Fifth Biannual Report of the Cochrane Haematologic Malignancies Group—Focus on Multiple Myeloma

Naumann, Frauke; Weingart, Olaf; Kruse, Eva; Schulz, H.; Bohlius, Julia; Hülsewede, Helge; Engert, Andreas

doi:10.1093/jnci/djj328

Cited by 4 publications

(2 citation statements)

References 9 publications

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“…Although many advances have been achieved in recent studies, MM remains an incurable disease and novel treatment strategies or agents are urgently needed [1,2]. A number of purine nucleoside analogs are rationally designed anticancer drugs that exert cytotoxicity via inhibition of DNA and RNA synthesis, and are currently used in the treatment of hematologic malignancies [3,4].…”

Section: Introductionmentioning

confidence: 99%

Therapeutic potential of cladribine in combination with STAT3 inhibitor against multiple myeloma

Wang

Zhao³

et al. 2011

BMC Cancer

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BackgroundCladribine or 2-chlorodeoxyadenosine (2-CDA) is a well-known purine nucleoside analog with particular activity against lymphoproliferative disorders, such as hairy cell leukemia (HCL). Its benefits in multiple myeloma (MM) remain unclear. Here we report the inhibitory effects of cladribine on MM cell lines (U266, RPMI8226, MM1.S), and its therapeutic potential in combination with a specific inhibitor of the signal transducer and activator of transcription 3 (STAT3).MethodsMTS-based proliferation assays were used to determine cell viability in response to cladribine. Cell cycle progression was examined by flow cytometry analysis. Cells undergoing apoptosis were evaluated with Annexin V staining and a specific ELISA to quantitatively measure cytoplasmic histone-associated DNA fragments. Western blot analyses were performed to determine the protein expression levels and activation.ResultsCladribine inhibited cell proliferation of MM cells in a dose-dependent manner, although the three MM cell lines exhibited a remarkably different responsiveness to cladribine. The IC50 of cladribine for U266, RPMI8226, or MM1.S cells was approximately 2.43, 0.75, or 0.18 μmol/L, respectively. Treatment with cladribine resulted in a significant G1 arrest in U266 and RPMI8226 cells, but only a minor increase in the G1 phase for MM1.S cells. Apoptosis assays with Annexin V-FITC/PI double staining indicated that cladribine induced apoptosis of U266 cells in a dose-dependent manner. Similar results were obtained with an apoptotic-ELISA showing that cladribine dramatically promoted MM1.S and RPMA8226 cells undergoing apoptosis. On the molecular level, cladribine induced PARP cleavage and activation of caspase-8 and caspase-3. Meanwhile, treatment with cladribine led to a remarkable reduction of the phosphorylated STAT3 (P-STAT3), but had little effect on STAT3 protein levels. The combinations of cladribine and a specific STAT3 inhibitor as compared to either agent alone significantly induced apoptosis in all three MM cell lines.ConclusionsCladribine exhibited inhibitory effects on MM cells in vitro. MM1.S is the only cell line showing significant response to the clinically achievable concentrations of cladribine-induced apoptosis and inactivation of STAT3. Our data suggest that MM patients with the features of MM1.S cells may particularly benefit from cladribine monotherapy, whereas cladribine in combination with STAT3 inhibitor exerts a broader therapeutic potential against MM.

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Section: Introductionmentioning

confidence: 99%

Therapeutic potential of cladribine in combination with STAT3 inhibitor against multiple myeloma

Wang

Zhao³

et al. 2011

BMC Cancer

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“…Despite recent advances in treatment, MM remains incurable in the majority of patients [1; 2]. In addition to autologous stem cell transplantation following high dose melphalan, other chemotherapeutic agents, such as bortezomib, thalidomide, doxorubicin, and dexamethasone, have been the mainstay of treatment for MM [3].…”

Section: Introductionmentioning

confidence: 99%

HDAC inhibition synergistically enhances alkylator-induced DNA damage responses and apoptosis in multiple myeloma cells

et al. 2010

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Histone deacetylase (HDAC) inhibitors induce chromatin destabilization. We sought to determine whether HDAC inhibition may amplify alkylator-induced mitotic cell death in multiple myeloma (MM) cells. The combination of SNDX-275, a class I HDAC inhibitor, with melphalan, showed a powerful synergism on growth inhibition with the combination index ranged from 0.27 to 0.75 in MM1.S and RPMI8226 cells. Their combinations as compared with either agent alone promoted much more caspase-dependent apoptosis. Flow cytometry analysis showed that SNDX-275 had minimal effects on cell cycle progression of MM1.S cells, but clearly increased the percentage of S phase in RPMI8226 cells associated with an upregulation in p21 waf1 and a reduction in cyclin D1 and E2F1. Melphalan alone significantly arrested both MM1.S and RPMI8226 cells at S phase and enhanced expression of p53 and p21 waf1 . Furthermore, studies on DNA damage response revealed that phospho-histone H2A.X (γH2A.X), a hall marker of DNA double strand break, along with phosphorylated CHK1 (P-CHK1) and CHK2 (P-CHK2) was dramatically induced by SNDX-275 or melphalan. The increase in γH2A.X and P-CHK1 was considerably higher on combination than either agent alone. These molecular changes correlated well with the significant increase in mitotic catastrophe. Our data indicate that SNDX-275 synergistically enhances melphalan-induced apoptosis in MM cells via intensification of DNA damage, suggesting that SNDX-275 in combination with melphalan may be a novel therapeutic strategy for MM.

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Correlation of CD74 expression with the Ki-67-labeling index and CD138 in multiple myeloma

El-badawi¹,

Ahmed²,

Ali³

et al. 2012

Egyptian Journal of Pathology

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Introduction Despite the advancements in multiple myeloma (MM) therapy, it is still considered an incurable disease. The fact that CD74 is highly expressed in MM implicates it as a potential therapeutic target. Ki-67 is a nuclear protein that is strictly associated with cell proliferation. The antibody to Ki-67 has been used as a marker of proliferative activity in MM. CD138 is a transmembrane protein whose expression is highly specific for terminally differentiated plasma cells.Aim of the study The aim of the study was to assess the possible correlation between CD74 expression with proliferative activity (represented by the Ki-67-labeling index) and plasma cell differentiation (represented by CD138 expression) in MM tumor cells.Patients and methods This study included 22 patients with MM. Biopsy specimens were obtained from the lesions and stained using hematoxylin and eosin. Immunohistochemical staining for CD74, Ki-67, and CD138 expression was performed for all the cases. The slides were examined and the results were tabulated and statistically analyzed. ResultsThe mean age of the study group was 52.9 ± 11.4 years, with slight male predilection (59% men and 41% women). CD74 expression was observed in tumor cells of all patients with MM with variable degrees of immunoreactivity. Ki-67-labeling index ranged from 5 to 40%. Significant positive correlation was found between the proliferation index and CD74 immunoexpression (r = 0.5, P < 0.03). Weak positive correlation was found between CD74 and CD138 expression by the tumor cells.Conclusion There is a significant positive correlation between the expression of CD74 and the Ki-67-labeling index, suggesting an important role for CD74 in the proliferation and aggressiveness of MM. There is a weak positive correlation between CD74 and plasma cell differentiation (represented by CD138 expression) of MM tumor cells. The presence of CD74 in all cases of MM supports the fact that it is a suitable target for MM immunotherapy.

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Fifth Biannual Report of the Cochrane Haematologic Malignancies Group—Focus on Multiple Myeloma

Cited by 4 publications

References 9 publications

Therapeutic potential of cladribine in combination with STAT3 inhibitor against multiple myeloma

Therapeutic potential of cladribine in combination with STAT3 inhibitor against multiple myeloma

HDAC inhibition synergistically enhances alkylator-induced DNA damage responses and apoptosis in multiple myeloma cells

Correlation of CD74 expression with the Ki-67-labeling index and CD138 in multiple myeloma

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