Cellular and Molecular Effects of NVP-BKM120 in Lymphoblastic Leukemia Cells

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2241-2241
Author(s):  
João Kleber Novais Pereira ◽  
João Agostinho Machado-Neto ◽  
Matheus Rodrigues Lopes ◽  
Fabiola Traina ◽  
Fernando Ferreira Costa ◽  
...  
Keyword(s):  
Cell Lines ◽  
Lymphoblastic Leukemia ◽  
Cyclin B1 ◽  
Pyrimidine Derivative ◽  
Leukemia Cells ◽  
Dependent Manner ◽  
Daudi Cell ◽  
Induction Of Apoptosis ◽  
Orally Bioavailable ◽  
Dose Dependent

Abstract Background: PI3K/AKT/mTOR signaling controls most hallmarks of cancer. Constitutive activation of PIK3 pathway in T cells acute lymphoblastic leukemia (T-ALL) has been reported; in a mouse model, PI3K activation, together with MYC, cooperates in Burkitt lymphoma (BL) pathogenesis. NVP-BKM120 is an orally bioavailable 2,6-dimorpholine pyrimidine derivative, and considered a highly selective pan-class I PI3K inhibitor. In preclinical studies, it has shown efficacy in a variety of malignancies and is currently being investigated in phase I/II/III clinical testing, mainly for advanced solid tumors (clinicaltrials.gov). Aims: Here, we described the effects of the pan-PI3K/AKT/mTOR inhibitor NVP-BKM120 on T-ALL and BL cell lines. Methods: T-ALLcell lines, Jurkat and MOLT-4, and BL cell lines, NAMALWA and Daudi, were obtained from ATCC. NVP-BKM120 was kindly provided by Novartis, and was prepared as a 10mM stock solution in DMSO. Different concentrations of the drug were used as indicated, where cells treated only with DMSO served as control. Cell viability was measured by MTT. Colony formation was carried out in semisolid methyl cellulose medium. The induction of apoptosis was assessed by annexin-V-APC/PI and by caspase cleavage. The cell cycle was analyzed by a PI-staining method. Western blot analysis was performed by standard methods. Vital staining and flow cytometry analysis with acridine orange was performed for the detection and quantification of acidic vesicular organelles (AVOs). Comparisons between the two groups were performed by the t test. Pvalue <0.05 was considered statistically significant. Results: Cell viability decreased in a concentration-dependent manner, with an IC50 range of 7-8 μM and the clonogenic growth was significantly decreased at the concentration of 1μM and at 10µM the colony formation was completely inhibited in all cells tested. After 6 hours of NVP-BKM120 treatment, we observed an increase in apoptotic cells, as well as an increase in the cleavage of procaspase 3, 8 and 9 in Jurkat, MOLT-4 and NAMALWA cells. Compared with DMSO control, NVP-BKM120 does not have any effect during apoptosis induction in the Daudi cell line. NVP-BKM120 treatment also resulted in G2/M arrest, associated with a decrease in the G1population and a decrease in Cyclin B1 protein levels. Immunoblotting analysis of cells treated with the drug revealed decreased phosphorylation, in a dose-dependent manner, of AKT, P70SK6 and 4EBP1, with stable total proteins levels. Additionally, we observed a dose-dependent decrease in BAD phosphorylation, followed by an increase in BAX:BCL2 ratio. Quantification of AVOs showed a dose-dependent increase of AVOs in all cells tested, after NVP-BKM120 treatment. Conclusions: NVP-BKM120 induced apoptosis in a dose-dependent manner in Jurkat, MOLT-4 and NAMALWA cells, while effects of the drug in the Daudi cell line were mainly cytostatic. In those cells, the induction of apoptosis suggested that the death receptor and mitochondrial pathways were activated after drug treatment. In our study, we found that NVP-BKM120 decreased the phosphorylation levels of BAD, which is linked to a pro-apoptotic activity, and up-regulated the BAX:BCL2 ratio. These results are consistent with the activation of caspase-9 and 3, related to the mitochondrial apoptosis. The accumulation of leukemia cells in the G2/M phase of the cell cycle has been associated with enhanced apoptosis. Our results suggest that decreased Cyclin B1 protein expression might be the molecular mechanism through which NVP-BKM120 induces G2/M arrest. The effects of NVP-BKM120 on the PI3K pathway indicate that NVP-BKM120 treatment may overcome rapamycin-induced AKT activation. P70SK6 and 4EBP1 are the two best-characterized substrates of mTOR1. Hence, the decrease in the phosphorylation levels of P70SK6 and 4EBP1 results in impaired oncogenic protein synthesis. Moreover, P70SK6 is one of the kinases whose phosphorylation by mTOR1 results in opposing autophagy. Accordingly, NVP-BKM120 resulted in increased AVOs, which is a characteristic feature of cells engaged in autophagy. In summary, our present study establishes that NVP-BKM120 effectively presents an antitumor activity against T-ALL and BL cell lines. The reduction of proliferation is possibly by down-regulation of Cyclin B1 and the increased BAX:BCL2 ratio is one of the mechanisms involved in the induction of apoptosis. Disclosures Off Label Use: NVP-BKM120 is an orally bioavailable 2,6-dimorpholino pyrimidine derivative, and considered a highly selective pan-class I PI3K inhibitor. .

Janus Kinase (JAK)-2 Does Not Play a Role in Bcr-Abl Signaling in Philadelphia Chromosome (Ph)-Positive (p190) Acute Lymphoblastic Leukemia (ALL) Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4241-4241
Author(s):  
Stefan H. Faderl ◽  
Quin Van ◽  
Patricia E. Koch ◽  
David M. Harris ◽  
Inbal Hallevi ◽  
...  
Keyword(s):  
Cell Lines ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Janus Kinase ◽  
Myelogenous Leukemia ◽  
Dependent Manner ◽  
Western Immunoblotting ◽  
Gm Csf ◽  
Dose Dependent

Abstract Novel immunochemotherapy regimens combined with imatinib mesylate (IA) have significantly improved treatment outcome of Ph+ ALL. Nevertheless, most adult patients with Ph+ ALL relapse and succumb to their disease. Recent reports suggested that Jak-2 is engaged in the signaling of Bcr-Abl in chronic myelogenous leukemia (CML) cells. Because Jak-2 inhibitory agents are currently investigated in clinical trials, we sought to explore the role of Jak-2 in the signaling of Bcr-Abl in Ph+ ALL assuming that inhibition of Jak-2 might be beneficial in the treatment of Ph+ ALL. To do this, we used our Ph+ (p190) ALL cell lines Z-119 and Z-181 (Estrov et al. J Cell Physiol166: 618, 1996). We chose these cells because in both lines Jak-2 can be activated. Both Z-119 and Z-181 cells express granulocyte-macrophage colony-stimulating factor (GM-CSF) receptors and GM-CSF activates Jak-2 and stimulates the proliferation of both cell lines. Using a clonogenic assay, we found that IA inhibited the proliferation of these cells at concentrations ranging from 50 to 500 nM. Because Bcr-Abl was found to activate the signal transducer and activator of transcription (STAT)-5 in CML cells, we used Western immunoblotting and found that IA inhibited the phosphorylation (p) of STAT5 in a dose-dependent manner in Ph+ ALL cells. To test whether JAk-2 plays a role in Bcr-Abl (p190) signaling we incubated Z-181 cells for 4 hours with or without 50, 100, 250, and 500 nM IA, extracted cellular protein and immunoprecipitated total STAT5 protein. Then, using Western immunoblotting we detected the Bcr-Abl p190 protein in all STAT5 immunoprecipitates and by using specific pSTAT5 antibodies, we demonstrated that IA induced a dose-dependent reduction in the levels of pSTAT5, but not of p190 protein, suggesting that the p190 Bcr-Abl kinase binds to and activates STAT5. Remarkably, neither Jak-2 nor pJak-2 was detected in either immunoprecipitate. To further delineate the role of Jak-2 in Bcr-Abl signaling we extracted protein from Z-181 cells and immunoprecipitated Jak-2. Neither Bcr-Abl nor STAT5 was detected in these immunoprecipitates, confirming that Jak-2 does not bind Bcr-Abl p190 protein and does not participate in the activation of STAT5. Taken together, our data suggest that Bcr-Abl (p190) binds and phosphorylates STAT5 whereas, Jak-2 is not engaged in Bcr-Abl (p190) signaling in Ph+ ALL cells.

scholarly journals Synthetic Makaluvamine Analogs Decrease c-Kit Expression and Are Cytotoxic to Neuroendocrine Tumor Cells

Molecules ◽  
2020 ◽  
Vol 25 (21) ◽  
pp. 4940
Author(s):  
Zviadi Aburjania ◽  
Jason D. Whitt ◽  
Samuel Jang ◽  
Dwayaja H. Nadkarni ◽  
Herbert Chen ◽  
...  
Keyword(s):  
Neuroendocrine Tumor ◽  
Cell Lines ◽  
Neuroendocrine Tumors ◽  
Topoisomerase Ii ◽  
Myeloid Cell ◽  
Chemotherapeutic Agents ◽  
Dependent Manner ◽  
Induction Of Apoptosis ◽  
Induced Apoptosis ◽  
Dose Dependent

In an effort to discover viable systemic chemotherapeutic agents for neuroendocrine tumors (NETs), we screened a small library of 18 drug-like compounds obtained from the Velu lab against pulmonary (H727) and thyroid (MZ-CRC-1 and TT) neuroendocrine tumor-derived cell lines. Two potent lead compounds (DHN-II-84 and DHN-III-14) identified from this screening were found to be analogs of the natural product makaluvamine. We further characterized the antitumor activities of these two compounds using pulmonary (H727), thyroid (MZ-CRC-1) and pancreatic (BON) neuroendocrine tumor cell lines. Flow cytometry showed a dose-dependent increase in apoptosis in all cell lines. Induction of apoptosis with these compounds was also supported by the decrease in myeloid cell leukemia-1 (MCL-1) and X-chromosome linked inhibitor of apoptosis (XIAP) detected by Western blot. Compound treatment decreased NET markers chromogranin A (CgA) and achaete-scute homolog 1 (ASCL1) in a dose-dependent manner. Moreover, the gene expression analysis showed that the compound treatment reduced c-Kit proto-oncogene expression in the NET cell lines. Induction of apoptosis could also have been caused by the inhibition of c-Kit expression, in addition to the known mechanisms such as damage of DNA by topoisomerase II inhibition for this class of compounds. In summary, makaluvamine analogs DHN-II-84 and DHN-III-14 induced apoptosis, decreased neuroendocrine tumor markers, and showed promising antitumor activity in pulmonary, thyroid, and pancreatic NET cell lines, and hold potential to be developed as an effective treatment to combat neuroendocrine tumors.

scholarly journals Huang Qi Huai Granules Induce Apoptosis in Acute Lymphoblastic Leukemia Cells through the Akt/FoxO1 Pathway

2016 ◽  
Vol 38 (5) ◽  
pp. 1803-1814 ◽  
Author(s):  
Juan Han ◽  
Ming Lin ◽  
Dongfeng Zhou ◽  
Zhiquan Zhang ◽  
Runming Jin ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Tumor Therapy ◽  
Leukemia Cells ◽  
Cell Cycle Distribution ◽  
Dependent Manner ◽  
Apoptotic Pathway ◽  
Phosphorylated Akt ◽  
Dose Dependent

Background/Aims: In recent years, a traditional Chinese medicine named Huang Qi Huai (HQH) has been frequently used in China for solid tumor therapy. However, the role of HQH on leukemia cells and its underlying mechanisms have not been elucidated. In this study, we investigated the effect of HQH on the proliferation and apoptosis of acute lymphoblastic leukemia (ALL) cell lines. Methods: Sup-B15 and Nalm-6 cells were treated with gradient doses of HQH for 24, 48 or 72 h. Cell viability was measured using a CCK8 assay and cell cycle distribution and apoptosis levels were analyzed using flow cytometry. Western blotting was used to assess the levels of proteins associated with the apoptotic pathway. Results: The results revealed that cell survival decreased significantly with increasing concentrations of HQH. HQH induced G2 cell-cycle arrest and cell apoptosis in a dose-dependent manner. HQH inhibited phosphorylated-Akt, phosphorylated- FoxO1 and Bcl2 expression and upregulated Bim, cleaved-caspase-3 and Bax expression in a dose-dependent manner, which suggests that HQH induces the apoptosis of ALL cells via the Akt/FoxO1 pathway. Conclusion: HQH is a potential complementary agent for the treatment of acute lymphoblastic leukemia.

Sphingosine Kinase 1 as a Potential Target To Inhibit Proliferation of Myeloid Leukemia Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4196-4196
Author(s):  
Clara Ricci ◽  
Francesco Onida ◽  
Katia Todoerti ◽  
Franca Radaelli ◽  
Antonino Neri ◽  
...  
Keyword(s):  
Cell Lines ◽  
Myeloid Leukemia ◽  
Kinase Activity ◽  
Sphingosine Kinase ◽  
Leukemia Cells ◽  
Dependent Manner ◽  
Sphingosine Kinase 1 ◽  
Vitro Effect ◽  
Dose Dependent

Abstract Sphingolipids (SPLs), classically known as structural components of cellular membranes, are bioactive mediators of many processes. New data are available on SPLs as valid targets to induce death in leukemia cells and to overcome drug resistance. In this direction, an important role has been attributed to deregulation of sphingosine kinase 1 (SK1) that phosphorylates sphingosine (Sph) to Sphingosine-1-Phosphate (S1P). S1P in turn acts as a second messenger promoting cell survival and proliferation or as a ligand for the G-protein-coupled receptors S1P1–5, controlling physiological functions such as immunity, vasculogenesis and inflammation. SK1 is released into the cytoplasm from where, upon phosphorylation, it translocates to the plasma membrane where Sph is located. SK1 was shown to be oncogenic and growing evidences assigned it a role in solid as well as in hematological malignancies. In this study we aimed to define the role of SK1 in the growth and survival of myeloid leukemia cells and to identify target genes involved in the kinase signaling pathway. As in vitro models, cell lines representing different subtypes of myeloid leukemia were used: AR230, K562, RWLeu4, HL-60 and Eol-1. We observed a statistical correlation between the levels of SK1 expression and activity. Exposure of cells to “SK Inhibitor” (SKI, Calbiochem) caused an evident decrease of cell proliferation and viability in a time- and dose-dependent fashion, which was associated to a significant inhibition of kinase activity in all cell lines. When the in vitro effect of SKI was tested on the clonogenic potential of CD34+ cells from 3 healthy donors and 2 CML patients in chronic phase, a more effective inhibition was observed on leukemic than on normal progenitors (IC50: 3,9 and 7,5 μM respectively). Next, we focused on K562 as an in vitro model of CML. We demonstrated that SKI affects the activity but not the expression of SK1 in a time- and dose-dependent manner, and that inhibition regarded about 50% of kinase activity already after 6 hrs of treatment at the dose corresponding to the IC50, increasing up to 80% after 48 hrs. Concomitantly we observed an increase of the phosphorylated form of ERK1/2, known to phosphorylate SK1 at Ser225. Additionally, gene expression profiling of K562 exposed to SKI was investigated after 12 hrs of treatment: supervised analysis identified 11 genes down- and 99 genes up-regulated and functional analysis indicated involvement in protein biosynthesis, transcription regulation and cell cycle progression control. Finally, we tested the effect of Imatinib Mesylate (IM) on SK1. Treatment of K562 with IM at the IC50 for 48 hrs reduced SK1 activity compared to untreated cells, with no changes in kinase expression. Moreover, when K562 cells were exposed to the combination of IM and SKI, a strong synergistic effect was observed after 24 hrs, when cell viability was about 48% of control. We conclude that SK1 does have a role in the survival and proliferation of myeloid leukemia cells and that pharmacological inhibition of SK1 represents a possible novel strategy for the treatment of leukemias. Our results suggest that there might be a functional link between the Bcr/Abl and SPLs pathways, and support further investigations on possible treatment based on the combination of IM and SKI.

scholarly journals Pre-Clinical Evaluation of the Proteasome Inhibitor Ixazomib against Bortezomib-Resistant Leukemia Cells and Primary Acute Leukemia Cells

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 665
Author(s):  
Margot S.F. Roeten ◽  
Johan van Meerloo ◽  
Zinia J. Kwidama ◽  
Giovanna ter Huizen ◽  
Wouter H. Segerink ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Cell Lines ◽  
Proteasome Inhibitor ◽  
Ex Vivo ◽  
Lymphoblastic Leukemia ◽  
Unmet Need ◽  
Leukemia Cell ◽  
Leukemia Cells ◽  
Cross Resistance ◽  
Proteasome Subunit

At present, 20–30% of children with acute leukemia still relapse from current chemotherapy protocols, underscoring the unmet need for new treatment options, such as proteasome inhibition. Ixazomib (IXA) is an orally available proteasome inhibitor, with an improved safety profile compared to Bortezomib (BTZ). The mechanism of action (proteasome subunit inhibition, apoptosis induction) and growth inhibitory potential of IXA vs. BTZ were tested in vitro in human (BTZ-resistant) leukemia cell lines. Ex vivo activity of IXA vs. BTZ was analyzed in 15 acute lymphoblastic leukemia (ALL) and 9 acute myeloid leukemia (AML) primary pediatric patient samples. BTZ demonstrated more potent inhibitory effects on constitutive β5 and immunoproteasome β5i proteasome subunit activity; however, IXA more potently inhibited β1i subunit than BTZ (70% vs. 29% at 2.5 nM). In ALL/AML cell lines, IXA conveyed 50% growth inhibition at low nanomolar concentrations, but was ~10-fold less potent than BTZ. BTZ-resistant cells (150–160 fold) displayed similar (100-fold) cross-resistance to IXA. Finally, IXA and BTZ exhibited anti-leukemic effects for primary ex vivo ALL and AML cells; mean LC50 (nM) for IXA: 24 ± 11 and 30 ± 8, respectively, and mean LC50 for BTZ: 4.5 ± 1 and 11 ± 4, respectively. IXA has overlapping mechanisms of action with BTZ and showed anti-leukemic activity in primary leukemic cells, encouraging further pre-clinical in vivo evaluation.

scholarly journals The Olive Leaves Extract Has Anti-Tumor Effects against Neuroblastoma through Inhibition of Cell Proliferation and Induction of Apoptosis

Nutrients ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 2178
Author(s):  
Fabio Morandi ◽  
Veronica Bensa ◽  
Enzo Calarco ◽  
Fabio Pastorino ◽  
Patrizia Perri ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Viability ◽  
Cell Cycle Progression ◽  
Treatment Strategies ◽  
Annexin V ◽  
Dependent Manner ◽  
Induction Of Apoptosis ◽  
Dose Dependent

Neuroblastoma (NB) is the most common extra-cranial solid tumor of pediatric age. The prognosis for high-risk NB patients remains poor, and new treatment strategies are desirable. The olive leaf extract (OLE) is constituted by phenolic compounds, whose health beneficial effects were reported. Here, the anti-tumor effects of OLE were investigated in vitro on a panel of NB cell lines in terms of (i) reduction of cell viability; (ii) inhibition of cell proliferation through cell cycle arrest; (iii) induction of apoptosis; and (iv) inhibition of cell migration. Furthermore, cytotoxicity experiments, by combining OLE with the chemotherapeutic topotecan, were also performed. OLE reduced the cell viability of NB cells in a time- and dose-dependent manner in 2D and 3D models. NB cells exposed to OLE underwent inhibition of cell proliferation, which was characterized by an arrest of the cell cycle progression in G0/G1 phase and by the accumulation of cells in the sub-G0 phase, which is peculiar of apoptotic death. This was confirmed by a dose-dependent increase of Annexin V+ cells (peculiar of apoptosis) and upregulation of caspases 3 and 7 protein levels. Moreover, OLE inhibited the migration of NB cells. Finally, the anti-tumor efficacy of the chemotherapeutic topotecan, in terms of cell viability reduction, was greatly enhanced by its combination with OLE. In conclusion, OLE has anti-tumor activity against NB by inhibiting cell proliferation and migration and by inducing apoptosis.

scholarly journals Overcoming Microenvironment-Mediated Chemoprotection through Stromal Galectin-3 Inhibition in Acute Lymphoblastic Leukemia

2021 ◽  
Vol 22 (22) ◽  
pp. 12167
Author(s):  
Somayeh S. Tarighat ◽  
Fei Fei ◽  
Eun Ji Joo ◽  
Hisham Abdel-Azim ◽  
Lu Yang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Acute Lymphoblastic Leukemia ◽  
Stromal Cells ◽  
Lymphoblastic Leukemia ◽  
High Specificity ◽  
Leukemia Cells ◽  
Cell Precursor ◽  
Cell Responses ◽  
Galectin 3 ◽  
Dose Dependent

Environmentally-mediated drug resistance in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) significantly contributes to relapse. Stromal cells in the bone marrow environment protect leukemia cells by secretion of chemokines as cues for BCP-ALL migration towards, and adhesion to, stroma. Stromal cells and BCP-ALL cells communicate through stromal galectin-3. Here, we investigated the significance of stromal galectin-3 to BCP-ALL cells. We used CRISPR/Cas9 genome editing to ablate galectin-3 in stromal cells and found that galectin-3 is dispensable for steady-state BCP-ALL proliferation and viability. However, efficient leukemia migration and adhesion to stromal cells are significantly dependent on stromal galectin-3. Importantly, the loss of stromal galectin-3 production sensitized BCP-ALL cells to conventional chemotherapy. We therefore tested novel carbohydrate-based small molecule compounds (Cpd14 and Cpd17) with high specificity for galectin-3. Consistent with results obtained using galectin-3-knockout stromal cells, treatment of stromal-BCP-ALL co-cultures inhibited BCP-ALL migration and adhesion. Moreover, these compounds induced anti-leukemic responses in BCP-ALL cells, including a dose-dependent reduction of viability and proliferation, the induction of apoptosis and, importantly, the inhibition of drug resistance. Collectively, these findings indicate galectin-3 regulates BCP-ALL cell responses to chemotherapy through the interactions between leukemia cells and the stroma, and show that a combination of galectin-3 inhibition with conventional drugs can sensitize the leukemia cells to chemotherapy.

Metabolic Profile Of Leukemia Cells Influences Treatment Efficacy Of L‑Asparaginase

2019 ◽  
Author(s):  
Katerina Hlozkova ◽  
Alena Pecinova ◽  
David Pajuelo Reguera ◽  
Marketa Simcikova ◽  
Lenka Hovorkova ◽  
...  
Keyword(s):  
Membrane Potential ◽  
Mitochondrial Membrane Potential ◽  
Cell Lines ◽  
Mitochondrial Membrane ◽  
Metabolic Profile ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cell ◽  
Leukemia Cells ◽  
Lower Sensitivity ◽  
Leukemia Cell Lines

Abstract Background Effectiveness of L-asparaginase administration in acute lymphoblastic leukemia treatment is mirrored in overall outcome of patients. Generally, leukemia patients differ in their sensitivity to L-asparaginase; however, the mechanism underlying their inter-individual differences is still not fully understood. We have previously shown that L-asparaginase rewires the biosynthetic and bioenergetic pathways of leukemia cells to activate both anti-leukemic and pro-survival processes. Herein, we investigated the relationship between the metabolic profile of leukemia cells and their sensitivity to currently used cytostatic drugs.Methods Altogether, 19 leukemia cell lines and primary leukemia cells from 11 patients were used. Glycolytic function and mitochondrial respiration were measured using Seahorse bioanalyzer. Sensitivity to cytostatics was measured using MTS assay and/or absolute count and flow cytometry. Mitochondrial membrane potential was determined as TMRE fluorescence.Results We characterized the basal metabolic state of the cells derived from different leukemia subtypes using cell lines and primary samples and assessed their sensitivity to cytostatic drugs. We found that leukemia cells cluster into distinct groups according to their metabolic profile, which is mainly driven by their hematopoietic lineage of origin from which they derived. However, majority of lymphoid leukemia cell lines and patients with lower sensitivity to L-asparaginase clustered regardless their hematopoietic phenotype together with myeloid leukemias. Furthermore, we observed a correlation of specific metabolic parameters with sensitivity to L-asparaginase. Greater ATP-linked respiration and lower basal mitochondrial membrane potential in cells significantly correlated with higher sensitivity to L-asparaginase. No such correlation was found in other tested cytostatic drugs.Conclusions These data support the prominent role of the cell metabolism in the treatment effect of L-asparaginase. Based on these findings metabolic profile could identify leukemia patients with lower sensitivity to L-asparaginase with no specific genetic characterization.

scholarly journals Hif-1α Inhibitors Could Successfully Inhibit the Progression of Differentiated Thyroid Cancer in Vitro

2020 ◽  
Vol 13 (9) ◽  
pp. 208
Author(s):  
Min-Hee Kim ◽  
Tae Hyeong Lee ◽  
Jin Soo Lee ◽  
Dong-Jun Lim ◽  
Peter Chang-Whan Lee
Keyword(s):  
Cell Proliferation ◽  
Thyroid Cancer ◽  
Cell Lines ◽  
Cancer Progression ◽  
Hypoxia Inducible Factor ◽  
Soft Agar ◽  
Dependent Manner ◽  
Thyroid Cancer Cell Lines ◽  
Dose Dependent

Hypoxia-inducible factor (HIF)-1α plays an important role in cancer progression. In various cancers, including thyroid cancer, overexpression of HIF-1α is related to poor prognosis or treatment response. However, few studies have investigated the role of HIF-1α inhibition in thyroid cancer progression. We evaluated the utility of the HIF-1α inhibitor IDF-11774 in vitro utilizing two thyroid cancer cell lines, K1 and BCPAP. Both cell lines were tested to elucidate the effects of IDF-11774 on cell proliferation and migration using soft agar and invasion assays. Here, we found that a reduction of HIF-1α expression in BCPAP cells was observed after treatment with IDF-11774 in a dose-dependent manner. Moreover, cell proliferation, migration, and anchorage-independent growth were effectively inhibited by IDF-11774 in BCPAP cells but not in K1 cells. Additionally, invasion of BCPAP but not K1 cells was controlled with IDF-11774 in a dose-dependent manner. Our findings suggest that promoting the degradation of HIF-1α could be a strategy to manage progression and that HIF-1α inhibitors are potent drugs for thyroid cancer treatment.

scholarly journals Anticancer Potential of Fruit Extracts from Vatica diospyroides Symington Type SS and Their Effect on Program Cell Death of Cervical Cancer Cell Lines

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Atchara Chothiphirat ◽  
Kesara Nittayaboon ◽  
Kanyanatt Kanokwiroon ◽  
Theera Srisawat ◽  
Raphatphorn Navakanitworakul
Keyword(s):  
Cervical Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Morphological Changes ◽  
Annexin V ◽  
Siha Cell ◽  
Caspase 8 ◽  
Dependent Manner ◽  
Cervical Cancer Cells ◽  
Dose Dependent

Vatica diospyroides Symington is locally known as Chan-Ka-Pho in Thailand. Ancient people have used it as therapeutic plant for cardiac and blood tonic cure. The purpose of this study was to investigate the potential cytotoxicity and selectivity of the extracts from V. diospyroides type SS fruit on cervical cancer HeLa and SiHa cell lines and to examine its underlying mechanism of action. MTT assay revealed that the extracts showed inhibition of cell survival in a dose-dependent manner and exhibited highly cytotoxic activity against both HeLa and SiHa cells with IC50 value less than 20 μg/mL along with less toxicity against L929 cells. Acetone cotyledon extract (ACE) showed the best selectivity index value of 4.47 (HeLa) and 3.51 (SiHa). Distinctive morphological changes were observed in ACE-treated cervical cancer cells contributing to apoptosis action. Flow cytometry analysis with Annexin V-FITC and PI staining precisely indicated that ACE induced apoptosis in HeLa and SiHa cell lines in a dose-dependent manner. Treatment of ACE with half IC50 caused DNA fragmentation and also activated increasing of bax and cleaved caspase-8 protein in HeLa cells after 48 h exposure. The results suggest that ACE has potent and selective cytotoxic effect against cervical cancer cells and the potential to induce bax and caspase-8-dependent apoptosis. Hence, the ACE could be further exploited as a potential lead in cancer treatment.

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