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Carbosilane Dendrimers Loaded with siRNA Targeting Nrf2 as a Tool to Overcome Cisplatin Chemoresistance in Bladder
Leanne Ambrosio1,2, Monica Argenziano3, Marie Angèle Cucci1
1Department of Clinical and Biological Science, University of Turin, 10125 Turin, Italy.
Abstract:
The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is considered as the master regulator of antioxidant and cytoprotective gene expressions. Moreover, it plays a pivotal role in cancer progression. Nrf2 mediates the adaptive response which contributes to the resistance to chemotherapeutic pro-oxidant drugs, such as cisplatin (CDDP), in various tumors, including bladder cancers. For this reason, Nrf2 could be a promising target to overcome chemoresistance. There are several known Nrf2 pharmacological inhibitors; however, most of them are not specific. The use of a specific small interfering RNA (siRNA) targeting the Nrf2 gene (siNrf2) loaded into nanovehicles is an attractive alternative, since it can increase specificity. This study aimed to evaluate the biological activity of siNrf2 loaded on guanidine-terminated carbosilane dendrimers (GCDs) in overcoming CDDP resistance in bladder cancer cells with a high level of Nrf2. Parameters such as viability, proliferation, apoptosis, migration, and oxidative stress level were taken into account. Results demonstrated that siNrf2-GCD treatment sensitized CDDP-resistant cells to CDDP treatment. Moreover, data obtained by treating the non-cancerous human kidney HK-2 cell line strongly suggest a good safety profile of the carbosilane dendrimers loaded with siNrf2. In conclusion, we suggest that siNrf2-GCD is a promising drug delivery system for gene therapy to be used in vivo; and it may represent an important tool in the therapy of CDDP-resistant cancer.
Insights
Nuclear factor erythroid 2-related factor 2 (Nrf2) drives chemoresistance in bladder cancer. Targeting Nrf2 with siRNA delivered via guanidine-terminated carbosilane dendrimers (siNrf2-GCD) resensitized resistant cells to cisplatin and showed a good safety profile.
Area of Science:
- Oncology
- Nanotechnology
- Gene Therapy
Background:
- Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key regulator of antioxidant responses and is implicated in cancer progression.
- Nrf2 activation confers resistance to chemotherapy, particularly pro-oxidant drugs like cisplatin (CDDP), in various cancers, including bladder cancer.
- Targeting Nrf2 is a potential strategy to overcome chemoresistance, but specific and effective delivery methods are needed.
Purpose of the Study:
- To evaluate the efficacy of small interfering RNA targeting Nrf2 (siNrf2) delivered by guanidine-terminated carbosilane dendrimers (GCDs) in overcoming CDDP resistance in bladder cancer cells.
- To assess the impact of siNrf2-GCD treatment on cell viability, proliferation, apoptosis, migration, and oxidative stress.
- To investigate the safety profile of the siNrf2-GCD nanocarrier system.
Main Methods:
- Bladder cancer cells with high Nrf2 expression were treated with CDDP-resistant models.
- siNrf2 was encapsulated within guanidine-terminated carbosilane dendrimers (GCDs).
- Cell viability, proliferation, apoptosis, migration, and oxidative stress markers were analyzed post-treatment. Non-cancerous HK-2 cells were used for safety assessment.
Main Results:
- siNrf2-GCD treatment significantly sensitized CDDP-resistant bladder cancer cells to cisplatin therapy.
- The treatment modulated key cellular processes including viability, proliferation, apoptosis, and migration.
- Treatment with siNrf2-GCD demonstrated a favorable safety profile in non-cancerous human kidney HK-2 cells.
Conclusions:
- siNrf2-GCD represents a promising nanodelivery system for gene therapy targeting Nrf2 in CDDP-resistant bladder cancers.
- This approach holds potential for enhancing the effectiveness of chemotherapy and overcoming drug resistance.
- siNrf2-GCD may serve as a valuable tool in the future treatment of resistant cancers.
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