Targeting HMG-CoA Reductase in Acute Lymphoblastic Leukemia (ALL): Statins Inhibit Proliferation and Induce Apoptosis in ALL Cells

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2927-2927
Author(s):  
David Teachey ◽  
Cecilia Sheen ◽  
Alix Eden Seif ◽  
Valerie I. Brown ◽  
Stephan A. Grupp
Keyword(s):  
Signal Transduction ◽  
Acute Lymphoblastic Leukemia ◽  
Cell Lines ◽  
Lymphoblastic Leukemia ◽  
Cholesterol Biosynthesis ◽  
Large Population ◽  
Single Agent ◽  
Cytotoxic Agents ◽  
Hmg Coa Reductase ◽  
Coa Reductase

Abstract HMG-CoA reductase inhibitors (statins) are commonly used, FDA-approved agents for the treatment of hypercholesterolemia. In addition to reducing serum cholesterol, statins have been shown to have anti-inflammatory properties and anti-proliferative effects on a number of cell types, including lymphocytes. Many of these effects occur because inhibition of HMG-CoA reductase results in depletion of a number of important cellular intermediates required for signal transduction through the AKT, Ras, and Erk pathways. Statins have been demonstrated to have anti-proliferative effects in a number of malignancies, including acute myeloid leukemia using preclinical models; however, there are no published reports evaluating the efficacy of these agents against acute lymphoblastic leukemia. Large population studies have also suggested that statins may reduce the incidence of a number of cancers, furthering interest in the use of these agents in malignancies, especially since the dose-limiting toxicities (hepatitis and rhabdomyolysis) do not overlap with the majority of commonly used cytotoxic agents. We hypothesized that ALL cells are dependent on the function of HMG-CoA reductase for survival. We tested this hypothesis by studying the efficacy of statins against ALL cells. We studied the effects of 5 different compounds (mevastatin, pravastatin, fluvastatin, lovastatin, and simvastatin) against 7 ALL cell lines (4 human and 3 murine). We found that the more potent 2nd generation statins (fluvastatin, lovastatin, and simvastatin) had marked effects on ALL cells, whereas the less potent first generation statins (mevastatin and pravastatin) had less significant effects. We found that fluvastatin, lovastatin, and simvastatin inhibited proliferation of all 7 ALL cell lines using MTT assay (p <0.05). We also found these three statins induced apoptosis, leading to profound cell death in all 7 cell lines (p<0.05) as assessed by flow cytometry for Annenix-V staining and 7-AAD. IC50 dosing for the three agents ranged between 500nM and 5uM depending on the cell line, levels easily obtainable in humans. The most likely explanation for this remarkable, single-agent effect on ALL is that ALL cells are indeed dependent on cholesterol biosynthesis. Other potential explanations include the possibility that ALL cells are dependant on one of the signal transduction pathways affected by targeting HMG-CoA reductase, or the formal possibility of an off-target effect of statins separate from the inhibition of cholesterol biosynthesis. To determine if the effects of the statins were due to a direct effect on HMG-CoA reductase, we treated cells with melavonolactone, the product of conversion of HMG-CoA by HMGCoA reductase. We found that the addition of melavonolactone completely reversed the effects of all statins even at high doses (>10uM) in all cell lines, making the explanation of an off-target, non-HMG-CoA reductase-based mechanism unlikely. Ongoing work includes the testing of statins in NOD/SCID xenograft models of primary human ALL models, assessing the effects of statins on AKT, Ras, and Erk in ALL cells, and assessing the combination of statins with cytotoxic agents in ALL. In conclusion, we found that ALL cells are dependent of HMG-CoA reductase for survival. Since statins are safe and well-tolerated, this class of agents should be further explored in patients with ALL.

The Inhibition of Checkpoint Kinase 1 As a Promising Strategy to Increase the Effectiveness of Different Treatments in Acute Lymphoblastic Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2478-2478
Author(s):  
Andrea Ghelli Luserna Di Rora ◽  
Ilaria Iacobucci ◽  
Enrica Imbrogno ◽  
Enrico Derenzini ◽  
Anna Ferrari ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Acute Lymphoblastic Leukemia ◽  
Cell Viability ◽  
Cytotoxic Activity ◽  
Cell Lines ◽  
Propidium Iodide ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Dna Damages ◽  
Checkpoint Kinase

Abstract Nowadays the effectiveness of the treatments for adult Acute Lymphoblastic Leukemia (ALL) patients is still inadequate and frequently many patients after years of response to treatments develop relapses. Thus there is a need to find novel targets for specific therapies and to maximize the effect of the actual treatments. Recently different Checkpoint Kinase (Chk)1/Chk2 inhibitors has been assessed for the treatment of different type of cancers but only few studies have been performed on hematological diseases. We evaluated the effectiveness of the Chk1 inhibitor, LY2606368, as single agent and in combination with tyrosine kinase inhibitors (imatinib and dasatinib) or with the purine nucleoside antimetabolite clofarabine in B-/T- acute lymphoblastic leukemia (ALL) cell lines and in primary blasts. Human B (BV-173, SUPB-15, NALM-6, NALM-19 and REH) and T (MOLT-4, RPMI-8402 and CEM) ALL cell lines were incubated with increasing concentrations of drug (1-100 nM) for 24 and 48 hours and the reduction of the cell viability was evaluated using WST-1 reagent. LY2606368 deeply reduced the cell viability in a dose and time dependent manner in all the cell lines, with the BV-173 (6.33 nM IC50 24hrs) and RPMI-8402 (8.07 nM IC50 24hrs) being the most sensitive while SUP-B15 (61.4 nM IC50 24hrs) and REH (96.7 nM IC50 24hrs) being the less sensitive cell lines. Moreover the sensitivity to the compound was no correlated with the different sub-type of ALL or with the mutational status of p53, which is a marker of the functionality of the G1/S checkpoint. The cytotoxic activity was confirmed by the significant increment of apoptosis cells (Annexin V/Propidium Iodide), by the increment of gH2AX foci and by the activation of different apoptotic markers (Parp-1 and pro-Caspase3 cleavage). To understand the relationship between the activation of apoptosis and the effect on cell cycle and to identify hypothetical mechanisms of death, different cell cycle analyses were performed (Propidium Iodide staining). The inhibition of Chk1, deeply changed the cell cycle profile. Indeed in all the cell lines the percentage of cells in S phase and in G2/M phase were reduced by the treatment while the numbers of cells in sub-G1 and G1 phase were increased. The hypothetical function of LY2606368 as a chemosensitizer agent was evaluated combining the compound with different drugs normally used in clinical trials. For each drugs the combination strongly reduced the cell viability when compared to the cytotoxic effect of the single drugs. Moreover the combination showed an additive efficacy in term of induction of DNA damages as showed by the increase number of gH2AX foci and the activation of pChk1 (ser 317). The results found on the cell lines were confirmed also using primary leukemic blast isolated from adult Philadelphia-positive ALL patients. Indeed LY2606368 as single agent or in combination with the Tki, imatinib, was able to deeply reduce the cell viability and to induce DNA damages (gH2AX foci). In conclusion LY2606368 showed a strong cytotoxic activity on B-/T-All cell lines and primary blasts as single agent and in combination with other drugs. In our opinion this data are the basis for a future clinical evaluation of this compound in the treatment of leukemia. Supported by ELN, AIL, AIRC, progetto Regione-Università 2010-12 (L. Bolondi), FP7 NGS-PTL project. Disclosures Soverini: Novartis, Briston-Myers Squibb, ARIAD: Consultancy. Cavo:JANSSEN, CELGENE, AMGEN: Consultancy. Martinelli:ROCHE: Consultancy; Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy; Ariad: Consultancy; AMGEN: Consultancy; MSD: Consultancy.

AMN107, Novel Aminopyrimidine Inhibitor of Bcr-Abl, Is Significantly More Potent Than Imatinib Mesylate Against Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2737-2737
Author(s):  
Mirna Golemovic ◽  
Miloslav Beran ◽  
Francis Giles ◽  
Taghi Manshouri ◽  
Deborah Thomas ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Cell Line ◽  
Imatinib Mesylate ◽  
Cell Lines ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Philadelphia Chromosome ◽  
Imatinib Treatment ◽  
Significant Activity ◽  
Mts Assay

Abstract Imatinib mesylate is effective against Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) but, when used as a single agent, responses are transient and most patients relapse within 4–6 months. AMN107 is a novel oral aminopyrimidine ATP-competitive inhibitor of the protein tyrosine kinase activity of Bcr-Abl. Following oral administration to animals, AMN107 is well absorbed, has a good pharmacokinetic profile, and is well tolerated. The activity of AMN107, relative to imatinib, in both Ph-positive (Z-119 and Z-181) and Ph-negative (Z-138) ALL cell lines was studied. Z-119 and Z-181 cells were derived from Ph-positive ALL patients and retained typical B-cell characteristics and phenotypes of the original leukemia, including cytogenetic abnormality t(9;22) and p190 Bcr/Abl kinase. Z-138, a Ph-negative cell line, was derived from a patient with chronic lymphocytic leukemia and supervening ALL. Treatment with AMN107 or imatinib for 3 days (MTS assay) inhibited proliferation of Z-119 cells with the IC50 values of 19.3 nM and 620.0 nM, respectively, revealing AMN107 to be 32 fold more potent than imatinib. Treatment of Z-181 cell line lasted for 4 days (MTS assay) because of lower growth rate of these cells: IC50 for AMN107 and imatinib were 1.6 nM and 63.9 nM, respectively, showing AMN107 to be 40 fold more potent than imatinib. Neither drug showed activity against Ph-negative Z-138 cells. We also compared the activity of AMN107 in Ph-positive ALL cell lines expressing p190 Bcr/Abl protein to that in Ph-positive chronic myeloid leukemia cell lines KBM5 and KBM7 expressing p210 Bcr/Abl protein. The activity was similar with IC50 in KBM5 cells of 11.3 nM and in KBM7 cells of 4.3 nM. In experiments focused on cell cycle analysis we found that at equipotent doses (as determined by MTS assay) both drugs induced cell accumulation in G0/G1 phase in Z-119 but not in Z-181. We demonstrated that increasing equipotent concentrations of AMN107 and imatinib induced activation of caspase-3 that resulted in apoptosis, as assessed by propidium iodide staining, in Z-119 cells, while Z-181 cells showed lack of apoptotic response. Following treatment with a broad range of AMN107 and imatinib doses for 3 hrs, Bcr/Abl expression and phosphorylation were determined in Z-119 cells by immunoprecipitation and Western blotting: Bcr/Abl phosphorylation was inhibited completely with AMN107 at 125.0 nM, and with imatinib at 2500 nM, confirming again the higher potency of AMN107. Finally, similar differential effect of AMN107 and imatinib on Bcr/Abl protein expression and phosphorylation was observed in leukemic cells obtained from blood of Ph-positive ALL patients. We conclude that AMN107 has significant activity against Ph-positive ALL cells and warrants investigation in patients with Ph-positive ALL.

scholarly journals Rational drug combinations with CDK4/6 inhibitors in acute lymphoblastic Leukemia

Haematologica ◽  
2021 ◽  
Author(s):  
Karen L. Bride ◽  
Hai Hu ◽  
Anastasia Tikhonova ◽  
Tori J. Fuller ◽  
Tiffaney L. Vincent ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Rational Design ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Transcriptome Profiling ◽  
Cytotoxic Agents ◽  
Cyclin D3 ◽  
Conventional Chemotherapy ◽  
Relapsed Disease

Despite improvements in outcomes for children with B and T-cell acute lymphoblastic leukemia (B-ALL and T-ALL), patients with resistant or relapsed disease fare poorly. Previous studies have demonstrated the essential role of cyclin D3 in T-ALL disease initiation and progression and that targeting of the CDK4/6-cyclin D complex can suppress T-ALL proliferation, leading to efficient cell death in animal models. Studies in leukemia and other malignancies, suggest that schedule is important when combining CDK4/6 inhibitors (CDKis) with cytotoxic agents. Based on these observations, we broadened evaluation of two CDKis, palbociclib (PD-0332991, Pfizer) and ribociclib (LEE011, Novartis) in B and T-ALL as single agent and in combination with conventional cytotoxic chemotherapy, using different schedules in preclinical models. As monotherapy, CDKis caused cell cycle arrest with a significant decrease in S phase entry and were active in vivo across a broad number of patient-derived xenograft samples. Prolonged monotherapy induces resistance, for which we identified a potential novel mechanism using transcriptome profiling. Importantly, simultaneous but not sequential treatment of CDKis with conventional chemotherapy (dexamethasone, L-asparaginase and vincristine) led to improved efficacy compared to monotherapy in vivo. We provide novel evidence that combining CDKis and conventional chemotherapy can be safe and effective. These results led to the rational design of a clinical trial.

scholarly journals BCL-2 dependence and ABT-737 sensitivity in acute lymphoblastic leukemia

Blood ◽  
2008 ◽  
Vol 111 (4) ◽  
pp. 2300-2309 ◽  
Author(s):  
Victoria Del Gaizo Moore ◽  
Krysta D. Schlis ◽  
Stephen E. Sallan ◽  
Scott A. Armstrong ◽  
Anthony Letai
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Cancer Cells ◽  
Cell Lines ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Primary Cells ◽  
Intrinsic Apoptotic Pathway ◽  
Combination Therapies ◽  
Apoptotic Pathway ◽  
Oncogene Activation

Cancer cells acquire disruptions in normal signal transduction pathways and homeostatic mechanisms that would trigger apoptosis in normal cells. These abnormalities include genomic instability, oncogene activation, and growth factor independent proliferation. Therefore, cancer cells likely require a block in apoptosis in order to survive. Overexpression of the antiapoptotic protein BCL-2 provides a block in apoptosis that is frequently observed in cancer cells. We have developed methods for the detection and analysis of BCL-2 dependence and here apply them to acute lymphoblastic leukemia (ALL). BH3 profiling, a mitochondrial assay that classifies blocks in the intrinsic apoptotic pathway, indicated a dependence on BCL-2 of both ALL cell lines and primary samples. This dependence predicted that BCL-2 would be complexed with select pro-death BH3 family proteins, a prediction confirmed by the isolation of BCL-2 complexes with BIM. Furthermore, the BH3 profiling and protein analysis predicted that ALL cell lines and primary cells would be sensitive to ABT-737 as a single agent. Finally, BH3 profiling and protein studies accurately predicted a relative degree of sensitivity to BCL-2 antagonism in cell lines. The ALL cells studied exhibit BCL-2 dependence, supporting clinical trials of BCL-2 antagonists in ALL as single agents or combination therapies.

Cyclic-AMP Responsive Element Binding Protein 1 (CREB) As a New Potential Druggable Target in Pediatric Acute Lymphoblastic Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1368-1368
Author(s):  
Naomi E van der Sligte ◽  
Arja ter Elst ◽  
Kim R Kampen ◽  
Frank JG Scherpen ◽  
Hendrik Mulder ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Acute Lymphoblastic Leukemia ◽  
Cell Viability ◽  
Signaling Pathways ◽  
Cell Lines ◽  
Lymphoblastic Leukemia ◽  
Human Proteome ◽  
Time Dependent ◽  
Phosphorylated Protein ◽  
Phosphorylated Proteins

Abstract Abstract 1368 New treatment options are necessary to improve survival rates for patients with Acute Lymphoblastic Leukemia (ALL), especially for patients with unfavorable prognostic predictors. As a new therapeutic approach specific protein kinase inhibitors are being developed that can down-regulate vital signaling pathways in leukemic blasts (McCubrey et al, 2008). The main goal of the present study is to obtain a better understanding of the kinase signaling pathways active in ALL cells and to identify potential targets for therapeutic intervention, To identify active signaling pathways in ALL we have used kinase activity arrays containing 1024 peptides representing all major signaling pathways and human proteome profiler arrays containing 46 phospho-antibodies on lysates of primary ALL blasts. In 20 patient samples a total of 10.6% 109(1024) peptides were found to be phosphorylated in 90% of the samples. About 46% 50(109). Activities for kinases including PKC, PKA, Akt, CAMK2, CDC2, CDK2, ERK, GSK3beta, JAK and MAPK were detected in these lysates. The human proteome profiler array demonstrated high levels of protein phosphorylation of CREB and RSK. We constructed a provisional signal transduction scheme of active kinases and phosphorylated proteins in ALL cells (Fig. 1A). Consistent with earlier reports, we identified a prominent role for the Raf/MEK/ERK and the PI3K/Akt/mTOR pathways in these ALL cells. Based on this provisional signal transduction scheme we composed a list of possible new druggable targets. Two proteins were selected for further investigation, CREB and RSK. Inhibition of RSK by the p90 RSK inhibitor BI-D1870 had no effect on cell viability as measured with WST-1 cell viability assay in ALL cell lines. Interestingly, inhibition of CREB by the CREB inhibitor KG-501 showed a dose- and time-dependent decrease in cell viability in all cell lines tested (LC50 values after 24h: Jurkat: 18.55 mM, Molt 4: 13.02 mM, RCH-ACV: 38.11 mM, and RS4;11 45.36 mM (Fig. 1B). LC50 values after 48h: Jurkat: 7.36 mM, Molt 4: 6.53 mM, RCH-ACV: 31.73 mM, RS4;11 36.66 mM (Fig. 1C)). In addition, apoptosis measured by AnnexinV/ PI staining showed an increased percentage of apoptotic cells in a dose- and time-dependent manner in all cell lines upon treatment with the CREB inhibitor (apoptosis after 24h: Jurkat 35.83% to 79.7%, Molt 4: 12.19% to 48.5%), RCH-ACV 11.30% to 45.9%, and RS4;11 9.84% to 19.16. Apoptosis after 48h: Jurkat 53.40% to 86.4%, Molt 4: 27.70% to 92.9%, RCH-ACV 14.07% to 63.32%, and RS4;11 7.11% to 20.75%) (Fig. 1D). To investigate the downstream effect of CREB inhibition we measured the mRNA expression of a know CREB target gene: BCL-2. Upon inhibition of CREB (50 mM KG-501) mRNA levels of BCL-2 were found to be significantly decreased compared to vehicle treated cells. In conclusion we have identified the transcription factor CREB in vitro as a potential druggable target for ALL. It is known that CREB plays an important role as a downstream target of hematopoietic growth factor signaling in hematopoiesis (Cheng et al, 2008). Based on these results, we propose CREB as a promising potential druggable target in ALL. Figure 1. (A) Provisional signal transduction scheme of active kinases and phosphorylated proteins in ALL. Green: active kinase; Yellow: phosphorylated protein; Green-Yellow: active kinase and phosphorylated protein. (B) Cell viability percentages plotted against concentration of KG-501 (mM) after 24h. (C) Cell viability percentages plotted against concentration of KG-501 (mM) after 48h. (D) Representative flow cytometric dot-plots of AnnexinV/ PI flow cytometry, inhibition of CREB induced a dose- and time-dependent apoptosis in the Molt 4 cell line. Disclosures: No relevant conflicts of interest to declare.

Gamma-Tocotrienol and Simvastatin Synergistically Induce Cytotoxicity In Leukemia Cell Lines, K-562 and HL-60

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4927-4927 ◽  
Author(s):  
Ko Maung ◽  
Victoria Palau ◽  
Janet Lightner ◽  
Marianne Brannon ◽  
Koyamangalath Krishnan
Keyword(s):  
Cell Lines ◽  
Fetal Bovine Serum ◽  
Cholesterol Biosynthesis ◽  
Leukemia Cell ◽  
Leukemia Cells ◽  
Hmg Coa Reductase ◽  
Leukemia Cell Lines ◽  
Fetal Bovine ◽  
Coa Reductase ◽  
Gamma Tocotrienol

Abstract Introduction Statins and tocotrienols modulate the cholesterol biosynthesis pathway by inhibiting the 3-hydroxy-3- methylglutaryl coenzyme A (HMG-CoA) reductase. Tocotrienols modulate HMG-CoA reductase by post-transcriptional downregulation. In addition, tocotrienols contain a farnesol moiety in its side-chain that triggers degradation of HMG-CoA reductase. These effects lead to suppression of cell proliferation, cell cycle arrest, and apoptosis. Several studies have shown that statins have suppressive effects in in vitro experiments on acute myelocytic leukemia cell lines. Since both statins and gamma-tocotrienol are associated with decreased cholesterol biosynthesis, we hypothesized that if the cytotoxicity of these drugs on cancer cells is related to impaired biosynthesis of cholesterol, combination of them could synergize in cytotoxicity on leukemic cells. Materials and Methods K-562 and HL-60 leukemia cells were grown in Iscove's Modified Dulbecco's medium with penicillin/streptomycin, 10% fetal bovine serum and 20% fetal bovine serum added respectively. K-562 and HL-60 leukemia cells were seeded in 96 well plates, grown overnight, and treated for 24, 48 and 72 hours with simvastatin in concentrations of 1,2,4, and5 µM; gamma-tocotrienol in concentrations of 20, 40, and 80 µM; and a combination of the two drugs in the same concentrations. For 24 hour dose, cells were seeded at a density of 5000/well and for 48 and 72 hour doses, at  3500/well. Following the treatment, MTS/PMS reagent (Promega, Madison, WI), [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt] mixed with and an electron coupling reagent (phenazine methosulfate), was added at 40 µg/well and incubated at 37°C for 2 hours. We measured the solubilized formazan crystals at 450 nm as an indicator of cytotoxicity. The presence of ATP  as an indicator of cell viability was measured with the CellTiter Glo®  assay (Promega). Cells were again seeded, grown overnight, and dosed as indicated above.  Following treatment, the assay was conducted as specified by the manufacturer. Results Both simvastatin and gamma-tocotrienol induce cytotoxicity in K-562 and HL-60 cell lines by the MTS and Cell Titer Glo Assays.  The IC50 at 72 hour incubation are as follows 1) HL-60: simvastatin - 16.543 uM, gamma tocotrienol - 36.297 uM;  2) K-562: simvastatin - 5.235 uM, gamma tocotrienol - 34.947 uM.  We used CompuSyn to calculate the IC50.  When combined, simvastatin and gamma-tocotrienol exhibit synergy at lower concentrations when examined by isobologram analysis. Conclusion Gamma-tocotrienol, an isoform of vitamin E, and simvastatin, a cholesterol lowering drug exhibit synergy in induction of cytotoxicity in K-562 and HL-60 leukemia cell lines. Rescue experiments and mechanistic pathway analysis are being explored to confirm these observations. Disclosures: No relevant conflicts of interest to declare.

Monoclonal Antibody-Based Therapies in the Treatment of Acute Lymphoblastic Leukemia

2013 ◽  
pp. 294-299 ◽  
Author(s):  
Mark R. Litzow
Keyword(s):  
Monoclonal Antibody ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Response Rates ◽  
Cytotoxic Agents ◽  
Single Chain ◽  
Stages Of Development

Recent studies have suggested that pediatric-intensive chemotherapy regimens can improve outcomes in adults with acute lymphoblastic leukemia (ALL) up to the age of 45. Above this age, toxicities increase. Monoclonal antibody-based therapies bring the promise of increased response rates without excessive toxicity. The addition of rituximab to combination chemotherapy has shown encouraging results. Newer monoclonal antibody-based therapies linked to cytotoxic agents show promise. These include inotuzumab ozogamicin, an anti-CD22 antibody linked to calicheamicin that has produced significant single-agent responses in relapsed and refractory ALL. Other monoclonal antibodies linked to plant or bacterial toxins are in earlier stages of development. Blinatumomab is a novel bispecific T-cell engaging antibody that combines single chain antibodies to CD19 and CD3 and brings a T cell in close proximity to a leukemic lymphoblast with resulting redirected lysis. This agent has demonstrated encouraging results in both the minimal residual disease setting and the relapsed/refractory setting. Autologous chimeric antigen receptor cells have shown promising responses in indolent B-cell lymphoid malignancies and are being tested in ALL. Many of these agents have the potential to increase response rates in older adults. Trials of many of these monoclonal antibody-based therapies are in various stages of development in the treatment of newly diagnosed ALL.

Restraining the Proliferation of Acute Lymphoblastic Leukemia Cells by Genistein through Up-regulation of B-cell Translocation Gene-3 at Transcription Level

2019 ◽  
Vol 8 ◽  
Author(s):  
Masoumeh Abedi Nejad ◽  
Mohsen Nikbakht ◽  
Masoomeh Afsa ◽  
Kianoosh Malekzadeh
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Cancer Cells ◽  
Cell Lines ◽  
Lymphoblastic Leukemia ◽  
Suppressor Gene ◽  
Transcription Level ◽  
Hematopoietic Malignancy ◽  
Proliferative Effect ◽  
Cancer Agent

Background: Acute lymphoblastic leukemia (ALL) is a highly prevalent pediatric cancer accounting for approximately 78% of leukemia cases in patients younger than 15 years old. Different studies have demonstrated that B-cell translocation gene 3 (BTG3) plays a suppressive role in the progress of different cancers. Genistein is considered a natural and biocompatible compound and a new anti-cancer agent. In this study, we evaluate the effect of genistein on BTG3 expression and proliferation of ALL cancer cells. Materials and Methods: ALL cell lines (MOLT4, MOLT17, and JURKAT) were cultured in standard conditions. Cytotoxicity of genistein was detected using MTT assay. The cells were treated with different concentrations of genistein (10, 25, 40, and 55μM) for 24, 48, and 72 hours, and then cell viability and growth rate were measured. The quantitative real-time polymerase chain reaction was applied to investigate the effect of genistein on BTG3 expression. Results: The percentage of vital cells treated with genistein significantly decreased compared to the non-treated cells, showed an inverse relationship with an increasing genistein concentration. The present study suggests a dose of 40μM for genistein as a potent anticancer effect. Genistein could elevate BTG3 for 1.7 folds in MOLT4 and JURKAT and 2.7 folds in MOLT17 cell lines at transcription level conveged with 60 to 90% reduction in the proliferation rate of cancer cells. Conclusion: Up-regulation of BTG3 as a tumor suppressor gene can be induced by genistein. It seems that BTG3 reactivation can be introduced as another mechanism of anti-proliferative effect of genistein and could be considered as a retardant agent candidate against hematopoietic malignancy.[GMJ. 2019;inpress:e1229]

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