Extracellular Vesicle Delivery of TRAIL Eradicates Resistant Tumor Growth in Combination with CDK Inhibition by Dinaciclib.

Changhong Ke,Chaohong Huang,Jiayu Li,Huan Hou,Kui Su,Zhengqiang Yuan,Zhiqiang Lu,Yue Lin,Wen Tan,Zhiyun Du

doi:10.3390/cancers12051157

Abstract

Tumour necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) is a promising anti-cancer agent that rapidly induces apoptosis in cancer cells. Unfortunately, the clinical application of recombinant TRAIL (rTRAIL) has been hampered by its common cancer resistance. Naturally TRAIL is delivered as a membrane-bound form by extracellular vesicles (EV-T) and is highly efficient for apoptosis induction. SCH727965 (dinaciclib), a potent cyclin-dependent kinase (CDK) inhibitor, was shown to synergize with other drugs to get better efficacy. However, it has never been investigated if dinaciclib coordinates with EV-T to enhance therapeutic results. This study explores the potential of combination therapy with EV-T and dinaciclib for cancer treatment. EV-T was successfully derived from human TRAIL transduced cells and shown to partially overcome resistance of A549 cells. Dinaciclib was shown to drastically enhance EV-T killing effects on cancer lines that express good levels of death receptor (DR) 5, which are associated with suppression of CDK1, CDK9 and anti-apoptotic proteins. Combination therapy with low doses of EV-T and dinaciclib induced strikingly enhanced apoptosis and led to complete regression in A549 tumors without any adverse side effects observed in a subcutaneous xenograft model. Tumor infiltration of mass NK cells and macrophages was also observed. These observations thus indicate that the combination of EV-T with dinaciclib is a potential novel therapy for highly effective and safe cancer treatment.

Highlights

Tumour necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) is a promising pro-apoptotic protein that rapidly induces extrinsic apoptosis in tumor cells while sparing normal cells
Previous studies have revealed that TRAIL could be secreted via Extracellular vesicles (EVs) by cells that express
The 293T cell line was used to produce TRAIL-EVs in this study considering its plausibility for easy transduction and expansion and readily approachable mass production of EVs

Summary

Introduction

Tumour necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) is a promising pro-apoptotic protein that rapidly induces extrinsic apoptosis in tumor cells while sparing normal cells. As a homotrimeric form, TRAIL binds to its cognate death receptor 4 (DR4) or DR5 on the target cell surface, resulting in the recruitment of the adaptor protein FAS-associated protein with death domain (FADD), in turn, the assembling and activation of caspase-8 and -10 at the death-inducing signaling complex (DISC) [1]. Its soluble recombinant N-terminus truncated form, namely rTRAIL, has been extensively tested as a cancer therapeutic agent in vitro and in vivo [3,4]. Cancers 2020, 12, 1157 bioavailability and common cancer cell resistance [5]. To overcome these shortcomings, strategies for efficient TRAIL delivery and circumvention of TRAIL resistance are necessary

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