Sensitivity of mesenchymal stromal cells to a new imidazole-based cationic Pt(II) complex with high in vitro anticancer activity

OBJECTIVE: Platinum drugs endowed with a novel chemical structure could offer an alternative therapeutic strategy, allowing to enlarge the spectrum of activity and to overcome the many drawbacks of the well-known cisplatin (CisPt) and its derivatives. Our group synthesised a new caPt(II)-complex that showed a very effective cytotoxic effect on triple-negative breast cancer cells and on cell lines partially resistant to cisplatin. In this study, we compared the in vitro stability of CisPt and caPt(II)-complex and their in vitro activity against human tumour cell lines. The drug sensitivity of Mesenchymal Stromal Cells (MSCs) and their ability to uptake and release the drugs was also investigated. MATERIALS AND METHODS: AT-MSCs were isolated, characterized and expanded from human adipose tissue. Drug stability was studied following incubation at 37°C in complete cell culture medium both in the absence and in the presence of a monolayer of MSCs. The effect of CisPt and caPt(II)-complex was tested against mesothelioma (NCI-H28), glioblastoma (U87MG), pancreatic adenocarcinoma (CFPAC-1) and AT-MSCs by using a MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium) anti-proliferative assay in 96 multiwell plates. The amount of drugs incorporated and released by AT-MSCs drugs was evaluated by inductively coupled plasma mass spectrometry (ICP-MS). RESULTS: We found that caPt(II)-complex had a high stability until 9 days of treatment while CisPt lost its anticancer activity after only 24 hours of treatment. CisPt was significantly more active (IC50= 9.64 ± 5.10 µM) than caPt(II)-complex (IC50= 21.25 ± 6.68 µM) on CFPAC1 proliferation. On the contrary, caPt(II)-complex showed a significant higher activity than CisPt both against NCI-H28 mesothelioma (19.37 ± 9.57 µM versus 34.66 ± 7.65 µM for CisPt) and U87 MG (19.85 ± 0.97 µM versus 54.14 ± 3.19 for CisPt). AT-MSCs showed a sensitivity to the cytotoxic effect of caPt(II)-complex (IC50=92.8 ± 28.9 µM) and CisPt (IC50= 93.5 ± 47.6 µM) that does not differ significantly but with a higher variability of response to CisPt expressed by different donors of AT-MSCs. To the antiproliferative activity of caPt(II)-complex and CisPt, AT-MSCs showed a significant different sensitivity (IC50= 71.9 ± 15.1 µM for caPt(II)-complex and 8.7 ± 4.5 µM for CisPt). AT-MSCs are able to uptake both the drugs in a similar amount of 2.49 pM /cell. DISCUSSION AND CONCLUSION: The high stability of caPt(II)-complex together with its significant anticancer activity against mesothelioma and glioblastoma makes this new platinum derivative a very interesting molecule able to improve cancer chemotherapy. The low sensitivity of AT- MSCs to the antiproliferative action exerted by caPt(II)-complex together with their ability to uptake and release the drug will be further investigated in order to optimize the drug loading procedure and verify the possibility to set up a system of cell mediated delivery of caPt(II) complex.