Introduction Malignant pleural mesothelioma (MPM) is a highly aggressive, incurable, chemoresistant tumour. Recent studies have shown that Mesenchymal stem cells (MSC) can home to and incorporate into the tumour stroma. Their tumour tropism can be used to deliver Tumour necrosis factor related apoptosis inducing ligand (TRAIL), a transmembrane protein that selectively induces apoptosis in transformed cells. However, not all tumours are sensitive to TRAIL. TRAIL works through triggering the extrinsic apoptotic pathway while conventional chemotherapeutic agents act by triggering the intrinsic apoptotic pathway. We hypothesised the crosstalk between these two pathways could be exploited by combining chemotherapy and MSC-TRAIL in MPM tumour cell lines.
Methods MSC were engineered to express TRAIL using a lentiviral plasmid vector. A Tetracycline (Tet)-inducible system was used as a backbone to control the expression of TRAIL. Apoptosis induced by recombinant TRAIL, MSC-TRAIL in MPM cell lines on combination with Vorinostat, a chemotherapeutic agent, was measured by Annexin-V/DAPI based flow cytometry.
Results The combination of recombinant TRAIL and Vorinostat act synergistically to induce apoptosis in MPM cell lines. Recombinant TRAIL and Vorinostat, as monotherapies induce 7.17% and 51.35% apoptosis in an MPM cell line JU77 respectively. In CRL2081 and ONE58 cell lines, recombinant TRAIL induces 56.75% and 13.41% apoptosis while Vorinostat leads to 78.95% and 43.97% apoptosis respectively. The combination of recombinant TRAIL and Vorinostat shows an increased amount of apoptosis in JU77, CRL2081 and ONE58 cell lines at 80.77%, 96.6% and 77.27% respectively (Table 1).
Similar synergistic affect was observed when TRAIL expressing MSCs were co-cultured with Vorinostat treated MPM cell lines. MSC-TRAIL induced apoptosis in JU77 (48.73%), CRL2081 (57.63%) and ONE58(53.8%). Combined treatment of Vorinostat and MSC-TRAIL significantly increased apoptosis to 77.7% in JU77, 90.93% in CRL2081 and 77.8% in ONE58 cells (Table 1).
Conclusion The combination of Vorinostat and recombinant TRAIL acts synergistically to induce apoptosis in malignant plural mesothelioma cells. Similar affect is observed with the combination of MSC-TRAIL and Vorinostat. This study indicates that Mesenchymal stem cells can be used as vectors for delivery of TRAIL and upon combination with Vorinostat, could be a potential therapy for malignant pleural mesothelioma.
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