Abstract
Heat shock protein 27 (Hsp27) has an established role in tumor progression and chemo-resistance of castration-resistant prostate cancer (CRPC). Hsp27 protects eukaryotic translation initiation factor 4E (eIF4E) from degradation, thereby maintaining survival during treatment. Phenazine derivative compound #14 was demonstrated to specifically disrupt Hsp27/eIF4E interaction and significantly delay castration-resistant tumor progression in prostate cancer xenografts. In the present work, various strategies of encapsulation of phenazine #14 with either DOTAU (N-[5′-(2′,3′-dioleoyl)uridine]-N′,N′,N′-trimethylammonium tosylate) and DOU-PEG2000 (5′-PEG2000-2′,3′-dioleoyluridine) nucleolipids (NLs) were developed in order to improve its solubilization, biological activity, and bioavailability. We observed that NLs-encapsulated phenazine #14-driven Hsp27-eIF4E interaction disruption increased cytotoxic effects on castration-resistant prostate cancer cell line and inhibited tumor growth in castration-resistant prostate cancer cell xenografted mice compared to phenazine #14 and NLs alone. Phenazine #14 NL encapsulation might represent an interesting nanostrategy for CRPC therapy.
Highlights
IntroductionProstate cancer (PC) is the fifth leading cause of death from cancer in men worldwide, with an estimated 307,000 deaths representing 6.6% of total male cancer mortality [1]
We previously showed that Heat shock protein 27 (Hsp27) drives treatment-resistance by protecting major client proteins such as eukaryotic translation initiation factor 4E (eIF4E) from their ubiquitin-proteasome degradation [12,13]. eIF4E binds the m7GTP cap structure at the 50 -end of mRNAs, stimulating the translation of proteins implicated in cancer cell growth and metastasis [14]
In order to obtain stable nanoparticles loaded with phenazine derivative, we developed a simple encapsulation procedure by dissolving a nucleolipid/phenazine #14 film in an aqueous medium
Summary
Prostate cancer (PC) is the fifth leading cause of death from cancer in men worldwide, with an estimated 307,000 deaths representing 6.6% of total male cancer mortality [1]. Most patients with advanced PC are treated with androgen deprivation therapy (ADT, called castration). Despite the initial response to ADT, patients will experience disease progression to a castration resistant (CRPC) state. Patients with CRPC currently have few treatment options, and there is an unmet medical need in this area for new compounds that target the cancer differently and offer alternative therapeutic options for patients at this late stage of PC. Several therapeutic agents (abiraterone acetate, enzalutamide, docetaxel, cabazitaxel, radium-223, and sipuleucel-T) were found to improve overall survival and Pharmaceutics 2021, 13, 623.
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