Liposomal delivery of a Pin1 inhibitor complexed with cyclodextrins as new therapy for high-grade serous ovarian cancer

Abstract

Pin1, a prolyl isomerase that sustains tumor progression, is overexpressed in different types of malignancies. Functional inactivation of Pin1 restrains tumor growth and leaves normal cells unaffected making it an ideal pharmaceutical target. Although many studies on Pin1 have focused on malignancies that are influenced by sex hormones, studies in ovarian cancer have lagged behind. Here, we show that Pin1 is an important therapeutic target in high-grade serous epithelial ovarian cancer. Knock down of Pin1 in ovarian cancer cell lines induces apoptosis and restrains tumor growth in a syngeneic mouse model. Since specific and non-covalent Pin1 inhibitors are still limited, the first liposomal formulation of a Pin1 inhibitor was designed. The drug was efficiently encapsulated in modified cyclodextrins and remotely loaded into pegylated liposomes. This liposomal formulation accumulates preferentially in the tumor and has a desirable pharmacokinetic profile. The liposomal inhibitor was able to alter Pin1 cancer driving-pathways trough the induction of proteasome-dependent degradation of Pin1 and was found to be effective in curbing ovarian tumor growth in vivo.

E2F1 as a molecular drug target in ovarian cancer

“…Moreover, in the OC cell line OVCAR3, cell growth reduction was paralleled by the down regulation of cyclin D1 a known activator of E2F1. Although the authors [12] have not specifically evaluated E2F1 level, it is highly probable that cyclin D1 decrease could have induced a reduction of E2F1. The tumorigenic role of the Pin1-E2F1-cyclinD1 axis, although not yet specifically addressed in OC, is known to be relevant in other tumors like HCC [13].…”

“…A very recent report [12] opens the possibility of a relation between E2F1 and the peptidylprolyl cis/trans isomerase, NIMAinteracting 1 (PIN1). PIN1, recently indicated as an E2F1 target, catalyzes the specific isomerization of Ser/Thr-Pro motifs following phosphorylation.…”

Molecular crosstalk between cancer and neurodegenerative diseases

“…4). Many therapeutic studies for treating cancers have developed Pin1 inhibitors based on the fact that Pin1 is a generally recognized tumor-promoting factor [213][214][215][216][217][218][219][220][221][222][223][224][225][226]. Considering that Pin1 has also been reported to have a tumor suppressing function, Pin1-directed inhibitors must be carefully implicated in cancers.…”

PIN1 in Cell Cycle Control and Cancer

“…Some compounds show more potent effect against PIN1 PPIase activity, but the lack of solubility limits their use for cancer treatment. A liposomal/cyclodextrin (LC) complex is designed to encapsulate a potent PIN1 inhibitor Compound 8 ( Guo et al, 2009 ) to enhance the effectiveness of its delivery to the tumor site in a murine model ( Russo Spena et al, 2018 ). After encapsulation in LC complex, the solubility of Compound 8 increases by 6 times.…”