Carbosilane Dendrimers Loaded with siRNA Targeting Nrf2 as a Tool to Overcome Cisplatin Chemoresistance in Bladder Cancer Cells.

Leanne Ambrosio,Monica Argenziano,Marie Angèle Cucci,Giuseppina Barrera,Margherita Grattarola,Stefania Pizzimenti,Chiara Dianzani,Rafael Gomez,Roberta Cavalli,Javier Sánchez Nieves,Inge A.M De Graaf

doi:10.3390/antiox9100993

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.

Highlights

The nuclear factor E2-related factor 2 (Nrf2) seems to play a pivotal role in drug resistance in several types of tumors, including bladder cancer
A plant extract able to inhibit nuclear factor erythroid 2-related factor 2 (Nrf2) expression transiently [10], we have recently demonstrated that ailanthone, a quassinoid extracted from the Ailanthus altissima plant, is a potent inhibitor of Nrf2, able to overcome the chemoresistance in bladder cancer [5,6]
This study aimed to evaluate the biological activity of small interfering RNA (siRNA) targeting Nrf2, loaded in a guanidine-terminated carbosilane dendrimer (GCD), in reducing CDDP resistance in bladder cancer cells with a high level of Nrf2, by analyzing parameters such as viability, proliferation, apoptosis, migration, and oxidative stress level

Summary

Introduction

The nuclear factor E2-related factor 2 (Nrf2) seems to play a pivotal role in drug resistance in several types of tumors, including bladder cancer. Nrf is found in the cytosol linked to its inhibitor, the Kelch-like erythroid cell-derived protein with. In response to an oxidative stimulus, Keap undergoes a conformational change and releases Nrf. Nrf translocates into the nucleus and binds to the antioxidant response elements (ARE) sequences present in the promoter of genes coding for antioxidant enzymes, such as heme oxygenase-1 (HO-1) and numerous genes related to glutathione (GSH) metabolism, such as γ-glutamate-cysteine ligase and glutathione-S-transferase A4 (GSTA4) [1]. Due to its ability to detoxify carcinogens and protect cells from oxidative stress damage, a protective role was attributed to Nrf in the early stages of malignant transformation. More recent data showed an opposite role in the advanced stages of the cancer disease, since aberrant activation of

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