Nrf2 siRNA as a tool to overcome chemo- resistance in bladder cancer cells

Ambrosio, Leanne (2019) Nrf2 siRNA as a tool to overcome chemo- resistance in bladder cancer cells. Research Project, Pharmacy.

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Abstract

The transcription factor Nrf2 (NF-E2-related factor 2) is the master regulator of antioxidant and cytoprotective systems. Nrf2 activation is critical for resistance to drugs in various tumors, including bladder cancers. Thereby, cancer cells often depend on high Nrf2 activity for survival. For this reason, it has been postulated that Nrf2 could represent an interesting target to combat chemo-resistance. Several inhibitors of Nrf2 are already identified. However, lack of potency and selectivity of these compounds makes the use of a specific small interfering RNA (siRNA) against this gene an attractive possibility. Since siRNAs are unstable in blood and have very poor ability to cross lipophilic cell membranes, a carrier is needed. The use of nanostructures as carriers for nucleic acid delivery could overcome these obstacles, as they can protect siRNA from degradation during systemic circulation, and transport siRNA to target cells avoiding nonspecific delivery. This project aimed to evaluate the biological activity of cationic carbosilane dendrimers containing siRNA against Nrf2 in reducing cisplatin resistance and tumor growth in bladder cancer cell lines with a high level of Nrf2. We found that the used delivery system was able to enhance the uptake of anti-Nrf2 siRNA with a downregulation of the Nrf2 protein expression and its target protein GSTA4 as a result. Furthermore, the inhibition of the Nrf2 expression resulted in an increase in cisplatin sensitivity and apoptosis induction, and a decrease in the migration and growth of resistant bladder cancer cells. These findings indicate that anti-Nrf2 siRNA carried by dendrimers is a potential new therapy for patients diagnosed with chemotherapy resistant (bladder) cancer.

Item Type:	Thesis (Research Project)
Supervisor name:	Graaf, I.A.M. de
Degree programme:	Pharmacy
Thesis type:	Research Project
Language:	English
Date Deposited:	20 Jun 2019
Last Modified:	21 Jun 2019 11:58
URI:	https://fse.studenttheses.ub.rug.nl/id/eprint/19649

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