis-related proteins showed Bcl2, survivin, NF B, and Mcl1 to be prominently up-regulated in drug-resistant cells. Human siRNA libraries against apoptosis-related proteins and kinases were screened using lipid-substituted polymers as non-viral carrier, and siRNAs were selected to diminish cell growth without affecting growth of skin fibroblasts. Surprisingly, the selected siRNAs led to similar responses in wild-type and drug-resistant cells, despite their phenotypic differences. Promising kinase siRNAs were co-delivered with anti-apoptotic Mcl-1 siRNA and Ribosomal Protein S6 Kinase (RPS6KA5) was found the most promising candidate for simultaneous silencing with Mcl-1. In both MDA435 wild type (WT) and MDA435 resistant (R) xenografts in nude mice, double silencing of Mcl-1/RPS6KA5 also led to improved inhibition of tumor growth in the absence of chemotherapy. We conclude that combinational silencing of well-selected targets could be a feasible therapeutic strategy in the absence of drug therapy and could provide a new avenue for therapy of drug-resistant breast cancers.
Insights
Combinational siRNA silencing of Mcl-1 and RPS6KA5 effectively inhibits drug-resistant breast cancer growth, offering a novel therapeutic strategy independent of chemotherapy.
Area of Science:
- Oncology
- Molecular Biology
- Gene Therapy
Background:
- Chemotherapy is effective against cancer but often fails due to drug resistance.
- Drug-resistant breast cancer cells exhibit increased expression of anti-apoptotic proteins.
- Targeting these resistance mechanisms is crucial for effective treatment.
Purpose of the Study:
- To investigate combinational siRNA silencing as a strategy to inhibit drug-resistant breast cancer cell growth.
- To identify specific siRNA targets that reduce proliferation independent of chemotherapy.
- To evaluate the efficacy of dual siRNA silencing in preclinical models.
Main Methods:
- Breast cancer cell lines were rendered doxorubicin-resistant.
- Microarray analysis identified upregulated apoptosis-related proteins.
- siRNA libraries targeting apoptosis proteins and kinases were screened using lipid-substituted polymers.
- Selected siRNAs were co-delivered with Mcl-1 siRNA.
- Efficacy was assessed in vitro and in MDA435 xenografts in nude mice.
Main Results:
- Drug-resistant cells showed upregulation of Bcl2, survivin, NF-κB, and Mcl-1.
- Selected siRNAs reduced cell growth in both wild-type and resistant cells.
- Co-delivery of Mcl-1 and RPS6KA5 (Ribosomal Protein S6 Kinase A5) siRNA demonstrated significant tumor growth inhibition in vivo.
- This dual silencing was effective even without chemotherapy.
Conclusions:
- Combinational siRNA silencing of Mcl-1 and RPS6KA5 is a promising therapeutic strategy for drug-resistant breast cancer.
- This approach offers a chemotherapy-independent treatment avenue.
- Targeted gene silencing presents a novel therapeutic option for overcoming drug resistance in cancer.
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