targeting tumour-initiating cells with trail based combination therapy ensures complete and lasting eradication of multiple myeloma tumours in vivo针对基于轨迹的联合治疗肿瘤起始细胞确保完整和持久的根除多发性骨髓瘤肿瘤体内.pdf

Targeting Tumour-Initiating Cells with TRAIL Based Combination Therapy Ensures Complete and Lasting Eradication of Multiple Myeloma Tumours In Vivo 1,2 1 1 1,3 Srdjan Vitovski , Andrew D. Chantry , Michelle A. Lawson , Peter I. Croucher * 1The Mellanby Centre for Bone Research, Department of Human Metabolism, University of Sheffield Medical School, Sheffield, United Kingdom, 2 Department of Infection and Immunity, The Medical School, Sheffield, United Kingdom, 3 Garvan Institute for Medical Research, Sydney, Australia Abstract Multiple myeloma (MM) remains an incurable disease despite improvements to available treatments and efforts to identify new drug targets. Consequently new approaches are urgently required. We have investigated the potential of native tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), in combination with doxorubicin, to induce apoptotic cell death in phenotypically distinct populations of myeloma cells in vitro and in vivo. The cytotoxic potential of TRAIL alone, and in combination with DOX, was assessed in vitro in purified CD138+ and CD1382 cells from the MM cell lines and samples from patients with MM. Mouse xenografts obtained by implanting CD1382 MM cells were used to assess the efficacy of TRAIL, alone and in combination with DOX, in vivo. CD1382 cells were shown to be more resistant to the cytotoxic activity of TRAIL than CD138+ cells and have reduced expression of TRAIL death receptors. This resistance results in preferential killing of CD 138+ cells during exposure of MM culture to TRAIL. Furthermore, prolonged exposure results in the appearance of TRAIL-resistant CD138 2 cells. However, when TRAIL is combined with doxorubicin, this results in complet