2-methoxyestradiol disrupts aggresomes induction by bortezomib and potentiates apoptosis in multiple myeloma cells / 中华血液学杂志

<p><b>OBJECTIVE</b>To investigate the synergistic anti-multiple myeloma (MM) effect of 2-methoxyestradiol (2-ME2) and bortezomib, and explore the relationship between this effect and blockade of aggresomes formation by 2-ME2.</p><p><b>METHODS</b>Four MM cell lines RPMI-8226, NCI-H929, U266 and SKO-007 were used for study. Immunoflourescent anti-ubiquitin and Hoechst 33342 staining were used to examine aggresome-positive cells and apoptotic cells, respectively. Isobolographic analysis was used for determination of synergy.</p><p><b>RESULTS</b>(1) Quantitative assay showed that in the absence of bortezomib, only 6.6% - 8.9% of MM cells were aggresome-positive, but the percentage was increased to 71.9%-83.4% after treatment with bortezomib at IC(20) concentration for 24 h. Aggresome-positive cells with immunoreactivity to anti-ubiquitin were detected in almost all non-apoptotic cells, but not in apoptotic cells. (2) Treatment in a definite range of concentrations bortezomib plus 2-ME2 led to MM cell apoptosis compared with each agent alone and the significantly synergistic effect confirmed by isobolographic analysis. (3) Combination of bortezomib and 2-ME2 increased the apoptotic cells aggresome-negative cells (ANK) and decreased the non-apoptotic cells in aggresome positive cells (APC). In RPMI8226 and U266 cells, the apoptotic cells in ANC increased from (14.5 +/- 2.0)% and (20.1 +/- 2.9)% to (80.7 +/- 6.9)% and (71.6 +/- 6.2)%, and the non-apoptotic cells in APC decreased from (75.3 +/- 5.7)% and (69.1 +/- 8.6)% to (13.8 +/- 3.8)% and (19.5 +/- 4.2)%, respectively, in combined group and bortezomib alone group.</p><p><b>CONCLUSION</b>Bortezomib-induced aggresomes have a protective function for MM cells and combination of bortezomib with 2-ME2 induced a synergistic cytotoxicity to the cells.</p>

Myeloma stem/progenitor cells as new targets for therapy of multiple myeloma--review / 中国实验血液学杂志

Multiple myeloma (MM) is characterized by a population of functionally heterogeneous cells, in which identifying the target cells causing molecular lesion is a fundamental issue. The resultant tumor stem/progenitor cells comprise only a minor portion of the myeloma cells, which give rise through differentiation to more committed progenitors as well as differentiated blasts that constitute the bulk of the tumor. Although they are rare as compared with fully differentiated plasma cells, MM stem/progenitor cells are likely responsible for the maintenance and progression of disease through the production of new tumor cells. Thus, this is the cell population which must be eradicated for successful treatment. This article reviewed apparently conflicting evidence pertaining to the cellular origins of MM and proposed that myeloma may originate in more cellular components. In this article, the nature of the target cells, the identification and phenotypic analyses of clonogenic myeloma cells, the signaling pathways within myeloma stem/progenitor cells and the target therapy related were reviewed as well.