Liposomal AZD5363 Displays Antiproliferation Activities and Induces Apoptosis on Y79 Retinoblastoma Cancer Cells
Zahra Khabazian1, Nafiseh Esmaeil2,3, Maryam Khanehzad1
1Department of Anatomical Sciences, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
Objectives:
Retinoblastoma (RB) is an aggressive intraocular cancer that usually develops during infancy and childhood. As an Akt kinase inhibitor, AZD5363 is a novel drug whose encapsulation into liposomes enhances its bioavailability and biomedical potential. In the present study, a liposomal membrane was created around AZD5363 to assess its efficacy on the Y79 cancer cell line.
Materials And Methods:
AZD5363 nanoparticles were synthesized by the thin film hydration method. Dynamic light scattering (DLS) and field emission scanning electron microscopy (FESEM) techniques were applied to evaluate the particle size, and the morphology of the liposomal AZD5363 (Lipo-AZD5363). The MTT test was used to assess the half maximal inhibitory concentration (IC50) of Lipo-AZD5363, and the cytotoxic effects of Lipo-AZD5363 and doxorubicin (Dox) were investigated on the Y79 cell line. Flow cytometry was used to study apoptotic induction in selected groups. Also, the PTEN/AKT/FOXO1 gene expression level was measured using quantitative reverse transcription polymerase chain reaction (qRT-PCR) assay.
Results:
Treatment with Lipo-AZD5363 inhibited the proliferation of Y79 RB cancer cell line in a dose-dependent manner. Lipo-AZD5363, at a lower concentration, was significantly more cytotoxic than Dox in terms of enhanced cell death ( p < 0.05). Furthermore, flow cytometry showed that Lipo-AZD5363 and Dox induce apoptosis in these cells. However, the number of apoptotic cells in the Lipo-AZD5363 group was clearly higher than that in the Dox group ( p < 0.001). Real-time PCR analysis indicated that Lipo-AZD5363 treatment resulted in an increase in PTEN and FOXO1 gene expression and a decrease in AKT gene expression. Our study revealed that all results were statistically more significant in the Lipo-AZD5363 group than in the Dox group ( p < 0.01, <0.01, and <0.001, respectively).
Conclusion:
Lipo-AZD5363 inhibits proliferation and promotes apoptosis of RB cells by inhibiting the PI3K/AKT signaling pathway. Thus, Lipo-AZD5363 may be a promising candidate for cancer therapy. However, more experimental evidence is needed for its use in the pharmacological treatment of RB.
Insights
Liposomal AZD5363 (Lipo-AZD5363) effectively inhibits retinoblastoma (RB) cell proliferation and induces apoptosis. This novel formulation demonstrates superior cytotoxicity compared to doxorubicin, highlighting its potential in RB cancer therapy.
Area of Science:
- Oncology
- Nanomedicine
- Molecular Biology
Background:
- Retinoblastoma (RB) is an aggressive childhood intraocular cancer.
- AZD5363, an Akt kinase inhibitor, shows therapeutic potential.
- Encapsulating AZD5363 into liposomes can enhance its bioavailability and efficacy.
Purpose of the Study:
- To synthesize liposomal AZD5363 (Lipo-AZD5363).
- To evaluate the efficacy of Lipo-AZD5363 on the Y79 retinoblastoma cell line.
- To investigate the underlying molecular mechanisms of Lipo-AZD5363 action.
Main Methods:
- Synthesis of AZD5363 nanoparticles using the thin film hydration method.
- Characterization of Lipo-AZD5363 using Dynamic Light Scattering (DLS) and Field Emission Scanning Electron Microscopy (FESEM).
- Assessment of cytotoxicity (MTT assay), apoptosis induction (flow cytometry), and gene expression (qRT-PCR) of PTEN/AKT/FOXO1.
Main Results:
- Lipo-AZD5363 inhibited Y79 cell proliferation in a dose-dependent manner.
- Lipo-AZD5363 exhibited significantly higher cytotoxicity and induced more apoptosis than doxorubicin (Dox) (p < 0.05).
- Lipo-AZD5363 increased PTEN and FOXO1 expression while decreasing AKT expression, indicating PI3K/AKT pathway inhibition.
Conclusions:
- Lipo-AZD5363 effectively inhibits RB cell proliferation and promotes apoptosis by targeting the PI3K/AKT signaling pathway.
- Lipo-AZD5363 demonstrates promising potential as a therapeutic agent for retinoblastoma.
- Further research is warranted to explore the clinical application of Lipo-AZD5363 in RB treatment.
