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

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.

Suppression of Ovarian Cancer Cell Growth by AT-MSC Microvesicles

“…The downregulation of TRAIL-R3 and TRAIL-R4 is associated with an increased level of early apoptotic cells in the ES-2 cell line treated with the 100:1 ratio. A very recent study, performed on a murine xenograft model, documented that the EVs isolated from the TRAIL expressing cell line 293T in combination with cyclin-dependent kinase inhibitor (dinaciclib) successfully inhibited the growth of human lung cancer cell lines NCI-H727 and A549 and the human breast adenocarcinoma cell line MDAMB231 by inducing apoptosis [34].…”

TRAIL‐Armed ER Nanosomes Induce Drastically Enhanced Apoptosis in Resistant Tumor in Combination with the Antagonist of IAPs (AZD5582)

“…The disruption of actin cytoskeleton in treated cells indicates apoptosis occurrence. [16] control, low dose ERN-T alone treatment only produced slight tumor volume inhibition (TVI) that is (15.5 ± 2.1)%; by contrast the AZD alone or its combination with rTRAIL showed significantly better and similar efficacies of TVI (47.2 ± 3.1)% and (44.5 ± 3.5)%, respectively (Figure 2B). Notably, the combination therapy of low doses of AZD and ERN-T showed the best efficacy (TVI 76 ± 3.6%), suggesting that ERN-T is superior to rTRAIL when combined with AZD for tumor therapy.…”

“…We have previously established that TRAIL-armed extracellular vesicles (EV-Ts) secreted by TRAIL-expressing cells can be one type of cell-free therapeutics for cancer treatment. [15,16] Additionally, we have also observed abundant of intracellular TRAIL accumulation within endoplasmic reticulum (ER) in TRAIL-transduced MSCs. [12] However, these ER membranedocked TRAILs have never been investigated for isolation and examination of cytotoxicity on cancers.…”

Cyclin-dependent kinase inhibitors in head and neck cancer and glioblastoma—backbone or add-on in immune-oncology?

“…Dinaciclib-mediated infiltration of NK cells and macrophages was recently reported in A549 xenografts. Immune infiltration was boosted via TRAIL delivered by extracellular vesicles [95]. Another interesting approach is based on vaccination with dinaciclib-killed immunogenic tumor cells.…”