CAL-101, a Potent Selective Inhibitor of the p110d Isoform of Phosphatidylinositol 3-Kinase, Attenuates PI3K Signaling and Inhibits Proliferation and Survival of Acute Lympoblastic Leukemia in Addition to a Range of Other Hematological Malignancies

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 16-16 ◽  
Author(s):  
Brian J Lannutti ◽  
Sarah A. Meadows ◽  
Adam Kashishian ◽  
Bart Steiner ◽  
Sarah May ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Lines ◽  
Hematological Malignancies ◽  
B Cell Lymphoma ◽  
Class I ◽  
Pi3k Signaling ◽  
Wide Range ◽  
Normal Human ◽  
Phosphatidylinositol 3

Abstract The class I phosphatidylinositol 3-kinases (PI3K) regulate a variety of cellular functions including motility, metabolism, proliferation, growth, and survival, depending on cellular milieu. Deregulation of the PI3K/Akt pathway is one of the most frequently observed defects in human malignancies including those of hematological origin and has been shown to play an important role in tumor progression. Therefore, selective targeting of PI3K signaling in hematological tumor cells could provide an effective treatment strategy while limiting potential undesirable effects of pan-inhibitors that broadly block PI3K signaling in all cells. Of the class IA PI3Ks (p110a, p110b, p110d), p110d’s expression is largely restricted to cells of hematopoietic origin and is essential for PI3K signaling in lymphocytes. Here, we report on the characterization of a novel p110d specific inhibitor, CAL-101. This compound is a potent PI3K inhibitor with an IC50 of 1–10 nM against the purified p110d subunit and 30–70 nM cellular potency against p110d-mediated basophil activation in whole blood. Importantly, CAL-101 plasma concentrations of 500–5000 nM that greatly exceed those needed for p110d inhibition in blood were safely maintained in a 7 day multidose normal human volunteer study. CAL-101 demonstrates >30-fold selectivity over other class I, II and III PI3K family members as well as selectivity over other PI3K-related proteins including mTOR and DNA-PK. Furthermore, a genome wide screen of >350 protein kinases did not detect any activity. To investigate the potential role of p110d in hematologic tumors we screened a wide range of leukemia and lymphoma cell lines for p110 isoform expression and constitutive PI3K pathway activation. The expression of p110d was observed in >90% of these cell lines that was in many cases accompanied by constitutive Akt phosphorylation. In this context, CAL-101 was able to reduce p-Akt levels and block additional downstream effectors such as p-p70S6K, p-GSKb, and p-Bad in cells that represent a range of tumor types including acute myeloid leukemia, acute lymphoblastic leukemia (ALL), and diffuse large B-cell lymphoma among others. Recent studies have demonstrated the importance of PTEN loss and enhanced PI3K signaling in primary T-ALL cells. We report high levels of p110d protein and activated Akt in 6 of 6 ALL cell lines evaluated. Inhibition of p110d with CAL-101 treatment of both T-ALL and B-ALL cell lines resulted in a reduction of Akt and GSK-3b phosphorylation and a decrease in cellular proliferation that was accompanied by cell death demonstrating an essential role of PI3K signaling independent of PTEN status. Treatment of T-ALL cell lines with CAL-101 induced processing of pro-caspase-3 and cleavage of PARP supporting a role for caspase mediated cell death. These studies have now been extended to the analysis of primary patient blast samples to further establish preclinical proof of concept for therapeutic application of CAL-101 for the treatment of ALL. In summary, CAL-101 is a highly potent and selective p110d kinase inhibiter with broad anti-tumor activity against cancer cells of hematologic origin. Clinical studies in normal human volunteers demonstrated good tolerability with high drug exposure and favorable steady-state pharmacokinetic properties. Taken together, these data support the on going Phase 1 clinical trial that includes a wide range of hematological malignancies.

The xCT Antiporter Is a Therapeutic Target in the ABC Subtype of DLBCL

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3996-3996
Author(s):  
Xiaolei Wei ◽  
Yun Mai ◽  
Ru Feng ◽  
B. Hilda Ye
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
B Cell ◽  
Cell Lines ◽  
Critical Role ◽  
B Cell Lymphoma ◽  
Dependent Manner ◽  
Ros Accumulation

Abstract Diffuse large B cell lymphoma (DLBCL) is the most common lymphoid malignancy in the adult population and can be subdivided into two main subtypes, i.e. GCB-DLBCL and ABC-DLBCL. While both subtypes are derived from normal germinal center (GC) B cells, they differ in B cell maturation stage, transformation pathway, and clinical behavior. When treated with either the combination chemotherapy CHOP or the immuno-chemotherapy R-CHOP, the survival outcome of ABC-DLBCL patients is typically much worse than that of GCB-DLBCL patients. Although the molecular mechanisms underlying this survival disparity remain poorly understood, an attractive hypothesis is that there exist subtype-specific resistance mechanisms directed against the chemo-therapy drugs in the original CHOP formulation. In support of this notion, our previous study has revealed that Doxorubicin (Dox), the main cytotoxic ingredient in CHOP, has subtype-specific mechanisms of cytotoxicity in DLBCLs due to differences in its subcellular distribution pattern. In particular, Dox-induced cytotoxicity in ABC-DLBCLs is largely dependent on oxidative stress rather than DNA damage response. Based on these findings, we hypothesize that agents capable of disturbing the redox balance in ABC-DLBCL cells could potentiate the therapeutic activity of first line lymphoma therapy. As the major route of cystine uptake from extracellular space, the xCT cystine/glutamate antiporter controls the rate-limiting step for glutathione (GSH) synthesis in several types of cancer cells, including CLL. We focused the current study on xCT because its protein stability is known to be positively regulated by a splicing variant of CD44 and we have recently published that expression of CD44 and CD44V6 are poor prognosticators for DLBCL. Indeed, we found that surface CD44 is exclusively expressed in ABC-DLBCL (6/6) but not GCB-DLBCL (0/5) cell lines. In addition, the xCT proteins in two ABC-DLBCL cell lines, Riva and SuDHL2, are extraordinarily stable, with half-lives exceeding 24 hours. As such, transient transfection using siRNA oligos was ineffective in reducing the endogenous xCT protein in ABC-DLBCL cell lines. To circumvent this issue, we turned to a clinically approved anti-inflammatory drug, sulfasalazine (SASP), which is a validated xCT inhibitor in its intact form. When Riva and SuDHL2 cells were treated overnight with the IC50 dose of SASP, the endogenous GSH pool was drastically reduced, leading to significant increase in intracellular ROS, p38 and JNK activation, and progressive apoptosis. Unexpectedly, we found that Dox-treated cells had significantly elevated GSH levels, possibly the result of an antioxidant response to Dox-triggered ROS accumulation. This increase in GSH was completely suppressed when the IC25 dosage of SASP was included in the Dox treatment. As expected, SASP/Dox combination significantly enhanced Dox-triggered ROS accumulation and synergistically promoted cell death in Riva and SuDHL2 cells. Mechanistically, p38 activation and cell death induced by SASP/Dox combination could be markedly attenuated by pretreatment with glutathione monoethyl ester, demonstrating the critical role of oxidative stress. Furthermore, cytotoxicity triggered by SASP/Dox could also be suppressed by the p38 inhibitor, SB203580. We have developed stable cell lines expressing xCT shRNA to confirm the results obtained with SASP. In vivo interactions between SASP and Dox are also being evaluated in xenograft-based ABC-DLBCL models. In summary, we report here for the first time a critical role of xCT in sustaining in vivo GSH production in ABC-DLBCL cells. More importantly, pharmacologic inhibition of xCT function in ABC-DLBCL cells not only prevented Dox-induced endogenous GSH increase, but also potentiated Dox-induced ROS accumulation and cytotoxicity in a p38-dependent manner. With additional evidence from ongoing experiments, our study aims to provide a mechanistic basis for development of novel therapies that target either xCT or redox homeostasis to improve treatment outcomes for ABC-DLBCLs. Disclosures No relevant conflicts of interest to declare.

scholarly journals Derived from a Platform of Innovative Therapeutic Molecular Clusters (TMC), Ag5 Is a Highly Potent and Differentiated Molecule That Promises to be Efficacious in Hard-to-Treat Hematological Cancers

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 23-23
Author(s):  
Vanesa Porto González ◽  
Carmen Carneiro ◽  
Vanesa Santos ◽  
Erea Borrajo ◽  
Blanca Dominguez ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Cell Lines ◽  
Hematological Malignancies ◽  
Residual Disease ◽  
Water Soluble ◽  
Molecular Cluster ◽  
Medical Need ◽  
Wide Range ◽  
Hematological Cancers

[Background on medical need in hematology]Even though significant progress has been made in a number of hematological malignancies in recent years, an unmet medical need still remains in indications such as multiple myeloma (MM), chronic lymphocytic leukemia (CLL) or acute myeloid leukemia (AML) due to refractory disease, severe adverse events or the failure to achieve sustained minimal residual disease. As a consequence, novel therapies are required to prevent relapse, be safer in administration and to target residual disease. We present here for the first time a novel and innovative therapeutic approach with the potential to treat patients suffering from hard-to-treat hematological malignancies based on the tumor´s pathophysiology and reactive oxygen species (ROS) phenotype. [Background on Ag5]TMC are created by combining the atoms of certain transition metals under specific conditions to form novel molecules with entirely distinct properties from "traditional" metal. For example, silver can be used to create clusters of different and defined sizes, based on the number of atoms making up the final drug candidate. More specifically, Ag5 contains five silver atoms arranged in a specific conformation, is the first TMC derived from this novel platform and has entirely different physiological properties than the three silver atom containing Ag3. Ag5 is a water-soluble and heat stable molecule, it is orally bioavailable and a freely diffusible pan-tumor therapeutic. It selectively kills those cells with high ROS concentrations by oxidizing their antioxidant systems and subsequently drives these cells to programmed cell death. In consequence, Ag5 will preferentially kill cancer cells which typically have higher ROS levels, but will spare normal cells which display lower ROS due to their functional REDOX homeostasis. More specifically, Ag5 efficiently catalyzes the oxidation of thiol groups of thioredoxins and peroxiredoxins and thereby drives sensitive cells above a threshold to irreversible protein misfolding, protein degradation and programmed cell death. [Background on Ag5 experiments]We characterized Ag5 efficacy using a wide range ofin vitroassays and found potent Ag5 efficacy against a number of MM, CLL and AML cell lines with an IC50 in the low nM range. Ag5 sensitivity of all cell lines was correlated with ROS levels, more specifically superoxide, as measured by dihydroethidium (DHE) or MitoSOX. Furthermore, we were able to demonstrate that Ag5 treatment resulted in a concentration dependent cell cycle arrest in G1 phase, mitochondrial swelling and induction of apoptosis. Treatment of primary CLL tumor samples resulted in low nM efficacy. Finally, we could demonstrate that Ag5 was not only safely administered without any side effects in mouse and rat studies, but was equally effective as the stand-of-care bortezomib in a multiple myelomain vivomodel. [Conclusion and clinical significance]In summary, Ag5 is a novel and innovative therapeutic candidate that was shown to be safe and effective in preclinical studies, and has the promise to address the unmet medical need in hard-to-treat hematological malignancies. Keywords: Ag5, Therapeutic molecular cluster (TMC), Redox, ROS, catalysis, Ag3, AML, MM, CLL Disclosures Porto González: Arjuna:Research Funding.Carneiro:Arjuna:Research Funding.Lopez-Quintela:Arjuna:Current equity holder in private company.Treder:Arjuna:Current Employment.Dominguez:Arjuna:Current equity holder in private company.

Selective Activation of the Non-Classical Estrogen Receptor Gper Elicits Potent Anti-Tumor Activity in Multiple Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 916-916
Author(s):  
Nicola Amodio ◽  
Enrica Romeo ◽  
Maria Angelica Stamato ◽  
Eugenio Morelli ◽  
Mariateresa Fulciniti ◽  
...  
Keyword(s):  
Cell Death ◽  
Estrogen Receptor ◽  
Protein Kinases ◽  
Cell Lines ◽  
Hematological Malignancies ◽  
Mrna Levels ◽  
Selective Activation ◽  
Anti Tumor Activity ◽  
Dose Dependent

Abstract Within the hematopoietic compartment, estrogens influence the differentiation, proliferation and survival of B cells and also increase the number of plasmacells (PCs) and their capacity to produce immunoglobulins. In addition to the classical estrogen receptors, an extensive body of literature has shed light on a 7-transmembrane spanning G-protein coupled estrogen receptor, GPER (also known as GPR30). The discovery of GPER-selective agonists and antagonists has led to the comprehension of the pathophysiological role of GPER and its involvement in cancer biology. However, the functional role of GPER in hematological malignancies has not been previously investigated. We detected GPER expression in 12 MM cell lines, including dexamethasone, bortezomib and carfilzomib-resistant cell lines, as well as in Waldestrom Macroglobulinemia (WM) cell lines either at mRNA and protein level, as assessed by qRT-PCR and western blotting, respectively. Importantly, MM patients' expression dataset analysis revealed a progressive decline of GPER mRNA levels during MM progression. Moreover, adhesion of MM cell lines (NCI-H929, U266) to bone marrow stromal cells (BMSCs) reduced GPER mRNA and protein levels even further, supporting a potential role of the BM microenvironment in regulating GPER expression. To address the role of GPER-mediated signaling on MM cell survival and cell death, first we tested the selective GPER agonist G-1 ((±)-1-[(3aR *,4S *,9bS *)-4-(6-Bromo-1,3-benzodioxol-5-yl) -3a,4,5,9b-tetrahydro-3H cyclopenta [c]quinolin-8-yl] ethanone) in vitro. G-1 inhibited, in a dose-dependent manner, the survival of WM (n=2) and MM cell lines (n=9), as well as of primary MM cells (n=3), with an IC50 at 48 h ranging from 2 to 3 μM, while it did not affect the viability of healthy donors' PBMCs (n=3); moreover, G-1 synergized with bortezomib in MM1S MM cells and with ibrutinib in BCMW1 WM cells. Both in MM and WM cell lines, G-1 treatment increased cells in G2/M phase and induced a potent and dose-dependent apoptotic cell death, as assessed by Annexin V/7AAD staining and western blot analysis of active caspases 3, 7 and 9. G-1-induced apoptosis was reverted by the pan-caspase inhibitor ZVAD-FMK and was not impaired by co-colture with BMSCs or by exogenous IL-6, IGF-1 or HGF. 17β-estradiol (10nM) and the selective GPER-antagonist G-15 (0.5µM) slightly increased the survival of MM and WM cells, and this effect was overcome by G-1 treatment. Moreover, G-1 induced the occurrence of a cytoprotective autophagy, as shown by the expression of autophagic markers, such as beclin-1 and LC3A/B, the cytosolic punctate pattern of LC3B and down-regulation of p62/SQSTM1 expression, and treatment of MM and WM cell lines with the autophagy inhibitor chloroquine potentiated G-1-triggered anti-survival effects. Importantly, intraperitoneal injection of G-1 (2mg/kg) in SCID mice significantly reduced the growth of subcutaneous MM1S and bortezomib-resistant AMO-abzb xenografts, and prolonged survival of treated animals. Since GPER-dependent molecular effects in solid tumors have been attributed to modulation of MAPK activity, by using an antibody array we analyzed the phosphorylation status of 24 protein kinases after GPER activation. Notably, treatment with G-1 (2µM) reduced the phosphorylation of ERK1/2, p38α-γ, AKT and GSK3α-β. Finally, on the light of the emerging role of miRNAs in MM pathobiology, we investigated by TaqMan qPCR the effects of G-1 on the miRNA profile and found that G-1 induced the expression of tumor suppressor miR-29b by down-regulating Sp1, the major miR-29b-negative regulator, thus disrupting the previously reported miR-29b/Sp1 negative feedback loop. Consistently, an inverse correlation between GPER and Sp1 mRNA levels emerged in MM patient PCs. In addition, miR-29b canonical targets, such as CDK6 and MCL-1, were downregulated in G-1-treated MM cells. Altogether, our results indicate that GPER is expressed in MM and WM and its selective activation via G-1 triggers potent anti-tumor activity through inhibition of oncogenic protein kinases and activation of miR-29b, providing the preclinical rationale for clinical investigation of GPER-agonists to treat these hematological malignancies. Disclosures No relevant conflicts of interest to declare.

Targeting PKC: A Novel Role for Beta-catenin in ER Stress and Apoptotic Signaling

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2763-2763
Author(s):  
Marc S Raab ◽  
Iris Breitkreutz ◽  
Giovanni Tonon ◽  
Jing Zhang ◽  
Johannes Fruehauf ◽  
...  
Keyword(s):  
Cell Death ◽  
Er Stress ◽  
Tumor Cells ◽  
Cell Lines ◽  
Beta Catenin ◽  
Dependent Manner ◽  
Hek 293 ◽  
Pkc Isoforms ◽  
Wide Range

Abstract Targeting protein kinase C (PKC) isoforms by the small molecule inhibitor enzastaurin has shown promising pre-clinical activity in a wide range of tumor cells. In this study, we further delineated its mechanism of action in multiple myeloma (MM) cells and found a novel role of b-catenin in regulating growth and survival of tumor cells. Inhibition of PKC leads to rapid accumulation of b-catenin by preventing the phosphorylation required for its proteasomal degradation. Specifically, b-catenin was dephosphorylated at Ser33,37,41 and accumulated in a dose- and time-dependent manner in all cell lines tested (including primary MM cells and 10 MM cell lines, 3 colon cancer, HeLa, as well as HEK 293 cells). Microarray analysis and siRNA-mediated gene silencing in MM cells revealed that accumulated b-catenin activates early ER stress signaling via eIF2a, CHOP and p21, leading to immediate inhibition of proliferation. Conversely, knock-down of components of the ER stress response pathway by siRNA (i.e., CHOP) abrogated the inhibitory effect of enzastaurin on MM cell proliferation. Importantly, accumulated b-catenin also contributes to enzastaurin-induced cell death, since inhibition of b-catenin by siRNA partially rescued HeLa, HEK 293, and MM cells from cell death induced by enzastaurin. Analysis of downstream target molecules revealed a b-catenin -dependent up-regulation of c-Jun, but not of c-Myc or Cyclin D1. c-Jun has been reported to stabilize p73, a pro-apoptotic p53-family member; b-catenin induction by enzastaurin led to p73 (but not p53) activation, which was also abrogated by b-catenin -specific siRNA. In turn, specific knockdown of p73 by siRNA rescued cells from enzastaurin-induced apoptosis. Finally, ectopic overexpression of b-catenin in HeLa and MM cells induced c-Jun expression and p73 activation, followed by apoptotic cell death. In summary, our data reveal a novel role of b-catenin in ER stress-mediated growth inhibition and a new pro-apoptotic mechanism triggered by b-catenin upon inhibition of PKC isoforms, and further demonstrate that p73 represents a novel therapeutic target in MM. Based on these and previous data, enzastaurin is currently under clinical investigation in a variety of hematologic malignancies including MM.

scholarly journals Apoptotic and Non-Apoptotic Modalities of Thymoquinone-Induced Lymphoma Cell Death: Highlight of the Role of Cytosolic Calcium and Necroptosis

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3579
Author(s):  
Mimoune Berehab ◽  
Redouane Rouas ◽  
Haidar Akl ◽  
Hugues Duvillier ◽  
Fabrice Journe ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Lines ◽  
Apoptotic Cell ◽  
Critical Role ◽  
B Cell Lymphoma ◽  
Cytosolic Calcium ◽  
Store Operated Calcium Entry ◽  
Safe Mechanism ◽  
Apoptotic Pathways

Targeting non-apoptotic modalities might be therapeutically promising in diffuse large B cell lymphoma (DLBCL) patients with compromised apoptotic pathways. Thymoquinone (TQ) has been reported to promote apoptosis in cancer cells, but little is known about its effect on non-apoptotic pathways. This work investigates TQ selectivity against DLBCL cell lines and the cell death mechanisms. TQ reduces cell viability and kills cell lines with minimal toxicity on normal hematological cells. Mechanistically, TQ promotes the mitochondrial caspase pathway and increases genotoxicity. However, insensitivity of most cell lines to caspase inhibition by z-VAD-fmk (benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone) pointed to a critical role of non-apoptotic signaling. In cells dying through non-apoptotic death, TQ increases endoplasmic reticulum (ER) stress markers and substantially increases cytosolic calcium ([Ca2+]c) through ER calcium depletion and activation of store-operated calcium entry (SOCE). Chelation of [Ca2+]c, but not SOCE inhibitors, reduces TQ-induced non-apoptotic cell death, highlighting the critical role of calcium in a non-apoptotic effect of TQ. Investigations showed that TQ-induced [Ca2+]c signaling is primarily initiated by necroptosis upstream to SOCE, and inhibition necroptosis by necrostatin-1 alone or with z-VAD-fmk blocks the cell death. Finally, TQ exhibits an improved selectivity profile over standard chemotherapy agents, suggesting a therapeutic relevance of the pro-necroptotic effect of TQ as a fail-safe mechanism for DLBCL therapies targeting apoptosis.

scholarly journals STAT3, a Hub Protein of Cellular Signaling Pathways, Is Triggered by β-Hexaclorocyclohexane

2018 ◽  
Vol 19 (7) ◽  
pp. 2108 ◽  
Author(s):  
Elisabetta Rubini ◽  
Fabio Altieri ◽  
Silvia Chichiarelli ◽  
Flavia Giamogante ◽  
Stefania Carissimi ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Cell Lines ◽  
Molecular Mechanisms ◽  
Cellular Signaling ◽  
Environmental Pollutants ◽  
Altered Expression ◽  
Exposed Population ◽  
Wide Range ◽  
Hepg2 Cell Lines

Background: Organochlorine pesticides (OCPs) are widely distributed in the environment and their toxicity is mostly associated with the molecular mechanisms of endocrine disruption. Among OCPs, particular attention was focused on the effects of β-hexaclorocyclohexane (β-HCH), a widely common pollutant. A detailed epidemiological study carried out on exposed population in the “Valle del Sacco” found correlations between the incidence of a wide range of diseases and the occurrence of β-HCH contamination. Taking into account the pleiotropic role of the protein signal transducer and activator of transcription 3 (STAT3), its function as a hub protein in cellular signaling pathways triggered by β-HCH was investigated in different cell lines corresponding to tissues that are especially vulnerable to damage by environmental pollutants. Materials and Methods: Human prostate cancer (LNCaP), human breast cancer (MCF-7 and MDA-MB 468), and human hepatoma (HepG2) cell lines were treated with 10 μM β-HCH in the presence or absence of specific inhibitors for different receptors. All samples were subjected to analysis by immunoblotting and RT-qPCR. Results and Conclusions: The preliminary results allow us to hypothesize the involvement of STAT3, through both its canonical and non-canonical pathways, in response to β-HCH. Moreover, we ascertained the role of STAT3 as a master regulator of energy metabolism via the altered expression and localization of HIF-1α and PKM2, respectively, resulting in a Warburg-like effect.

Aldehyde biphenyl chalcones induce immunogenic apoptotic-like cell death and are promising new safe compounds against a wide range of hematologic cancers

2020 ◽  
Vol 12 (8) ◽  
pp. 673-688
Author(s):  
Mariana F Maioral ◽  
Natália M Stefanes ◽  
Patrícia D Neuenfeldt ◽  
Louise D Chiaradia-Delatorre ◽  
Ricardo J Nunes ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Endoplasmic Reticulum Stress ◽  
Hematological Malignancies ◽  
Promyelocytic Leukemia ◽  
Leukemic Cells ◽  
Leukemia Cells ◽  
Promyelocytic Leukemia Protein ◽  
Wide Range ◽  
Antileukemic Effect

Aim: Investigate the apoptotic mechanisms of two new aldehyde biphenyl chalcones on leukemia cells. Materials & methods: From a series of 71 new chalcones, we selected the two most cytotoxic. Results: JA3 and JA7 were cytotoxic not only against hematological malignancies but also against solid tumor and cancer stem cells, yet with no toxicity to normal cells. Moreover, they induced immunogenic apoptotic-like cell death independently of promyelocytic leukemia protein, with extensive mitochondrial damages downstream of endoplasmic reticulum stress. Preventing endoplasmic reticulum stress and the upregulation of proapoptotic machinery inhibited JA3- and JA7-induced cell death. Likewise, blocking receptor Fas protected cells from killing. They increased the antileukemic effect of cytarabine and vincristine and killed leukemic cells collected from patients with different acute leukemia subtypes. Conclusion: JA3 and JA7 represent new promising prototypes for the development of new chemotherapeutics.

scholarly journals Role of notch pathway and HNF1 in cell death induced by HDACs inhibitors in ovarian cancer cell lines, serous and clear cells

2010 ◽  
Vol 4 (S2) ◽  
Author(s):  
Fernanda Silva ◽  
Jacinta Serpa ◽  
Germana Domingues ◽  
Gabriela Silva ◽  
António Almeida ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Death ◽  
Cell Lines ◽  
Cancer Cell ◽  
Ovarian Cancer Cell ◽  
Notch Pathway ◽  
Cancer Cell Lines ◽  
Clear Cells ◽  
Ovarian Cancer Cell Lines

scholarly journals Side-by-side comparison of BH3-mimetics identifies MCL-1 as a key therapeutic target in AML

2019 ◽  
Vol 10 (12) ◽  
Author(s):  
Larissa Ewald ◽  
Jessica Dittmann ◽  
Meike Vogler ◽  
Simone Fulda
Keyword(s):  
Cell Death ◽  
Cell Lines ◽  
Therapeutic Target ◽  
Treatment Options ◽  
B Cell Lymphoma ◽  
Bh3 Mimetics ◽  
Domain 3 ◽  
Functional Relevance ◽  
Induced Apoptosis ◽  
Apoptosis Inducing Agents

AbstractDespite advances in the treatment of acute myeloid leukemia (AML), prognosis of AML patients is still dismal and better treatment options are required. B-cell Lymphoma 2 (BCL-2) homology domain 3 (BH3)-mimetics are emerging as a novel class of apoptosis-inducing agents that are currently being tested for the treatment of different hematological malignancies including AML. Particularly, the selective BCL-2 inhibitor ABT-199/Venetoclax is demonstrating clinical responses and has recently been approved in combination for the treatment of AML. Compounds targeting the related protein MCL-1 have recently entered clinical trials, highlighting the urgency to compare the different BH3-mimetics and identify the most promising antiapoptotic target in AML. We performed a side-by-side comparison of different highly selective and potent BH3-mimetics targeting BCL-2 (ABT-199), MCL-1 (S63845) or BCL-xL (A1331852) in a panel of AML cell lines and primary patient cells. Gene knockdown using siRNAs was utilized to investigate the functional relevance of BCL-2 proteins. Western blotting and immunoprecipitations were used to explore the influence of BH3-mimetics on interactions between pro- and antiapoptotic BCL-2 proteins. A1331852 induced apoptosis only in selected cases, indicating that BCL-xL is not a very promising therapeutic target in AML. However, S63845 displayed higher potency than ABT-199, with more cell lines and primary cells responding to S63845 than to ABT-199. MCL-1 dependency in AML cells was confirmed by siRNA-mediated knockdown of MCL-1, which was sufficient to induce apoptosis. S63845-induced cell death was accompanied by a displacement of the BH3-only protein BIM as well as BAK, resulting in BAK-dependent apoptosis. In contrast, ABT-199-induced cell death was mediated by BAX rather than BAK, indicating distinct non-redundant molecular functions of BCL-2 and MCL-1 in AML. Our study reveals that MCL-1 may be a more prevalent therapeutic target than BCL-2 in AML and identifies BIM and BAK as important mediators of S63845-induced apoptosis in AML.

Cannabis-induced cytotoxicity in leukemic cell lines: the role of the cannabinoid receptors and the MAPK pathway

Blood ◽  
2005 ◽  
Vol 105 (3) ◽  
pp. 1214-1221 ◽  
Author(s):  
Thomas Powles ◽  
Robert te Poele ◽  
Jonathan Shamash ◽  
Tracy Chaplin ◽  
David Propper ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Cell Death ◽  
Cell Lines ◽  
Leukemic Cell ◽  
Cytotoxic Agents ◽  
Complex Signal ◽  
Signal Transduction Pathways ◽  
Potent Inducer ◽  
Leukemic Cell Lines

Abstract Δ9-Tetrahydrocannabinol (THC) is the active metabolite of cannabis. THC causes cell death in vitro through the activation of complex signal transduction pathways. However, the role that the cannabinoid 1 and 2 receptors (CB1-R and CB2-R) play in this process is less clear. We therefore investigated the role of the CB-Rs in mediating apoptosis in 3 leukemic cell lines and performed microarray and immunoblot analyses to establish further the mechanism of cell death. We developed a novel flow cytometric technique of measuring the expression of functional receptors and used combinations of selective CB1-R and CB2-R antagonists and agonists to determine their individual roles in this process. We have shown that THC is a potent inducer of apoptosis, even at 1 × IC50 (inhibitory concentration 50%) concentrations and as early as 6 hours after exposure to the drug. These effects were seen in leukemic cell lines (CEM, HEL-92, and HL60) as well as in peripheral blood mononuclear cells. Additionally, THC did not appear to act synergistically with cytotoxic agents such as cisplatin. One of the most intriguing findings was that THC-induced cell death was preceded by significant changes in the expression of genes involved in the mitogen-activated protein kinase (MAPK) signal transduction pathways. Both apoptosis and gene expression changes were altered independent of p53 and the CB-Rs.

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