Paclitaxel Priming of TRAIL Expressing Mesenchymal Stromal Cells (MSCs-TRAIL) Increases Antitumor Efficacy of Their Secretome

Valentina Coccè; Arianna Bonomi; Loredana Cavicchini; Francesca Sisto; Aldo Giannì; Giampietro Farronato; Giulio Alessandri; Francesco Petrella; Valeria Sordi; Eugenio Parati; Gianpietro Bondiolotti; Francesca Paino; Augusto Pessina

doi:10.2174/1568009620666201116112153

Paclitaxel Priming of TRAIL Expressing Mesenchymal Stromal Cells (MSCs-TRAIL) Increases Antitumor Efficacy of Their Secretome

Curr Cancer Drug Targets. 2020 Nov 15. doi: 10.2174/1568009620666201116112153. Online ahead of print.

Affiliations

¹ CRC StaMeTec, Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan. Italy.
² Department of Biomedical, Surgical and Dental Sciences, Unit of Orthodontics and Paediatric Dentistry, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico di Milano. Italy.
³ Cellular Neurobiology Laboratory, Department of Cerebrovascular Diseases, IRCCS Neurological Institute C. Besta, Milan. Italy.
⁴ Department of Oncology and Hematology, University of Milan, Milan. Italy.
⁵ San Raffaele Diabetes Research Institute; San Raffaele Scientific Institute, Milan. Italy.
⁶ Department of Medical Biotechnology and Translational Medicine, University of Milan. Italy.

PMID: 33200709
DOI: 10.2174/1568009620666201116112153

Abstract

Background: Adipose tissue derived MSCs engineered with the tumor necrosis factor-related apoptosis-inducing ligand protein (MSCs-TRAIL) have a significant anticancer activity. MSCs, without any genetic modifications, exposed to high doses of chemotherapeutic agents are able to uptake the drug and release it in amount affecting tumor proliferation. The purpose of this study was to verify the ability of MSCs-TRAIL to uptake and release paclitaxel (PTX) by providing an increased antitumor efficacy.

Methods: MSCs and MSCs-TRAIL were tested for their sensitivity to Paclitaxel (PTX) by MTT assay and the cells were loaded with PTX according to a standardized procedure. The secretome was analysed by HPLC for the presence of PTX, microarray assay for soluble TRAIL (s-TRAIL) and tested for in vitro anticancer activity.

Results: MSCs-TRAIL were resistant to PTX and able to incorporate and then release the drug. The secretion of s-TRAIL by PTX loaded MSCs-TRAIL was not inhibited and the PTX delivery together with s-TRAIL secretion resulted into an increased antitumor efficacy of cell secretoma as tested in vitro on human pancreatic carcinoma (CFPAC-1) and glioblastoma (U87-MG).

Conclusions: Our result is the first demonstration of the possible merging of two new MSCs therapy approaches based on genetic manipulation and drug delivery. If confirmed in vivo, this could potentiate the efficacy of MSCs-TRAIL and strongly contribute to reduce the toxicity due to the systemic treatment of PTX.

Keywords: Paclitaxel; TRAIL-Mesenchymal Stromal Cells; U87-MG; CFPac-1.; drug delivery mechanism; secretome.