Coccè Valentina, Bonomi Arianna, Cavicchini Loredana, Sisto Francesca, Giannì Aldo, Farronato Giampietro, Alessandri Giulio, Petrella Francesco, Sordi Valeria, Parati Eugenio, Bondiolotti Gianpietro, Paino Francesca, Pessina Augusto
CRC StaMeTec, Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan. Italy.
Department of Biomedical, Surgical and Dental Sciences, Unit of Orthodontics and Paediatric Dentistry, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico di Milano. Italy.
Curr Cancer Drug Targets. 2020 Nov 15. doi: 10.2174/1568009620666201116112153.
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.
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.
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).
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.
用肿瘤坏死因子相关凋亡诱导配体蛋白（MSCs-TRAIL）工程化的脂肪组织来源的间充质干细胞具有显著的抗癌活性。未经过任何基因改造的间充质干细胞，在暴露于高剂量化疗药物时能够摄取药物并以影响肿瘤增殖的量释放药物。本研究的目的是通过提高抗肿瘤疗效来验证MSCs-TRAIL摄取和释放紫杉醇（PTX）的能力。
通过MTT法检测间充质干细胞和MSCs-TRAIL对紫杉醇（PTX）的敏感性，并按照标准化程序使细胞加载PTX。通过HPLC分析分泌蛋白组中PTX的存在情况，通过微阵列分析可溶性TRAIL（s-TRAIL），并测试其体外抗癌活性。
MSCs-TRAIL对PTX具有抗性，能够摄取并随后释放药物。加载PTX的MSCs-TRAIL分泌s-TRAIL不受抑制，并且PTX递送与s-TRAIL分泌一起导致细胞分泌产物在体外对人胰腺癌（CFPAC-1）和胶质母细胞瘤（U87-MG）的抗肿瘤疗效增加。
我们的结果首次证明了基于基因操作和药物递送的两种新的间充质干细胞治疗方法可能合并。如果在体内得到证实，这可能增强MSCs-TRAIL的疗效，并有力地有助于降低由于PTX全身治疗引起的毒性。
