scholarly journals Evaluating the efficacy of multiple myeloma cell lines as models for patient tumors via transcriptomic correlation analysis

2019 ◽  
Author(s):  
Vishesh Sarin ◽  
Katharine Yu ◽  
Ian D. Ferguson ◽  
Olivia Gugliemini ◽  
Matthew A. Nix ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Correlation Analysis ◽  
Cell Lines ◽  
Large Scale ◽  
Myeloma Cell ◽  
Multiple Myeloma Cell ◽  
Quantitative Correlation ◽  
Immunocompromised Mice ◽  
Rpmi 8226 ◽  
Biological Differences

AbstractMultiple myeloma (MM) cell lines are routinely used to model the disease. However, a long-standing question is how well these cell lines truly represent tumor cells in patients. Here, we employ a recently-described method of transcriptional correlation profiling to compare similarity of 66 MM cell lines to 779 newly-diagnosed MM patient tumors. We found that individual MM lines differ significantly with respect to patient tumor representation, with median R ranging from 0.35-0.54. ANBL-6 was the “best” line, markedly exceeding all others (p < 2.2e-16). Notably, some widely-used cell lines (RPMI-8226, U-266) scored poorly in our patient similarity ranking (48 and 52 of 66, respectively). Lines cultured with interleukin-6 showed significantly improved correlations with patient tumor (p = 9.5e-4). When common MM genomic features were matched between cell lines and patients, only t(4;14) and t(14;16) led to increased transcriptional correlation. To demonstrate utility of our top-ranked line for preclinical studies, we showed that intravenously-implanted ANBL-6 proliferates in hematopoietic organs in immunocompromised mice. Overall, our large-scale quantitative correlation analysis, utilizing emerging datasets, provides a resource informing the MM community of cell lines that may be most reliable for modeling patient disease while also elucidating biological differences between cell lines and tumors.

scholarly journals Evaluating the efficacy of multiple myeloma cell lines as models for patient tumors via transcriptomic correlation analysis

Leukemia ◽  
2020 ◽  
Vol 34 (10) ◽  
pp. 2754-2765 ◽  
Author(s):  
Vishesh Sarin ◽  
Katharine Yu ◽  
Ian D. Ferguson ◽  
Olivia Gugliemini ◽  
Matthew A. Nix ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Correlation Analysis ◽  
Cell Lines ◽  
Large Scale ◽  
Myeloma Cell ◽  
Multiple Myeloma Cell ◽  
Quantitative Correlation ◽  
Immunocompromised Mice ◽  
Rpmi 8226 ◽  
Biological Differences

Abstract Multiple myeloma (MM) cell lines are routinely used to model the disease. However, a long-standing question is how well these cell lines truly represent tumor cells in patients. Here, we employ a recently described method of transcriptional correlation profiling to compare similarity of 66 MM cell lines to 779 newly diagnosed MM patient tumors. We found that individual MM lines differ significantly with respect to patient tumor representation, with median R ranging from 0.35 to 0.54. ANBL-6 was the “best” line, markedly exceeding all others (p < 2.2e−16). Notably, some widely used cell lines (RPMI-8226, U-266) scored poorly in our patient similarity ranking (48 and 52 of 66, respectively). Lines cultured with interleukin-6 showed significantly improved correlations with patient tumor (p = 9.5e−4). When common MM genomic features were matched between cell lines and patients, only t(4;14) and t(14;16) led to increased transcriptional correlation. To demonstrate the utility of our top-ranked line for preclinical studies, we showed that intravenously implanted ANBL-6 proliferates in hematopoietic organs in immunocompromised mice. Overall, our large-scale quantitative correlation analysis, utilizing emerging datasets, provides a resource informing the MM community of cell lines that may be most reliable for modeling patient disease while also elucidating biological differences between cell lines and tumors.

Simvastatin Induces Death of Multiple Myeloma Cell Lines

2004 ◽  
Vol 52 (5) ◽  
pp. 335-344 ◽  
Author(s):  
Naomi Gronich ◽  
Liat Drucker ◽  
Hava Shapiro ◽  
Judith Radnay ◽  
Shai Yarkoni ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Multiple Myeloma ◽  
Cell Death ◽  
Cell Lines ◽  
Myeloma Cell ◽  
Cytoplasmic Calcium ◽  
Multiple Myeloma Cell ◽  
Cycle Arrest ◽  
Rpmi 8226

BackgroundAccumulating reports indicate that statins widely prescribed for hypercholesteromia have antineoplastic activity. We hypothesized that because statins inhibit farnesylation of Ras that is often mutated in multiple myeloma (MM), as well as the production of interleukin (IL)-6, a key cytokine in MM, they may have antiproliferative and/or proapoptotic effects in this malignancy.MethodsU266, RPMI 8226, and ARH77 were treated with simvastatin (0-30 μM) for 5 days. The following aspects were evaluated: viability (IC50), cell cycle, cell death, cytoplasmic calcium ion levels, supernatant IL-6 levels, and tyrosine kinase activity.ResultsExposure of all cell lines to simvastatin resulted in reduced viability with IC50s of 4.5 μM for ARH77, 8 μM for RPMI 8226, and 13 μM for U266. The decreased viability is attributed to cell-cycle arrest (U266, G1; RPMI 8226, G2M) and cell death. ARH77 underwent apoptosis, whereas U266 and RPMI 8226 displayed a more necrotic form of death. Cytoplasmic calcium levels decreased significantly in all treated cell lines. IL-6 secretion from U266 cells was abrogated on treatment with simvastatin, whereas total tyrosine phosphorylation was unaffected.ConclusionsSimvastatin displays significant antimyeloma activity in vitro. Further research is warranted for elucidation of the modulated molecular pathways and clinical relevance.

CD40 activation mediates p53-dependent cell cycle regulation in human multiple myeloma cell lines

Blood ◽  
2000 ◽  
Vol 95 (3) ◽  
pp. 1039-1046 ◽  
Author(s):  
G. Teoh ◽  
Y.-T. Tai ◽  
M. Urashima ◽  
S. Shirahama ◽  
M. Matsuzaki ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Lines ◽  
Growth Arrest ◽  
Myeloma Cell ◽  
Luciferase Reporter ◽  
Temperature Sensitive ◽  
Multiple Myeloma Cell ◽  
Cd40 Activation ◽  
Human Multiple Myeloma ◽  
Rpmi 8226

It has been reported that the activation of multiple myeloma (MM) cells by CD40 induces proliferation, growth arrest, and apoptosis. To determine whether the biologic sequelae of CD40 activation in MM cells depends on p53 function, we identified temperature-sensitive p53 mutations in the RPMI 8226 (tsp53E285K) and the HS Sultan (tsp53Y163H) MM cell lines. These cells were then used as a model system of inducible wtp53-like function because wild-type-like p53 is induced at permissive (30°C) but not at restrictive (37°C) temperatures. Using p21-luciferase reporter assays, we confirmed that CD40 induces p53 transactivation in RPMI 8226 and HS Sultan cells cultured under permissive, but not restrictive, conditions. Furthermore, CD40 activation of these MM cells under permissive, but not restrictive, temperatures increased the expression of p53 and p21 mRNA and protein. Importantly, CD40 activation induced the proliferation of RPMI 8226 and HS Sultan cells at restrictive temperatures and growth arrest and increased subG1 phase cells at permissive temperatures. These data confirmed that CD40 activation might have distinct biologic sequelae in MM cells, depending on their p53 status.

Inhibition of Multiple Myeloma Cell Adhesion to Fibronectin by Ephrin Ligation.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2360-2360
Author(s):  
Stuart Ratner ◽  
Charles A. Schiffer ◽  
Jeffrey A. Zonder
Keyword(s):  
Multiple Myeloma ◽  
Cell Adhesion ◽  
Cell Surface ◽  
Cell Lines ◽  
Tyrosine Kinases ◽  
Myeloma Cell ◽  
Separate Experiment ◽  
Partial Recovery ◽  
Multiple Myeloma Cell ◽  
Rpmi 8226

Abstract Multiple myeloma (MM) cell adhesion to fibronectin (FN), mediated via VLA-4 and VLA-5, has been shown to induce resistance to several chemotherapeutic drugs. Disruption of MM cell adhesion to FN and other marrow microenvironment elements might therefore enhance the effects of therapy. We now present the first evidence that Eph-ephrin signaling may be exploited to inhibit MM cell binding to fibronectin. Ephs are transmembrane tyrosine kinases and ephrins are their cell-surface ligands. There are two classes of Ephs and ephrins, A and B. Both Ephs and ephrins can transduce repulsive signals that cause interacting cells to lose contact with each other and with extracellular matrix. We are not aware of any previous systematic study of Eph and ephrin expression or function in MM cells. We have found MM cell lines H929, U266, and RPMI 8226 express members of the A classes of both Ephs and ephrins, but not the B classes. First, we demonstrated ligation with commercially available anti-ephrin A3 antibody was followed by ephrin capping and shedding from the cell surface. We next explored whether ephrin ligation affects MM cell adhesiveness in culture. Whereas H929, U266, and RPMI 8226 cells adhered rapidly to fibronectin-coated plastic surfaces, all three cell lines failed completely to adhere to a mixed coating of FN and rabbit anti-ephrin A3 antibody for a period of 2 hrs. This effect was not seen with FN + normal rabbit Ig. This suggests binding of ephrin A3 (or another cross-reacting A-class ephrin) by solid-state antibody triggers intracellular signals that interfere with initial steps of integrin-mediated adhesion. After 2 hr, spontaneous partial recovery of adhesion occurred, reaching a plateau of approximately 30% of control values by 24 hr. We postulate this recovery occurs via clipping of the extracellular ephrin domain by transmembrane metalloproteases, since recovery of FN adhesion was partially prevented by the metalloprotease inhibitor GM6001 (25 uM). Also consistent with this theory, we found in a separate experiment that GM6001 reduced the shedding of cross-linked A-class ephrins from MM cell lines. In summary, we have demonstrated that manipulation of EPH-ephrin signaling can impair MM-cell adhesion to FN, and that this effect is enhanced by simultaneous inhibition of metalloprotease activity. We are currently studying the effect of A-class ephrin ligation on adhesion-mediated drug resistance in MM cell lines. We also intend to evaluate EPH-ephrin expression in marrow specimens from patients with MM.

scholarly journals Investigation of the Proliferation, Apoptosis/Necrosis, and Cell Cycle Phases in Several Human Multiple Myeloma Cell Lines. Comparison ofViscum albumQuFrF Extract with Vincristine in anIn VitroModel

2010 ◽  
Vol 10 ◽  
pp. 311-320 ◽  
Author(s):  
Eva Kovacs
Keyword(s):  
Cell Cycle ◽  
Multiple Myeloma ◽  
Cell Lines ◽  
Myeloma Cell ◽  
Cytostatic Effect ◽  
Multiple Myeloma Cell ◽  
Cytocidal Effect ◽  
Human Multiple Myeloma ◽  
Cell Cycle Phases ◽  
Rpmi 8226

Multiple myeloma is a haematological disorder of malignant plasma cells. Interleukin-6 (IL-6) is a potent growth factor for the proliferation of these cells. Vincristine as a chemotherapeutic agent is used mainly in combination with other chemotherapeutic substances in the treatment of different haematological disorders.Viscum albumQuFrF (VAQuFrF) extract is an experimental drug that is not used in the treatment in tumour patients. It contains 2000 ng lectin and 10 µg viscotoxin in 10 mg extract. In this study, the effects of VAQuFrF extract were compared with those of vincristine in six human multiple myeloma cell lines (Molp-8, LP-1, RPMI-8226, OPM-2, Colo-677, and KMS-12-BM) using anin vitromodel. As parameters, the IL-6 production, proliferation, apoptosis/necrosis, and cell cycle phases of the cells were taken. To measure the IL-6 production, apoptosis/necrosis, and cell cycle phases, the substances were tested in dose ranges of 10, 50, and 100 µg/106cells. To measure the proliferation of the cells, the substances were tested in dose ranges of 1, 5, and 10 µg/105cells. The profile of the antitumour effects of the two substances is identical. (1) Neither VAQuFrF extract nor vincristine produced IL-6 in any cell line. (2) Both substances inhibited the proliferation of the cells (cytostatic effect), arrested the cell cycle phases, and increased the number of apoptotic/necrotic cells (cytocidal effect). At a dose of 10 µg/105cells, VAQuFrF more effectively inhibited the proliferation than vincristine (p< 0.01) in the cell lines Molp-8, LP-1, and RPMI-8226. (3) VAQuFrF affected the tumour cells mainly via cytostatic effect. Vincristine had a clear cytocidal effect. These findings indicate that VAQuFrF extract could be a novel drug in the treatment of multiple myeloma.

scholarly journals Effectiveness of malabaricone-A in P-glycoprotein over-expressing cancer cell lines

2019 ◽  
Vol 8 (5) ◽  
pp. 1051
Author(s):  
Nafisha Yasmin ◽  
Alak Manna ◽  
Sritama D. Sarkar ◽  
Chandrakana Bandyopadhyay ◽  
Ajay K. Bauri ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Multidrug Resistance ◽  
Cell Lines ◽  
Cancer Cell ◽  
Myeloma Cell ◽  
Over Expression ◽  
Multiple Myeloma Cell ◽  
P Glycoprotein ◽  
Rpmi 8226 ◽  
Hematopoietic Cancer

Background: A major impediment in treatment for cancers is resistance to chemotherapy and is primarily attributed to over-expression of efflux pumps. This study aimed to establish the cytotoxicity of malabaricone-A (MAL-A) in P-glycoprotein/multidrug resistance (P-gp/MDR) over-expressing hematopoietic cancer cell lines.Methods: Leukemia and multiple myeloma cell lines were indirectly evaluated for their P-gp/MDR status by examining Calcein-AM fluorescence and cell viability was assessed by the MTS-PMS assay.Results: The fluorescence of calcein was significantly decreased in three cell lines LP-1, RPMI-8226 and CEM-ADR 5000 and reversal with verapamil endorsed their P-gp/MDR activity. The mean IC50 of MAL-A in these MDR+ cell lines (5.40±1.41 to 12.33±0.78 µg/ml) was comparable with the MDR- leukemic (9.72±1.08 to 19.26±0.75 µg/ml) and multiple myeloma cell lines (9.65±0.39 to 18.05±0.17 μg/ml).Conclusions: Irrespective of their P-gp activity, the cytotoxicity of MAL-A was comparable, making it worthy of future pharmacological consideration in multidrug resistance.

Bone sialoprotein mRNA and protein expression in human multiple myeloma cell lines and patients

2000 ◽  
Vol 111 (4) ◽  
pp. 1118-1121 ◽  
Author(s):  
A. Bellahcene ◽  
I. Van Riet ◽  
C. de Greef ◽  
N. Antoine ◽  
M. F. Young ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Protein Expression ◽  
Cell Lines ◽  
Myeloma Cell ◽  
Bone Sialoprotein ◽  
Multiple Myeloma Cell ◽  
Human Multiple Myeloma ◽  
Mrna And Protein Expression

Betulinic Acid Enhances the Sensitivity of Multiple Myeloma Cells to Bortezomib by the Inactivation of the AKT/mTOR Pathway

2020 ◽  
Vol 18 (3) ◽  
pp. 241-246
Author(s):  
Yu Dan ◽  
Wan Sheng ◽  
Hu Lili
Keyword(s):  
Multiple Myeloma ◽  
Betulinic Acid ◽  
Myeloma Cell ◽  
Mtor Pathway ◽  
Prolonged Treatment ◽  
Myeloma Cells ◽  
Multiple Myeloma Cell ◽  
Increased Sensitivity ◽  
Colony Number ◽  
Rpmi 8226

This study aimed to investigate the mechanism of betulinic acid on multiple myeloma cell resistance to bortezomib. To this end, the bortezomib-resistant RPMI-8226-R cells were generated by prolonged treatment of RPMI-8226 cells with increasing concentrations of bortezomib. Based on the measurements of cell viability and colony number, RPMI-8226-R cells exhibited enhanced resistance to bortezomib than RPMI-8226 cells. Treatment with betulinic acid resulted in increased sensitivity of RPMI-8226-R to bortezomib. When RPMI-8226-R cells were co-treated with bortezomib and betulinic acid, there was an increase in apoptosis rate, cleaved caspase-3, cleaved caspase-9 expression and the decrease in p-AKT/AKT and p-mTOR/mTOR levels. These results suggest that betulinic acid enhances the sensitivity of RPMI-8226-R cells to bortezomib by inhibiting the activation of the AKT/mTOR pathway in bortezomib-resistant multiple myeloma cells.

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