Therapeutic Targeting of the Bcl2 Family

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. SCI-42-SCI-42
Author(s):  
Anthony Letai ◽  
Matthew S. Davids ◽  
Triona Ni Chonghaile ◽  
Jing Deng ◽  
Luv Patel
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Lymphoblastic Leukemia ◽  
Lymphocytic Leukemia ◽  
Mitochondrial Outer Membrane ◽  
Short Term ◽  
Provocative Test ◽  
Mitochondrial Outer Membrane Permeabilization

Abstract Many, perhaps most, cancer chemotherapy agents kill cancer cells via the mitochondrial pathway of apoptosis that is controlled by the Bcl-2 family of proteins. Bcl-2 family proteins regulate commitment to cell death by controlling mitochondrial outer membrane permeabilization (MOMP). To better understand how cancer cells commit to apoptosis, and what drugs might make them commit to apoptosis, we have studied perturbing mitochondria with BH3 peptides that are derived from pro-death Bcl-2 family proteins. Using this provocative test, which we call BH3 profiling, we are able to measure how close a cell is to the threshold of apoptosis, a property we call “priming”. Priming corresponds to sensitivity to chemotherapy. Moreover, BH3 profiling can be used to detect dependence on Bcl-2 and Bcl-xL for survival, which predicts cytotoxic response to small molecule antagonists such as ABT-199 and ABT-263. In acute lymphoblastic leukemia, we find that dependence on either Bcl-2 or Bcl-xL varies from case to case, with very important consequences for sensitivity to ABT-199 and ABT-263. In chronic lymphocytic leukemia, ABT-199 has already demonstrated significant clinical activity that corresponds to its on-target activity in mitochondria in vitro. We have been testing how this in vitro mitochondrial activity in BH3 profiling assays might be translated into a useful clinical predictive biomarker. Finally, we can measure how short term incubation with many kinds of drugs, including targeted pathway inhibitors, can increase cancer cell priming, including for primary lymphoid malignancy cells. This short term increase in priming predicts subsequent cancer cell death, including in clinical treatment. We call this method “Dynamic BH3 Profiling” and are exploring how it might best be utilized in the clinic. Disclosures: Letai: Dana-Farber Cancer Institute: Patents & Royalties; AbbVie: Consultancy.

scholarly journals Anticancer Activity of Cynomorium coccineum

Cancers ◽  
2018 ◽  
Vol 10 (10) ◽  
pp. 354 ◽  
Author(s):  
Mouna Sdiri ◽  
Xiangmin Li ◽  
William Du ◽  
Safia El-Bok ◽  
Yi-Zhen Xie ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Anticancer Activity ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cell Cycle Progression ◽  
Cycle Progression

The extensive applications of Cynomorium species and their rich bioactive secondary metabolites have inspired many pharmacological investigations. Previous research has been conducted to examine the biological activities and numerous interesting pharmaceutical activities have been reported. However, the antitumor activities of these species are unclear. To understand the potential anticancer activity, we screened Cynomorium coccineum and Cynomorium songaricum using three different extracts of each species. In this study, the selected extracts were evaluated for their ability to decrease survival rates of five different cancer cell lines. We compared the cytotoxicity of the three different extracts to the anticancer drug vinblastine and one of the most well-known medicinal mushrooms Amaurederma rude. We found that the water and alcohol extracts of C. coccineum at the very low concentrations possessed very high capacity in decreasing the cancer cells viability with a potential inhibition of tumorigenesis. Based on these primitive data, we subsequently tested the ethanol and the water extracts of C. coccineum, respectively in in vitro and in vivo assays. Cell cycle progression and induction of programmed cell death were investigated at both biological and molecular levels to understand the mechanism of the antitumor inhibitory action of the C. coccineum. The in vitro experiments showed that the treated cancer cells formed fewer and smaller colonies than the untreated cells. Cell cycle progression was inhibited, and the ethanol extract of C. coccineum at a low concentration induced accumulation of cells in the G1 phase. We also found that the C. coccineum’s extracts suppressed viability of two murine cancer cell lines. In the in vivo experiments, we injected mice with murine cancer cell line B16, followed by peritoneal injection of the water extract. The treatment prolonged mouse survival significantly. The tumors grew at a slower rate than the control. Down-regulation of c-myc expression appeared to be associated with these effects. Further investigation showed that treatment with C. coccineum induced the overexpression of the tumor suppressor Foxo3 and other molecules involved in inducing autophagy. These results showed that the C. coccineum extract exerts its antiproliferative activity through the induction of cell death pathway. Thus, the Cynomorium plants appear to be a promising source of new antineoplastic compounds.

In-Vitro Anti-Proliferative, Apoptotic and Antioxidative Activities of Medicinal Herb Kalonji (Nigella sativa)

2019 ◽  
Vol 20 (15) ◽  
pp. 1288-1308
Author(s):  
Tahir Maqbool ◽  
Sana J. Awan ◽  
Sabeen Malik ◽  
Faheem Hadi ◽  
Somia Shehzadi ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Internal Control ◽  
Nigella Sativa ◽  
Annexin V ◽  
Cancer Cell Lines ◽  
Oxidative Enzymes

Background: Natural product with apoptotic activity could serve as a potential new source for anti-cancer medicine. Numerous phytochemicals from plants have shown to exert antineoplastic effects via programmed cell death (apoptosis). Cancer is one of the leading causes of death in prosperous countries. The subject study was intended to evaluate the anticancer properties of Kalonji extracts against cancer cell lines HeLa and HepG2 and normal cell lines BHK and VERO were used as normal controls. Materials & Methods: For the evaluation of anti-proliferative effects, cell viability and cell death in all groups of cells were evaluated via MTT, crystal violet and trypan blue assays. For the evaluation of angiogenesis, Immunocytochemistry and ELISA of VEGF were done. Immunocytochemistry and ELISA of Annexin-V and p53 were performed for the estimation of apoptosis in all groups of cells. Furthermore, LDH assay, antioxidant enzymes activity (GSH, APOX, CAT and SOD) and RT-PCR with proliferative and apoptotic markers along with internal control were also performed. Cancer cells of both cell lines HepG2 and HeLa cells showed reduced viability, angiogenesis and proliferation with increased apoptosis when treated with Kalonji extracts. Whereas anti-oxidative enzymes show enhanced levels in treated cancer cells as compared to untreated ones. Conclusion: It was observed that Kalonji extracts have the ability to induce apoptosis and improve the antioxidant status of HeLa and HepG2 cells. They can also inhibit the proliferation and angiogenesis in both these cancer cell lines.

scholarly journals Regorafenib Alteration of the BCL-xL/MCL-1 Ratio Provides a Therapeutic Opportunity for BH3-Mimetics in Hepatocellular Carcinoma Models

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 332 ◽  
Author(s):  
Blanca Cucarull ◽  
Anna Tutusaus ◽  
Miguel Subías ◽  
Milica Stefanovic ◽  
Tania Hernáez-Alsina ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Death ◽  
Hepatoma Cell ◽  
Mitochondrial Outer Membrane ◽  
Cytochrome C Release ◽  
Multikinase Inhibitor ◽  
Bh3 Mimetics ◽  
Mitochondrial Outer Membrane Permeabilization

Background: The multikinase inhibitor regorafenib, approved as second-line treatment for hepatocellular carcinoma (HCC) after sorafenib failure, may induce mitochondrial damage. BH3-mimetics, inhibitors of specific BCL-2 proteins, are valuable drugs in cancer therapy to amplify mitochondrial-dependent cell death. Methods: In in vitro and in vivo HCC models, we tested regorafenib’s effect on the BCL-2 network and the efficacy of BH3-mimetics on HCC treatment. Results: In hepatoma cell lines and Hep3B liver spheroids, regorafenib cytotoxicity was potentiated by BCL-xL siRNA transfection or pharmacological inhibition (A-1331852), while BCL-2 antagonism had no effect. Mitochondrial outer membrane permeabilization, cytochrome c release, and caspase-3 activation mediated A-1331852/regorafenib-induced cell death. In a patient-derived xenograft (PDX) HCC model, BCL-xL inhibition stimulated regorafenib activity, drastically decreasing tumor growth. Moreover, regorafenib-resistant HepG2 cells displayed increased BCL-xL and reduced MCL-1 expression, while A-1331852 reinstated regorafenib efficacy in vitro and in a xenograft mouse model. Interestingly, BCL-xL levels, associated with poor prognosis in liver and colorectal cancer, and the BCL-xL/MCL-1 ratio were detected as being increased in HCC patients. Conclusion: Regorafenib primes tumor cells to BH3-mimetic-induced cell death, allowing BCL-xL inhibition with A-1331852 or other strategies based on BCL-xL degradation to enhance regorafenib efficacy, offering a novel approach for HCC treatment, particularly for tumors with an elevated BCL-xL/MCL-1 ratio.

scholarly journals Curcumin a Multifaceted Compound with Hormetic Behaviour that Mediates an Intricate Crosstalk between Mitochondrial Biogenesis, Mitophagy, Mitophagic Death and Apoptosis

2017 ◽  
Author(s):  
Nathan Earl Rainey ◽  
Aoula Moustapha ◽  
Raphaelle Parker ◽  
Patrice Xavier Petit
Keyword(s):  
Cell Death ◽  
Mitochondrial Biogenesis ◽  
Calcium Release ◽  
Mitochondrial Outer Membrane ◽  
Protective Mechanism ◽  
High Dose ◽  
M Cell ◽  
Mitochondrial Outer Membrane Permeabilization

Curcumin, found in the rhizome of turmeric, has extensive therapeutic promises via its antioxidant, anti-inflammatory, and antiproliferative properties. Preclinical in vitro and in vivo data have shown curcumin to be an effective treatment for multiple cancers. These effects are drived by curcumin's ability to induce G2/M cell cycle arrest, induction of autophagy, activation of apoptotic pathways, disruption of molecular signaling, inhibition of invasion and metastasis, and by increasing the efficacy of existing chemotherapeutics. Here we focused on the hormetic behaviour of curcumin. Frequently, low doses of toxins and other stressors not only are harmless but also activate an adaptive stress whereas high dose activates acute responses like autophagy and cell death. This phenomenon is referred to as hormesis. Many molecules that cause cell death elicite an initial autophagic step that is a cytoprotective mechanism relying on elimination of dysfunctional structures intracellular, notably by mitophagy. This phenomenon is considered as a primarily protective mechanism against stressors. At higher doses, cells undergo mitochondrial outer membrane permeabilization due to calcium release from the endoplasmic reticulum and die. Herein, we address the complex crosstalk between the induced mitochondrial biogenesis, mitochondrial destabilization accompanied by mitophagy and cell death that can also be at play.

ATL

2014 ◽  
Vol 24 (3) ◽  
pp. 437-443 ◽  
Author(s):  
Jie Li ◽  
Geng Cui ◽  
Lu Sun ◽  
Shu-Juan Wang ◽  
Shuang Tian ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Proliferation ◽  
Cell Death ◽  
Epithelial Ovarian Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Cell Apoptosis ◽  
Cancer Cell Death ◽  
Ovarian Cells

ObjectiveARHIis a maternally imprinted tumor suppressor gene that is responsible for initiating programmed cell death and inhibiting cancer cell growth. However, the influence ofARHIon epithelial ovarian cancer cell death and the underlying mechanisms behind howARHIregulates cancer cells still require further studies.MethodsEpithelial ovarian cancer cells TOV112D and ES-2 were used in this in vitro study. Cell proliferation, apoptosis, and autophagy activities were compared in TOV112D and ES-2 cells transfected withARHIvectors or control vectors. Bcl-2 siRNA was transfected into TOV112D cells to investigate the roles of Bcl-2 played in regulating apoptosis and autophagy.ResultsARHIexpression was reduced in TOV112D and ES-2 cells compared with normal epithelial ovarian cells (NOE095 and HOSEpiC). OverexpressedARHIinhibited cancer cell proliferation, whereas induced forced cell apoptosis and excessive formation of autophagosomes inhibited promoted cell death. Furthermore, we found that Bcl-2 expression moderately declined in response toARHIoverexpressing in ES-2 and TOV112D cells; meanwhile, more apoptotic cells and higher LC3 level presented after silence of Bcl-2 in TOV112D cells. Reduced Bcl-2–Beclin 1 complex were observed inARHIoverexpressing cells. Moreover, modulation ofARHIto Bcl-2 expression could be ascribed partially to the activation of PI3k/AKT pathway. The addition of LY294002 enabled to suppress Bcl-2 expression and cell proliferation.ConclusionsThe silence ofARHIexpression in vitro seems to accelerate the malignant transformation of healthy ovarian cells by restraining apoptosis and autophagy. The overexpressedARHIin TOV112D cancer cells suppresses the activation of PI3K/AKT and reduces the expression of Bcl-2, leading to enhanced cell apoptosis and autophagic cancer cell death.

Venetoclax and dexamethasone synergize with inotuzumab-ozogamicin induced DNA damage signaling in B-lineage ALL

Blood ◽  
2020 ◽  
Author(s):  
Hanna Kirchhoff ◽  
Uemran Karsli ◽  
Caroline Schoenherr ◽  
Karin Battmer ◽  
Sergej Erschow ◽  
...  
Keyword(s):  
Dna Damage ◽  
Lymphoblastic Leukemia ◽  
Mitochondrial Outer Membrane ◽  
Dependent Manner ◽  
Inotuzumab Ozogamicin ◽  
Free Survival ◽  
Mitochondrial Outer Membrane Permeabilization ◽  
Dismal Prognosis ◽  
Pdx Models

Adult patients with relapsed B- cell precursor acute lymphoblastic leukemia (BCP-ALL) have a dismal prognosis. To improve pharmacotherapy we analyzed apoptosis induction by venetoclax and inotuzumab-ozogamicin in terms of cytotoxicity and mode of action. Flow cytometry-based analyses of mitochondrial outer membrane permeabilization (MOMP) and Ataxia telangiectasia mutated (ATM) activation demonstrates rapid MOMP induction by venetoclax and DNA-damage signalling by inotuzumab-ozogamicin, respectively. In primary ALL samples and patient-derived xenograft (PDX) models venetoclax and inotuzumab-ozogamicin cooperated and synergized in combination with dexamethasone in vitro in all ALL samples tested. In murine PDX models inotuzumab-ozogamicin but not venetoclax induced complete remission in a dose dependent manner but constantly failed to achieve relapse-free survival. In contrast combination therapy with venetoclax, dexamethasone and inotuzumab-ozogamicin induced long-term leukemia- and treatment-free survival in all three ALL-PDX models tested. These data demonstrate synergistic and highly efficient pharmacotherapy in preclinical models that qualifies for evaluation in clinical trials.

Short-Term Exposure of Cancer Cells to Micromolar Doses of Paclitaxel, with or without Hyperthermia, Induces Long-Term Inhibition of Cell Proliferation and Cell Death In Vitro

2007 ◽  
Vol 14 (3) ◽  
pp. 1220-1228 ◽  
Author(s):  
John Michalakis ◽  
Spyros D. Georgatos ◽  
Eelco de Bree ◽  
Hara Polioudaki ◽  
John Romanos ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Death ◽  
Cancer Cells ◽  
Short Term ◽  
Short Term Exposure

scholarly journals BDA-366, a putative Bcl-2 BH4 domain antagonist, induces apoptosis independently of Bcl-2 in a variety of cancer cell models

2020 ◽  
Vol 11 (9) ◽  
Author(s):  
Tamara Vervloessem ◽  
Binu K. Sasi ◽  
Elena Xerxa ◽  
Spyridoula Karamanou ◽  
Justin Kale ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Cell ◽  
Therapeutic Potential ◽  
B Cell Lymphoma ◽  
Cell Types ◽  
Lymphocytic Leukemia ◽  
Current View ◽  
Selective Toxicity ◽  
Protein Levels

Abstract Several cancer cell types, including chronic lymphocytic leukemia (CLL) and diffuse large B-cell lymphoma (DLBCL) upregulate antiapoptotic Bcl-2 to cope with oncogenic stress. BH3 mimetics targeting Bcl-2’s hydrophobic cleft have been developed, including venetoclax as a promising anticancer precision medicine for treating CLL patients. Recently, BDA-366 was identified as a small molecule BH4-domain antagonist that could kill lung cancer and multiple myeloma cells. BDA-366 was proposed to switch Bcl-2 from an antiapoptotic into a proapoptotic protein, thereby activating Bax and inducing apoptosis. Here, we scrutinized the therapeutic potential and mechanism of action of BDA-366 in CLL and DLBCL. Although BDA-366 displayed selective toxicity against both cell types, the BDA-366-induced cell death did not correlate with Bcl-2-protein levels and also occurred in the absence of Bcl-2. Moreover, although BDA-366 provoked Bax activation, it did neither directly activate Bax nor switch Bcl-2 into a Bax-activating protein in in vitro Bax/liposome assays. Instead, in primary CLL cells and DLBCL cell lines, BDA-366 inhibited the activity of the PI3K/AKT pathway, resulted in Bcl-2 dephosphorylation and reduced Mcl-1-protein levels without affecting the levels of Bcl-2 or Bcl-xL. Hence, our work challenges the current view that BDA-366 is a BH4-domain antagonist of Bcl-2 that turns Bcl-2 into a pro-apoptotic protein. Rather, our results indicate that other mechanisms beyond switching Bcl-2 conformation underlie BDA-366’s cell-death properties that may implicate Mcl-1 downregulation and/or Bcl-2 dephosphorylation.

The Effects of the Surface Properties of a Gold Nanorod on Its In Vitro/Vivo Toxicity Against Cancer Cells

2019 ◽  
Vol 15 (11) ◽  
pp. 2262-2270
Author(s):  
Jing Gong ◽  
Yingying Zhang ◽  
Yong Huang ◽  
Tingying Zhang ◽  
Beibei Liang ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Surface Properties ◽  
Cancer Cell ◽  
Surface Potential ◽  
Intracellular Transport ◽  
Laser Scanning Microscopy ◽  
Cancer Cell Death ◽  
Aspect Ratios

Gold nano rods (GNRs) have showed cytotoxicity to cancer cells. At the same time, it shows little effects on non-tumor cells. Between GNRs and sub-cellular organelles, the understanding of interaction plays a very important role to determine the intracellular mechanisms. The purpose of what we done is to explain the effects of the surface properties of GNRs on specific cancer cell death. Three GNR samples with different aspect ratios were finely prepared by the seed-mediated growth method. Then the intracellular transport and the in vitro/vivo mechanisms of cancer cell death were studied by transmission electron microscopy (TEM), confocal laser scanning microscopy (CLSM), laser light scattering, and flow cytometry (FCM). It was found that GNRs700 exhibited the largest photothermal conversion efficiency. However, the GNR660 with or without light stimulation exhibited the highest cytotoxicity against cancer cells, which was contradict to the general knowledge. Detailed intracellular investigations showed that the lysosome was the key sub-organelle affecting the GNR function. Further experiments revealed that cytotoxicity was strongly affected by the GNR's surface potential. This potential was actually related to the density of surface cationic molecules, which further regulated lysosomal membrane penetration. The results obtained herein indicated that the physicochemical properties of the surface potential mediated the specific toxicity of GNRs against tumours.

scholarly journals Synthesis, cellular evaluation, and mechanism of action of piperlongumine analogs

2012 ◽  
Vol 109 (38) ◽  
pp. 15115-15120 ◽  
Author(s):  
Drew J. Adams ◽  
Mingji Dai ◽  
Giovanni Pellegrino ◽  
Bridget K. Wagner ◽  
Andrew M. Stern ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Mechanism Of Action ◽  
Cell Types ◽  
Structural Modifications ◽  
Cancer Cell Death ◽  
Nontransformed Cell

Piperlongumine is a naturally occurring small molecule recently identified to be toxic selectively to cancer cells in vitro and in vivo. This compound was found to elevate cellular levels of reactive oxygen species (ROS) selectively in cancer cell lines. The synthesis of 80 piperlongumine analogs has revealed structural modifications that retain, enhance, and ablate key piperlongumine-associated effects on cells, including elevation of ROS, cancer cell death, and selectivity for cancer cells over nontransformed cell types. Structure/activity relationships suggest that the electrophilicity of the C2-C3 olefin is critical for the observed effects on cells. Furthermore, we show that analogs lacking a reactive C7-C8 olefin can elevate ROS to levels observed with piperlongumine but show markedly reduced cell death, suggesting that ROS-independent mechanisms, including cellular cross-linking events, may also contribute to piperlongumine’s induction of apoptosis. In particular, we have identified irreversible protein glutathionylation as a process associated with cellular toxicity. We propose a mechanism of action for piperlongumine that may be relevant to other small molecules having two sites of reactivity, one with greater and the other with lesser electrophilicity.

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