Abstract
BackgroundMultiple myeloma (MM) currently remains largely incurable. Cancer stem cells (CSCs) are believed to be responsible for drug resistance and eventual relapse. In this study, we exploited a novel agent to evaluate its inhibitory effect on MM CSCs.MethodsEpirubicin (EPI)-loaded lipid microbubbles (MBs) conjugated with anti-ABCG2 monoclonal antibody (EPI-MBs + mAb) were developed and their effect on MM 138−CD34− CSCs isolated from human MM RPMI 8226 cell line plus ultrasound exposure in vitro and in vivo in a nonobese diabetic/severe combined immunodeficient mouse model were assessed.ResultsEPI-MBs + mAb combined with ultrasound led to a significant decrease in the clone formation ability and the mitochondrial membrane potential along with an increase in MM CSC apoptosis. Moreover, treatment with EPI-MBs + mAb with ultrasound exposure remarkably inhibited the growth of MM CSC-derived tumors in xenograft nonobese diabetic/severe combined immunodeficient mice compared with a single agent or EPI-MBs + mAb without ultrasound exposure. The inhibitive efficacy was also correlated with an increased expression of caspase-3, Bax, and TUNEL and decreased expressions of PCNA, Bcl-2, and CD31.ConclusionsOur findings reveal that the EPI-MBs + mAb combined with therapeutic ultrasound may confer an effective approach for treatment of MM by induction of an apoptotic pathway in MM CSCs.
Highlights
Multiple myeloma (MM) currently remains largely incurable
Effect of EPI-MBs + monoclonal antibody (mAb) combined with ultrasound-targeted microbubble destruction (UTMD) on MM Cancer stem cell (CSC) First, we observed the effect of EPI-MBs + mAb combined with UTMD on MM CSCs in vitro
The clone formation rate was significantly lower in the EPI-MBs + mAb combined with UTMD group than that of the EPI-MBs + mAb without using UTMD group (4.3 ± 1.21% versus 27.2 ± 0.98%, P < 0.01), the EPI group (4.3 ± 1.21% versus 16.8 ± 1.15%, P < 0.05), or the phosphate-buffered saline (PBS) group (4.3 ± 1.21% versus 32.5 ± 4.54%, P < 0.01)
Summary
Cancer stem cells (CSCs) are believed to be responsible for drug resistance and eventual relapse. Cancer stem cells (CSCs), which show the features of self-renewal, multidirectional differentiation, and multidrug resistance, are thought to Epirubicin (EPI) is one of the anthracycline drugs commonly used for therapy in MM, breast, sarcoma, and many other malignant tumors. To reduce the side effects and enhance the local drug concentration in MM chemotherapy, we hypothesize that it may be feasible to use an ultrasound-targeted microbubble destruction (UTMD) technique combined with a. Shi et al Stem Cell Research & Therapy (2018) 9:144 specific antibody as a drug targeting MM CSCs to increase anti-MM efficacy [10]. Drug-loaded MBs conjugated with antibody in combination with UTMD appears to be a promising strategy for the treatment of tumors [11,12,13]
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