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 CD138− cells from the MM cell lines and samples from patients with MM. Mouse xenografts obtained by implanting CD138− MM cells were used to assess the efficacy of TRAIL, alone and in combination with DOX, in vivo. CD138− 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− cells. However, when TRAIL is combined with doxorubicin, this results in complete eradication of MM cells in vivo. Most importantly, this treatment successfully eliminates CD138− cells implicated in tumour initiation and growth maintenance. These findings may explain the failure of current therapies and offer a promising new approach in the quest to cure MM and disseminated cancers.
Highlights
Multiple myeloma (MM) is a clonal B cell malignancy characterised by the accumulation of plasma cells in the bone
In this study we report that tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce apoptosis of different populations of myeloma cells
We show that TRAIL treatment in combination with doxorubicin results in the complete and sustained eradication of MM cells in vivo
Summary
Multiple myeloma (MM) is a clonal B cell malignancy characterised by the accumulation of plasma cells in the bone. It is the second most prevalent blood cancer and accounts for approximately 10% of all haematological cancers [1]. Despite developments in treatment, current strategies have not been successful in the complete eradication of malignant plasma cells, and MM remains an incurable disease. Median survival with conventional chemotherapy (malphalan+prednisone) regimens is approximately 3 years [2] and more aggressive chemotherapy is associated with only a modest improvement [3,4]. High-dose therapy with stem cell transplantation improves response and long-term remission in younger patients, but results in only a modest survival advantage compared to conventional therapy [5]. Treatment with some chemotherapeutic drugs is associated with the appearance of secondary malignancies [8,9,10] suggesting that new approaches are urgently required
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
