Nocodazole Induces Multiple Myeloma Cell Death and Reduces Tumor Growth through Sequential Microtubular Network Damage and C-Jun N-Terminal Kinase-Mediated Bcl-2 Phosphorylation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 296-296
Author(s):  
Rentian Feng ◽  
Huihui Ma ◽  
Noriyoshi Kurihara ◽  
Shirong Li ◽  
Judy A Ziegler ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Cell Death ◽  
Tumor Growth ◽  
Murine Model ◽  
Immunofluorescent Staining ◽  
Solid Cancer ◽  
Dependent Manner ◽  
Microtubular Network ◽  
Induced Apoptosis

Abstract Abstract 296 Background: Benzimidazoles, originally categorized as broad-spectrum anthelmintic drugs, have been recently reported to induce growth arrest and apoptosis in some solid cancer models (e.g. colorectal and lung). We performed a multiplex drug-screening assay that identified benzimidazoles as potential anti-multiple myeloma (MM) agents. Methods and Results: In this study, we demonstrate that one of the benzimidazole members, nocodazole, inhibited proliferation and induced apoptosis in MM cell lines and primary MM cells alone and in co-culture with bone marrow stromal cells. The resistant phenotype of those MM cells resistant to conventional therapies could be completely reversed by nocodazole. The IC50 values were 60 nM (RPMI8226-S), 25 nM (RPMI8226-Dox40), 80 nM (RPMI8226-MR20), 60 nM (RPMI8226-LR5), 65 nM (MM.1S) and 60 nM (MM.1R). Viability of primary cells decreased by 66% in CD138+ cells and 7% in CD138− mononucleated bone marrow cells after 48 hour treatment. Cell cycle analysis revealed a G2/M arrest and subsequent cell death induced by nocodazole. Nocodazole also caused morphologic elongation in MM cells in a dose-dependent manner during prometaphase. The morphologically changed cells exhibited a microtubular network disarray as evidenced by microtubular immunofluorescent staining. Signaling studies indicated that increased expression of Bim protein and reduced XIAP and Mcl-1 levels were involved in nocodazole-induced apoptosis. Further investigation showed Bcl-2 phosphorylation as a critical mediator of cell death, which was triggered by the activation of JNK, instead of p38 kinase or ERKs. Treatment with JNK inhibitor SP600125 completely inhibited Bcl-2 phosphorylation at Ser70 and Thr56 induced by nocodazole. Nocodazole-induced cell death subsequently decreased from 79% to 28% after pretreatment with SP600125. Combination of nocodazole with dexamethasone induced significantly stronger induction of cell death at either drug dose. Dexamethasone at 20 nM, nocodazole at 15 or 30 nM could only induce 19%, 10.3% and 16% cell death, respectively. However, their combinations resulted in 67% and 92% nuclear fragmentation, respectively. Based on our in vitro data, we analyzed nocodazole in a SCID xenograft murine model. Nocodazole alone (5 and 20 mg/kg) or combined with dexamethasone (2 mg/kg) at a lower dose of 12 mg/kg significantly inhibited H929 tumor growth and prolonged survival in a SCID xenograft murine model. Conclusions: Our studies demonstrate that nocodazole has a potent anti-MM activity and might be a promising new treatment approach for MM. * Supported by a grant from the Multiple Myeloma Research Foundation. Disclosures: Roodman: Acceleron: Consultancy; Novartis: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy; Celgene: Consultancy. Lentzsch:Celgene: Consultancy, Speakers Bureau; Pfizer: Consultancy.

Nocodazole Induces Myeloma Cell Death by Disrupting the Microtubular Network, Resulting in G2/M Arrest

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3673-3673
Author(s):  
Rentian Feng ◽  
Jorge A Rios ◽  
Markus Mapara ◽  
Suzanne Lentzsch
Keyword(s):  
Cell Cycle ◽  
Multiple Myeloma ◽  
Bone Marrow ◽  
Cell Death ◽  
Cell Lines ◽  
Myeloma Cell ◽  
Caspase 8 ◽  
Inhibition Rate ◽  
Growth And Survival ◽  
Microtubular Network

Abstract Patients with relapsed multiple myeloma (MM) previously treated with bortezomib and lenalidomide often fail to respond to further therapies. To identify potential new treatment approaches for MM, we used Luminex technology to screen a library of 1,120 compounds provided by the Multiple Myeloma Research Foundation. By multiplex cytokine array, we identified benzimidazoles including the anthelmintics mebendazole, fenbendazole, albendazole, nocodazole and pyrvinium pamoate, as inhibiting the production of cytokines essential for MM cell growth and survival, such as IL-6 (inhibition rate 40–70%), MIP-1α (inhibition rate 65–75%), VEGF (inhibition rate 75%), and soluble IL-6R (inhibition rate 40–52%). Consequently, these anthelmintics demonstrated dose-dependent inhibition of myeloma cell (RPMI-8226, H929, U266 and MM1S) proliferation. The lead compound, nocodazole, caused nuclear fragmentation and caspase-8 activation in MM cell lines and primary CD138+ cells in dose- and time-dependent fashion (IC50: 30–60 nM). Importantly, growth and survival signals provided by bone marrow stromal cells in bone marrow co-cultures failed to protect MM cells from nocodazole-induced cell death. In the apoptotic cells, caspase-8 was more activated than caspase-9, suggesting that mitochondrial signaling is not a major apoptotic pathway. Cell cycle analysis indicated that G2/M cell cycle arrest reached a peak at 17 hr. Sub-G1 proportion was strongly increased after treatment for 24 hr in all tested cell lines. Electron microscope (EM) and nuclear staining studies consistently showed the accumulation of metaphase cells, and morphologic elongation at 7 hr, at which time G2/M arrest was obvious. Most of the elongated cells had only one nucleus, suggesting that they failed to progress to mitosis due to overall microtubular network disarray. We conclude that nocodazole exposure induced microtubular network disarray with cell elongation, and G2/M arrest with a late stage mitotic block resulting in cell death. Benzimidazoles including nocodazole, traditionally used as antihelmintic drugs, have shown antitumor activity against hepatocellular, lung and adrenocortical carcinoma, and melanoma. In our study, we identified the anthelmintic compound nocodazole as a new anti-myeloma agent. Nocodazole warrants further investigation for its anti-MM effects in vitro and in vivo.

Shikonin Induces Apoptosis by Inhibiting Phosphorylation of IGF-1 Receptor in Myeloma Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4858-4858
Author(s):  
Takehiro Kimura ◽  
Tomonori Nakazato ◽  
Takatsune Shimizu ◽  
Yasuo Ikeda ◽  
Masahiro Kizaki
Keyword(s):  
Multiple Myeloma ◽  
Cell Death ◽  
Cellular Growth ◽  
Great Promise ◽  
High Dose ◽  
Dependent Manner ◽  
Human Malignant Melanoma ◽  
Myeloma Cells ◽  
Induction Of Apoptosis ◽  
Induced Apoptosis

Abstract Multiple myeloma is an incurable hematological malignancy of plasma cells despite advances in conventional chemotherapy or high dose chemotherapy with stem cell transplantation. Recent advances in the biological treatment such as thalidomide and bortezomib will offer great promise to improve the outcome of refractory or relapsed patients with multiple myeloma; therefore, more novel biologically based therapies targeting both myeloma cells and its bone marrow microenvironment are urgently required. Shikonin, a Chinese herb derived from purple gromwell, Boraginaceae Lithospermum erythrorhizon, is previously known to have anti-inflammatory, anti-tumor, and anti-pyretic properties. Several studies have shown that Shikonin induces p53-mediated cell cycle arrest and apoptosis in human malignant melanoma cells, and induces apoptosis in human myeloid leukemic HL60 cells. However, none of the studies have concerned in the effects of Shikonin on myeloma cells. In this study, we investigated the possibilities to develop Shikonin as a novel promising agent for multiple myeloma. Shikonin suppressed the cellular growth of RPMI8226 and IM9 myeloma cells, via induction of apoptosis in a dose (0–1 μM)- and time (0–24 h)-dependent manner. Apoptotic cell death was induced in both RPMI8226 and IM9 cells within 3 h for treatment with only 0.5 μM of Shikonin, and finally 78% of RPMI8226 cells and 91% of IM9 cells were dead by apoptosis within18 h. Treatment with 0.5 μM Shikonin rapidly increased the population of cells in the G0/G1 phase with reduction of cells in the S phase, and then induction of apoptosis was confirmed by the appearance of cells in the sub-G1 fraction. Shikonin-induced apoptosis was in association with the loss of mitochondrial transmembrane potentials, and activation of caspase-3. Shikonin-induced apoptosis was completely blocked by the treatment with pan-caspase inhibitor (20 μM, Z-VAD), suggesting that caspase plays an important role in Shikonin-induced cell death in myeloma cells. Expression of p53 and Bax proteins was increased with down-regulation of Mcl-1 protein, but no changes were confirmed of the expression of Bcl-2 and Bcl-XL. Recent investigations have shown that cytokines such as IL-6, insulin growth factor (IGF), VEGF, and TNF-α mediate myeloma cell growth, survival and migration. IGF-1 increases survival of myeloma cells by activating various down-stream signal transduction molecules. Recently, inhibitors of IGF-1 receptor demonstrate promising anti-multiple myeloma activity in preclinical studies. Shikonin has reported to be an inhibitor of protein tyrosine kinase such as EGFR, v-Src, and KDR/Flk-1. To address the mechanism of Shikonin-induced apoptosis in myeloma cells, we thus examined the effects of Shikonin on the phosphorylation of IGF-1 receptor. IGF-1 (100 ng/ml) stimulated the proliferation of both RPMI8226 and IM9 cells. Interestingly, Shikonin (0.5 μM) overcame IGF-1-induced cell proliferation, and inhibited proliferation of myeloma cells via induction of apoptosis. Shikonin inhibited phosphorylation of IGF-1 receptor as early as 30 min with inhibition of PI3K/Akt signaling. These results suggest that Shikonin-induced apoptosis in myeloma cells was mediated by inhibiting phosphorylation of IGF-1 receptor and modulating its down-stream signaling pathway. In conclusion, Shikonin inhibited cellular growth by inhibiting IGF-1 receptor signaling in myeloma cells, and may have a potential as a novel biologically based therapeutic agent for the patients with multiple myeloma..

Poly-L-arginine: Enhancing Cytotoxicity and Cellular Uptake of Doxorubicin and Necrotic Cell Death

2019 ◽  
Vol 18 (10) ◽  
pp. 1448-1456 ◽  
Author(s):  
Bahareh Movafegh ◽  
Razieh Jalal ◽  
Zobeideh Mohammadi ◽  
Seyyede A. Aldaghi
Keyword(s):  
Cell Death ◽  
Cellular Uptake ◽  
Combined Treatment ◽  
Annexin V ◽  
Cell Penetrating Peptides ◽  
Short Exposure ◽  
Dependent Manner ◽  
Du145 Cells ◽  
Induced Apoptosis ◽  
Resistance To Doxorubicin

Objective: Cell resistance to doxorubicin and its toxicity to healthy tissue reduce its efficiency. The use of cell-penetrating peptides as drug delivery system along with doxorubicin is a strategy to reduce its side effects. In this study, the influence of poly-L-arginine on doxorubicin cytotoxicity, its cellular uptake and doxorubicin-induced apoptosis on human prostate cancer DU145 cells are assessed. Methods: The cytotoxicity of doxorubicin and poly-L-arginine, alone and in combination, in DU145 cells was evaluated at different exposure times using MTT assay. The influence of poly-L-arginine on doxorubicin delivery into cells was evaluated by fluorescence microscopy and ultraviolet spectroscopy. DAPI and ethidium bromide- acridine orange stainings, flow cytometry using annexin V/propidium iodide, western blot analysis with anti-p21 antibody and caspase-3 activity were used to examine the influence of poly-L-arginine on doxorubicininduced cell death. Results: Poly-L-arginine had no cytotoxicity at low concentrations and short exposure times. Poly-L-arginine increased the cytotoxic effect of doxorubicin in DU145 cells in a time-dependent manner. But no significant reduction was found in HFF cell viability. Poly-L-arginine seems to facilitate doxorubicin uptake and increase its intracellular concentration. 24h combined treatment of cells with doxorubicin (0.5 µM) and poly-L-arginine (1 µg ml-1) caused a small increase in doxorubicin-induced apoptosis and significantly elevated necrosis in DU145 cells as compared to each agent alone. Conclusion: Our results indicate that poly-L-arginine at lowest and highest concentrations act as proliferationinducing and antiproliferative agents, respectively. Between these concentrations, poly-L-arginine increases the cellular uptake of doxorubicin and its cytotoxicity through induction of necrosis.

scholarly journals Growth-factor-dependent phosphorylation of Bim in mitosis

2005 ◽  
Vol 388 (1) ◽  
pp. 185-194 ◽  
Author(s):  
Mário GRÃOS ◽  
Alexandra D. ALMEIDA ◽  
Sukalyan CHATTERJEE
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Growth Factor ◽  
Cell Fate ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Post Translational Modification ◽  
Proliferating Cells ◽  
Growth Factor Signalling ◽  
Induced Apoptosis

The regulation of survival and cell death is a key determinant of cell fate. Recent evidence shows that survival and death machineries are regulated along the cell cycle. In the present paper, we show that BimEL [a BH3 (Bcl-2 homology 3)-only member of the Bcl-2 family of proteins; Bim is Bcl-2-interacting mediator of cell death; EL is the extra-long form] is phosphorylated in mitosis. This post-translational modification is dependent on MEK (mitogen-activated protein kinase/extracellular-signal-regulated kinase kinase) and growth factor signalling. Interestingly, FGF (fibroblast growth factor) signalling seems to play an essential role in this process, since, in the presence of serum, inhibition of FGF receptors abrogated phosphorylation of Bim in mitosis. Moreover, we have shown bFGF (basic FGF) to be sufficient to induce phosphorylation of Bim in serum-free conditions in any phase of the cell cycle, and also to significantly rescue cells from serum-deprivation-induced apoptosis. Our results show that, in mitosis, Bim is phosphorylated downstream of growth factor signalling in a MEK-dependent manner, with FGF signalling playing an important role. We suggest that phosphorylation of Bim is a decisive step for the survival of proliferating cells.

Fas/APO-1 (CD95)–Mediated Apoptosis Is Activated by Interferon-γ and Interferon- in Interleukin-6 (IL-6)–Dependent and IL-6–Independent Multiple Myeloma Cell Lines

Blood ◽  
1998 ◽  
Vol 92 (8) ◽  
pp. 2914-2923 ◽  
Author(s):  
Helena Spets ◽  
Patrik Georgii-Hemming ◽  
Jan Siljason ◽  
Kenneth Nilsson ◽  
Helena Jernberg-Wiklund
Keyword(s):  
Multiple Myeloma ◽  
Cell Lines ◽  
Poor Response ◽  
Antigen Expression ◽  
Myeloma Cell ◽  
Interferon Γ ◽  
Dependent Manner ◽  
Multiple Myeloma Cell ◽  
Ifn Γ ◽  
Induced Apoptosis

Abstract A poor response to Fas-induced apoptosis is evident in some multiple myeloma (MM) cell lines and primary cells. In this study, we have examined the possibility to increase the sensitivity to Fas-induced apoptosis by pretreatment of MM cells with interferon-γ (IFN-γ) or interferon- (IFN-). Both IFN-γ and IFN- markedly increased the Fas-induced apoptosis in all cell lines tested (U-266-1970, U-266-1984, and U-1958). In the U-266-1970 and U-1958 cell lines, pretreatment with either IFN-γ or IFN- also inhibited proliferation in a dose-dependent manner. In contrast, IFN-γ activation of the Fas death pathway in the U-266-1984 cells was not accompanied by growth inhibition. Incubation with the IFNs increased the Fas antigen expression in one of three cell lines but did not alter the expression of Bcl-2 or Bax. The IFNs are important regulators of growth and survival in MM cells. Our results suggest that activation of Fas-mediated apoptosis is a novel mechanism by which the IFNs exert inhibitory effects on MM cells. © 1998 by The American Society of Hematology.

scholarly journals Alantolactone inhibits cell autophagy and promotes apoptosis via AP2M1 in acute lymphoblastic leukemia

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Ce Shi ◽  
Wenjia Lan ◽  
Zhenkun Wang ◽  
Dongguang Yang ◽  
Jia Wei ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Tumor Growth ◽  
Cell Lines ◽  
Lymphoblastic Leukemia ◽  
Dependent Manner ◽  
Nude Mouse Model ◽  
Hematopoietic Malignancy ◽  
Induced Apoptosis ◽  
Anti Tumor Activity

Abstract Background Acute lymphoblastic leukemia (ALL) is an aggressive hematopoietic malignancy that is most commonly observed in children. Alantolactone (ALT) has been reported to exhibit anti-tumor activity in different types of cancer. The aim of the present study was to investigate the anti-tumor activity and molecular mechanism of ALT in ALL. Methods ALL cell lines were treated with 1, 5 and 10 μM ALT, and cell viability was assessed using an MTT assay and RNA sequencing. Flow cytometry, JC-1 staining and immunofluorescence staining assays were used to measure cell apoptosis and autophagy. Additionally, western blot analysis was used to detect expression of apoptosis and autophagy related proteins. Finally, the effects of ALT on tumor growth were assessed in a BV173 xenograft nude mouse model. Results ALT inhibited the proliferation of ALL cells in a dose-dependent manner. Additionally, it was demonstrated that ALT inhibited cell proliferation, colony formation, autophagy, induced apoptosis and reduced tumor growth in vivo through upregulating the expression of adaptor related protein complex 2 subunit mu 1 (AP2M1). Moreover, the autophagy activator rapamycin, attenuated the pro-apoptotic effects of ALT on BV173 and NALM6 cell lines. Overexpression of AP2M1 decreased the expression of Beclin1 and the LC3-II/LC3-1 ratio, and increased p62 expression. Knockdown of Beclin1 increased the levels of bax, cleaved caspase 3 and cytochrome C, and decreased bcl-2 expression. Conclusions The present study demonstrated that ALT exerts anti-tumor activity through inducing apoptosis and inhibiting autophagy by upregulating AP2M1 in ALL, highlighting a potential therapeutic strategy for treatment of ALL.

scholarly journals Role of microRNAs in Diagnosis, Prognosis and Management of Multiple Myeloma

2020 ◽  
Vol 21 (20) ◽  
pp. 7539
Author(s):  
Amro M. Soliman ◽  
Teoh Seong Lin ◽  
Pasuk Mahakkanukrauh ◽  
Srijit Das
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Tumor Growth ◽  
Malignant Transformation ◽  
Bone Disease ◽  
Clinical Management ◽  
Potential Role ◽  
Plasma Cells ◽  
The Usa

Multiple myeloma (MM) is a cancerous bone disease characterized by malignant transformation of plasma cells in the bone marrow. MM is considered to be the second most common blood malignancy, with 20,000 new cases reported every year in the USA. Extensive research is currently enduring to validate diagnostic and therapeutic means to manage MM. microRNAs (miRNAs) were shown to be dysregulated in MM cases and to have a potential role in either progression or suppression of MM. Therefore, researchers investigated miRNAs levels in MM plasma cells and created tools to test their impact on tumor growth. In the present review, we discuss the most recently discovered miRNAs and their regulation in MM. Furthermore, we emphasized utilizing miRNAs as potential targets in the diagnosis, prognosis and treatment of MM, which can be useful for future clinical management.

scholarly journals DMPK is a New Candidate Mediator of Tumor Suppressor p53-Dependent Cell Death

Molecules ◽  
2019 ◽  
Vol 24 (17) ◽  
pp. 3175
Author(s):  
Katsuhiko Itoh ◽  
Takahiro Ebata ◽  
Hiroaki Hirata ◽  
Takeru Torii ◽  
Wataru Sugimoto ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Tumor Suppressor ◽  
Dependent Manner ◽  
Tumor Suppressor P53 ◽  
P53 Family ◽  
Gene Encoding ◽  
Myotonic Dystrophy Protein Kinase ◽  
Induced Apoptosis ◽  
Actomyosin Contraction

Tumor suppressor p53 plays an integral role in DNA-damage induced apoptosis, a biological process that protects against tumor progression. Cell shape dramatically changes when cells undergo apoptosis, which is associated with actomyosin contraction; however, it remains entirely elusive how p53 regulates actomyosin contraction in response to DNA-damaging agents. To identify a novel p53 regulating gene encoding the modulator of myosin, we conducted DNA microarray analysis. We found that, in response to DNA-damaging agent doxorubicin, expression of myotonic dystrophy protein kinase (DMPK), which is known to upregulate actomyosin contraction, was increased in a p53-dependent manner. The promoter region of DMPK gene contained potential p53-binding sequences and its promoter activity was increased by overexpression of the p53 family protein p73, but, unexpectedly, not of p53. Furthermore, we found that doxorubicin treatment induced p73 expression, which was significantly attenuated by downregulation of p53. These data suggest that p53 induces expression of DMPK through upregulating p73 expression. Overexpression of DMPK promotes contraction of the actomyosin cortex, which leads to formation of membrane blebs, loss of cell adhesion, and concomitant caspase activation. Taken together, our results suggest the existence of p53-p73-DMPK axis which mediates DNA-damage induced actomyosin contraction at the cortex and concomitant cell death.

Azacytidine Suppressors Autocrine IL-6 Secretion and Demonstrates In Vitro and In Vivo Activity Against Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1566-1566
Author(s):  
Tiffany Khong ◽  
Janelle Sharkey ◽  
Andrew Spencer
Keyword(s):  
Multiple Myeloma ◽  
Murine Model ◽  
Dna Methyltransferase ◽  
Myeloma Cell ◽  
Apoptotic Pathway ◽  
P16 Gene ◽  
Induced Apoptosis ◽  
The Impact

Abstract Azacytidine (AZA), a DNA methyltransferase inhibitor, has been shown to inhibit cell growth and induce apoptosis in some cancer cells. We determined the impact of AZA on a panel of human myeloma cell lines (HMCL); KMS 12PE, KMS 18, LP-1, NCI-H929, OPM-2, RPMI-8226 and U266 and in an in vivo murine model of multiple myeloma (5T33 model). Dose responsiveness to AZA was determined via MTS assays with a range of AZA doses (1–10mM) for 72 hours. FACS and cell cycle analysis were used to evaluate the profile of the cells after exposure to AZA for 72 hours. MTS assays demonstrated a dose and time dependent AZA-induced inhibition of HMCL viability with effective concentrations of AZA ranging from 1–10 mM. This was associated with accumulation of cells in the Go/G1 phase with decreasing number of cells in the S and G2/M phases. Western Blot analysis using antibodies against caspases 3,8,10, PARP, phospho-ERK, ERK, Stat3 and phospho -Stat3 were performed to help characterize the mechanism(s) of cell killing. Cleavage of caspases 3,8,10 and PARP within 24 hours of AZA treatment confirmed early AZA-induced HMCL apoptosis. phospho-ERK which was absent in untreated U266 appeared after 48 hours exposure to 5mM AZA. Similarly inhibitors of caspases 3,8 and 9 were used to determine which apoptotic pathway was being preferentially activated by AZA. Inhibitors of both caspase 3 and 9 effectively abrogated AZA-induced apoptosis in U266 and NCI-H929. In contrast caspase 8 inhibitor was less effective which is consistent with AZA acting via the mitochondrial apoptotic pathway. Reactivation of p16 gene by AZA-induced hypomethylation was assessed with methylation specific PCR. MSP-PCR of the p16 gene indicated a loss of methylation and up-regulated transcription after 48 hours treatment with 5 mM AZA. The level of IL-6 in conditioned media from U266 cells treated with AZA was determined by ELISA assay and demonstrated a rapid fall in autocrine IL-6 production. RT-PCR demonstrated rapid AZA-induced cessation of IL-6 transcription temporarily associated with the disappearance of upstream phospho -Stat3. Addition of exogenous IL-6 did not rescue U266 from AZA-induced apoptosis. AZA was also administered to a 5T33 murine model of multiple myeloma at increasing concentrations (1, 3, 10 mg/kg). At 10 mg/kg the median survival of vehicle versus AZA treated mice was 28 days versus 30+ days (p=0.003). These findings justify further evaluation of AZA as a potential therapeutic agent for multiple myeloma.

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