Circumventing AKT-Associated Radioresistance in Oral Cancer by Novel Nanoparticle-Encapsulated Capivasertib.

Liwei Lang,Yong Teng,Caleb Jensen,Alex Chen,Feng-Chong Kong,Tiffany Lam,Zoya B Kurago,Leslie Duncan,Chloe Shay

doi:10.3390/cells9030533

Liwei Lang, Yong Teng + Show 7 more

Open Access

https://doi.org/10.3390/cells9030533

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Journal: Cells	Publication Date: Feb 25, 2020
Citations: 23	License type: CC BY 4.0

Affiliation: Augusta University, Children's Center, Emory University

Abstract

Background: Development of radioresistance in oral squamous cell carcinoma (OSCC) remains a significant problem in cancer treatment, contributing to the lack of improvement in survival trends in recent decades. Effective strategies to overcome radioresistance are necessary to improve the therapeutic outcomes of radiotherapy in OSCC patients. Methods: Cells and xenograft tumors were irradiated using the Small Animal Radiation Research Platform. AKT inhibitor capivasertib (AZD5363) was encapsulated into cathepsin B-responsible nanoparticles (NPs) for tumor-specific delivery. Cell viability was measured by alamarBlue, cell growth was determined by colony formation and 3D culture, and apoptosis was assessed by flow cytometry with the staining of Fluorescein isothiocyanate (FITC) Annexin V and PI. An orthotopic tongue tumor model was used to evaluate the in vivo therapeutic effects. The molecular changes induced by the treatments were assessed by Western blotting and immunohistochemistry. Results: We show that upregulation of AKT signaling is the critical mechanism for radioresistance in OSCC cells, and AKT inactivation by a selective and potent AKT inhibitor capivasertib results in radiosensitivity. Moreover, relative to irradiation (IR) alone, IR combined with the delivery of capivasertib in association with tumor-seeking NPs greatly enhanced tumor cell repression in 3D cell cultures and OSCC tumor shrinkage in an orthotopic mouse model. Conclusions: These data indicate that capivasertib is a potent agent that sensitizes radioresistant OSCC cells to IR and is a promising strategy to overcome failure of radiotherapy in OSCC patients.

Highlights

Oral squamous cell carcinoma (OSCC) is a major subset of head and neck cancer, representing the 6th most common cancer worldwide [1,2]
To address whether AKT activity was directly responsible for radioresistance, we investigated the effect of ATP-competitive AKT inhibitor capivasertib (AZD5363) as a radiosensitizer in oral squamous cell carcinoma (OSCC)-derived cell lines and preclinical animal models
Our results suggest that radioresistance in OSCC cells can be reversed by capivasertib, providing a potential strategy to improve the therapeutic effects of radiotherapy

Summary

Introduction

Oral squamous cell carcinoma (OSCC) is a major subset of head and neck cancer, representing the 6th most common cancer worldwide [1,2]. Radiotherapy remains a mainstay of treatment for a great majority of patients with OSCC, which improves local tumor control and preserves normal tissues. OSCC cells often develop radioresistance, which leads to treatment failure and poor patient prognosis [3,4]. Cells 2020, 9, 533 radioresistance in OSCC and to develop effective strategies to counteract it in order to improve the efficacy of radiotherapy. Development of radioresistance in oral squamous cell carcinoma (OSCC). Effective strategies to overcome radioresistance are necessary to improve the therapeutic outcomes of radiotherapy in OSCC patients. Results: We show that upregulation of AKT signaling is the critical mechanism for radioresistance in OSCC cells, and AKT inactivation by a selective and potent AKT inhibitor capivasertib results in radiosensitivity.

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