abt-199 has been researched along with navitoclax* in 44 studies
16 review(s) available for abt-199 and navitoclax
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Co-Operativity between MYC and BCL-2 Pro-Survival Proteins in Cancer.
B-Cell Lymphoma 2 (BCL-2), c-MYC and related proteins are arguably amongst the most widely studied in all of biology. Every year there are thousands of papers reporting on different aspects of their biochemistry, cellular and physiological mechanisms and functions. This plethora of literature can be attributed to both proteins playing essential roles in the normal functioning of a cell, and by extension a whole organism, but also due to their central role in disease, most notably, cancer. Many cancers arise due to genetic lesions resulting in deregulation of both proteins, and indeed the development and survival of tumours is often dependent on co-operativity between these protein families. In this review we will discuss the individual roles of both proteins in cancer, describe cancers where co-operativity between them has been well-characterised and finally, some strategies to target these proteins therapeutically. Topics: Aniline Compounds; Antineoplastic Agents; Apoptosis; Biphenyl Compounds; Bridged Bicyclo Compounds, Heterocyclic; Carcinogenesis; Cell Line, Tumor; Cell Survival; Clinical Trials as Topic; Gene Expression Regulation, Neoplastic; Humans; Morpholinos; Neoplasms; Nitrophenols; Peptide Fragments; Piperazines; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-myc; Rituximab; Signal Transduction; Sulfonamides | 2021 |
Senotherapeutics for HIV and aging.
To summarize the state of chronic, treated HIV infection and its contribution to accelerated aging, and to evaluate recent research relevant to the study and treatment of aging and senescence.. Chronic treated HIV-1 infection is associated with significant risk of end-organ impairment, non-AIDS-associated malignancies, and accelerated physiologic aging. Coupled with the chronologic aging of the HIV-1-positive population, the development of therapies that target these processes is of great clinical importance. Age-related diseases are partly the result of cellular senescence. Both immune and nonimmune cell subsets are thought to mediate this senescent phenotype, a state of stable cell cycle arrest characterized by sustained release of pro-inflammatory mediators. Recent research in the field of aging has identified a number of 'senotherapeutics' to combat aging-related diseases, pharmacologic agents that act either by selectively promoting the death of senescent cells ('senolytics') or modifying senescent phenotype ('senomorphics').. Senescence is a hallmark of aging-related diseases that is characterized by stable cell cycle arrest and chronic inflammation. Chronic HIV-1 infection predisposes patients to aging-related illnesses and is similarly marked by a senescence-like phenotype. A better understanding of the role of HIV-1 in aging will inform the development of therapeutics aimed at eliminating senescent cells that drive accelerated physiologic aging. Topics: Aging; Aniline Compounds; Antibiotics, Antineoplastic; Antineoplastic Agents; Antiretroviral Therapy, Highly Active; Bridged Bicyclo Compounds, Heterocyclic; Cardiovascular Diseases; CD4-CD8 Ratio; Cell Cycle Checkpoints; Cellular Senescence; Histone Deacetylase Inhibitors; HIV Infections; HIV-1; Humans; Inflammation; Janus Kinases; Nitriles; Panobinostat; Pyrazoles; Pyrimidines; Sirolimus; Sulfonamides; T-Lymphocyte Subsets | 2020 |
Targeting cancer's Achilles' heel: role of BCL-2 inhibitors in cellular senescence and apoptosis.
Members of the antiapoptotic BCL-2 proteins are involved in tumor growth, progression and survival, and are also responsible for chemoresistance to conventional anticancer agents. Early efforts to target these proteins yielded some active compounds; however, newer methodologies involving structure-based drug design, Nuclear Magnetic Resonance (NMR)-based screening and fragment-based screening yielded more potent compounds. Discovery of specific as well as nonspecific inhibitors of this class of proteins has resulted in great advances in targeted chemotherapy and decrease in chemoresistance. Here, we review the history and current progress in direct as well as selective targeting of the BCL-2 proteins for anticancer therapy. Topics: Aniline Compounds; Antineoplastic Agents; Apoptosis; Arylsulfonates; Binding Sites; Bridged Bicyclo Compounds, Heterocyclic; Carboxylic Acids; Cell Line, Tumor; Cellular Senescence; Drug Screening Assays, Antitumor; Gene Expression Regulation; Humans; Hydrophobic and Hydrophilic Interactions; Hydroxyquinolines; Indoles; Molecular Structure; Molecular Targeted Therapy; Myeloid Cell Leukemia Sequence 1 Protein; Protein Binding; Protein Conformation; Proto-Oncogene Proteins c-bcl-2; Pyrimidines; Pyrogallol; Pyrroles; Salicylates; Structure-Activity Relationship; Sulfonamides | 2019 |
Emerging approaches to target mitochondrial apoptosis in cancer cells.
Apoptosis is a highly conserved programme for removing damaged and unwanted cells. Apoptosis in most cells is coordinated on mitochondria by the Bcl-2 family of proteins. The balance between pro- and anti-apoptotic Bcl-2 family proteins sets a threshold for mitochondrial apoptosis, a balance that is altered during cancer progression. Consequently, avoidance of cell death is an established cancer hallmark. Although there is a general perception that tumour cells are more resistant to apoptosis than their normal counterparts, the realities of cell death regulation in cancer are more nuanced. In this review we discuss how a profound understanding of this control has led to new therapeutic approaches, including the new class of BH3-mimetics, which directly target apoptosis as a vulnerability in cancer. We discuss recent findings that highlight the current limitations in our understanding of apoptosis and how these novel therapeutics work. Topics: Aniline Compounds; Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; Bridged Bicyclo Compounds, Heterocyclic; Humans; Mitochondria; Mitochondrial Membrane Transport Proteins; Neoplasms; Proto-Oncogene Proteins c-bcl-2; Pyrimidines; Sulfonamides; Thiophenes | 2019 |
Targeting BCL2 in Chronic Lymphocytic Leukemia and Other Hematologic Malignancies.
Apoptosis, the process of programmed cell death, occurs normally during development and aging. Members of the B-cell lymphoma 2 (BCL2) family of proteins are central regulators of apoptosis, and resistance to apoptosis is one of the hallmarks of cancer. Targeting the apoptotic pathway via BCL2 inhibitors has been considered a promising treatment strategy in the past decade. Initial efforts with small molecule BH3 mimetics such as ABT-737 and ABT-263 (navitoclax) pioneered the development of the first-in-class Food and Drug Administration (FDA)-approved oral BCL2 inhibitor, venetoclax. Venetoclax was approved for the treatment of chronic lymphocytic leukemia and acute myeloid leukemia, and is now being studied in a number of hematologic malignancies. Several other inhibitors targeting different BCL2 family members are now in early stages of development. Topics: Aniline Compounds; Antineoplastic Agents; Apoptosis; Biphenyl Compounds; Bridged Bicyclo Compounds, Heterocyclic; Drug Approval; Hematologic Neoplasms; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Molecular Targeted Therapy; Nitrophenols; Piperazines; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; United States; United States Food and Drug Administration | 2019 |
Targeting anti-apoptotic BCL2 family proteins in haematological malignancies - from pathogenesis to treatment.
Topics: Aniline Compounds; Antineoplastic Agents; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Hematologic Neoplasms; Humans; Molecular Targeted Therapy; Proto-Oncogene Proteins c-bcl-2; Sulfonamides | 2017 |
Control of cell death and mitochondrial fission by ERK1/2 MAP kinase signalling.
Topics: Aniline Compounds; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Apoptosis Regulatory Proteins; Bridged Bicyclo Compounds, Heterocyclic; Drug Screening Assays, Antitumor; Humans; Indoles; MAP Kinase Signaling System; Mitochondrial Dynamics; Molecular Targeted Therapy; Neoplasm Proteins; Neoplasms; Oncogene Addiction; Proto-Oncogene Proteins c-bcl-2; Pyrroles; Sulfonamides | 2017 |
The Development and Current Use of BCL-2 Inhibitors for the Treatment of Chronic Lymphocytic Leukemia.
The BCL-2 family of proteins integrates pro- and anti-apoptotic signals within the cell and is responsible for initiation of caspase-dependent apoptosis. Chronic lymphocytic leukemia (CLL) cells are particularly dependent on the anti-apoptotic protein BCL-2 for their survival, making this an attractive therapeutic target in CLL. Several early efforts to create inhibitors of the anti-apoptotic family members faced significant challenges, but eventually, the BCL-2 specific inhibitor venetoclax moved forward in CLL. Overall and complete response rates to venetoclax monotherapy in relapsed, refractory CLL are approximately 80 and 20%, respectively, even in patients with high-risk 17p deletion. Toxicities have been manageable and include neutropenia, diarrhea, and nausea. The risk of tumor lysis syndrome (TLS), seen in early experience with the drug, has been mitigated by the use of appropriate TLS risk assessment, prophylaxis, and management. Future studies of venetoclax will focus on combination approaches, predictive biomarker discovery, and mechanisms of resistance. Topics: Aniline Compounds; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Gossypol; Humans; Indoles; Leukemia, Lymphocytic, Chronic, B-Cell; Neutropenia; Proto-Oncogene Proteins c-bcl-2; Pyrroles; Sulfonamides; Thionucleotides | 2017 |
BCL-2: Long and winding path from discovery to therapeutic target.
In 1988, the BCL-2 protein was found to promote cancer by limiting cell death rather than enhancing proliferation. This discovery set the wheels in motion for an almost 30 year journey involving many international research teams that has recently culminated in the approval for a drug, ABT-199/venetoclax/Venclexta that targets this protein in the treatment of cancer. This review will describe the long and winding path from the discovery of this protein and understanding the fundamental process of apoptosis that BCL-2 and its numerous homologues control, through to its exploitation as a drug target that is set to have significant benefit for cancer patients. Topics: Aniline Compounds; Animals; Antineoplastic Agents; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Drug Design; Drug Discovery; Genes, bcl-2; Humans; Neoplasms; Protein Interaction Maps; Proto-Oncogene Proteins c-bcl-2; Sulfonamides | 2017 |
Targeting BCL-2-like Proteins to Kill Cancer Cells.
Mutations that impair apoptosis contribute to cancer development and reduce the effectiveness of conventional anti-cancer therapies. These insights and understanding of how the B cell lymphoma (BCL)-2 protein family governs apoptosis have galvanized the search for a new class of cancer drugs that target its pro-survival members by mimicking their natural antagonists, the BCL-2 homology (BH)3-only proteins. Successful initial clinical trials of the BH3 mimetic venetoclax/ABT-199, specific for BCL-2, have led to its recent licensing for refractory chronic lymphocytic leukemia and to multiple ongoing trials for other malignancies. Moreover, preclinical studies herald the potential of emerging BH3 mimetics targeting other BCL-2 pro-survival members, particularly myeloid cell leukemia (MCL)-1, for multiple cancer types. Thus, BH3 mimetics seem destined to become powerful new weapons in the arsenal against cancer. This review sketches the discovery of the BCL-2 family and its impact on cancer development and therapy; describes how interactions of family members trigger apoptosis; outlines the development of BH3 mimetic drugs; and discusses their potential to advance cancer therapy. Topics: Aniline Compounds; Animals; Antineoplastic Agents; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Humans; Neoplasms; Proto-Oncogene Proteins c-bcl-2; Sulfonamides | 2016 |
Targeting BCL-2 to enhance vulnerability to therapy in estrogen receptor-positive breast cancer.
The last three decades have seen significant progress in our understanding of the role of the pro-survival protein BCL-2 and its family members in apoptosis and cancer. BCL-2 and other pro-survival family members including Mcl-1 and BCL-XL have been shown to have a key role in keeping pro-apoptotic 'effector' proteins BAK and BAX in check. They also neutralize a group of 'sensor' proteins (such as BIM), which are triggered by cytotoxic stimuli such as chemotherapy. BCL-2 proteins therefore have a central role as guardians against apoptosis, helping cancer cells to evade cell death. More recently, an increasing number of BH3 mimetics, which bind and neutralize BCL-2 and/or its pro-survival relatives, have been developed. The utility of targeting BCL-2 in hematological malignancies has become evident in early-phase studies, with remarkable clinical responses seen in heavily pretreated patients. As BCL-2 is overexpressed in ~75% of breast cancer, there has been growing interest in determining whether this new class of drug could show similar promise in breast cancer. This review summarizes our current understanding of the role of BCL-2 and its family members in mammary gland development and breast cancer, recent progress in the development of new BH3 mimetics as well as their potential for targeting estrogen receptor-positive breast cancer. Topics: Aniline Compounds; Animals; Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; Biomarkers, Tumor; Breast; Breast Neoplasms; Bridged Bicyclo Compounds, Heterocyclic; Carcinoma; Drug Design; Drug Synergism; Estrogens; Female; Gene Expression Regulation, Neoplastic; Genes, bcl-2; Humans; Mice; Mitochondria; Molecular Targeted Therapy; Multigene Family; Neoplasm Proteins; Neoplasms, Hormone-Dependent; Peptide Fragments; Prognosis; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Receptors, Estrogen; Signal Transduction; Sulfonamides; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays | 2016 |
Attacking cancer's Achilles heel: antagonism of anti-apoptotic BCL-2 family members.
Malignant cells routinely violate cellular checkpoints that should initiate cell death in normal cells by triggering pro-apoptotic members of the BCL-2 family of proteins. To escape such death inducing signals, cancer cells often select for upregulation of anti-apoptotic BCL-2 family members including BCL-2, BCL-XL , BFL-1, BCL-W and MCL-1. These family members prevent death by sequestering pro-apoptotic molecules. To counter this resistance mechanism, small molecule inhibitors of anti-apoptotic BCL-2 family members have been under development. These molecules have shown promise in pre-clinical and clinical testing to overcome apoptotic resistance, prompting cancer cells to undergo apoptosis. Alternatively, other strategies have taken advantage of the normal regulatory machinery controlling anti-apoptotic molecules and have used inhibitors of signaling pathways to down-modulate the expression of anti-apoptotic molecules, thus tilting the balance in cancer cells to cell death. This review explores recent developments and strategies aimed at antagonizing anti-apoptotic BCL-2 family member action to promote the induction of cell death in cancer therapy. Topics: Aniline Compounds; Animals; Antineoplastic Agents; Apoptosis; bcl-2-Associated X Protein; Bridged Bicyclo Compounds, Heterocyclic; Drug Design; Humans; Inhibitor of Apoptosis Proteins; Models, Biological; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasms; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Sulfonamides | 2016 |
The first MCL-1-selective BH3 mimetics have therapeutic potential for chronic lymphocytic leukemia.
Small-molecule BH3 mimetics are designed to mimic the BH3 domain of BH3-only BCL-2 family members which are antagonists of the prosurvival members (such as BCL-2, BCL-XL and MCL-1). The BH3 mimetics are intended to bind with high affinity to prosurvival proteins, in order to inhibit their functional activity and hence to induce apoptosis in cancer cells. Both navitoclax (BCL-2/BCL-XL antagonist) and ABT-199/venetoclax (BCL-2-selective inhibitor) have demonstrated therapeutic efficacy especially in chronic lymphocytic leukemia (CLL). However, these BH3 mimetics cannot antagonize the prosurvival protein MCL-1 that is overexpressed and involved in therapeutic resistance in CLL. Furthermore, until now, none of the reported small-molecule MCL-1 inhibitors bound to their target with high affinity. The first MCL-1-selective BH3 mimetics capable of high-affinity binding and inducing apoptosis in cancer cells through an on-target mechanism have just been identified. This discovery should advance the translational research to implement novel drugs in treating CLL. Topics: Aniline Compounds; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Myeloid Cell Leukemia Sequence 1 Protein; Peptide Fragments; Proto-Oncogene Proteins; Sulfonamides | 2016 |
Novel agents in the treatment of chronic lymphocytic leukemia: a review about the future.
Half of a century ago, physicians managing chronic lymphocytic leukemia (CLL) recognized some of its presenting features such as lymphocytosis, lymphadenopathy, and splenomegaly. Subsequently, an enhanced understanding of the disease mechanisms involved in CLL led to new, more targeted treatments. There is now a plethora of treatments available for CLL. In this review article we discuss in detail several of the novel agents that are being studied or approved for the treatment of CLL including: phosphatidylinositol 3-kinase inhibitors (idelalisib and IPI-145), Bruton tyrosine kinase inhibitors (ibrutinib), B cell lymphoma 2 inhibitors (ABT-263 and ABT-199), new anti-CD20 monoclonal antibodies (obinutuzumab), cyclin-dependent kinase inhibitors (flavopiridol and dinaciclib), immunomodulators (lenalidomide) and chimeric antigen receptor T-cell therapy. Topics: Adenine; Aniline Compounds; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Cyclic N-Oxides; Flavonoids; Humans; Immunologic Factors; Indolizines; Isoquinolines; Lenalidomide; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-bcl-2; Purines; Pyrazoles; Pyridinium Compounds; Pyrimidines; Quinazolinones; Receptors, Antigen, T-Cell; Sulfonamides; Thalidomide | 2015 |
Targeting BCL2 for the treatment of lymphoid malignancies.
The failure of apoptosis (programmed cell death) underpins the development of many tumors and often renders them resistant to cytotoxic therapies. In hematologic malignancies, this impairment of apoptosis is often caused by overexpression of the pro-survival protein BCL2. Because abnormally high levels of BCL2 sustain these tumors, there has been much interest in targeting BCL2 as a novel approach to treating various hematologic malignancies. One such approach is the development of BH3 mimetic compounds, small molecules that mimic the action of the BH3-only proteins, natural antagonists of BCL2 and its pro-survival relatives. These compounds act by restoring the ability of a cell to undergo apoptotic cell death. Some of them have shown very encouraging results in early-phase clinical trials that are currently underway, particularly in patients with chronic lymphocytic leukemia and some non-Hodgkin lymphomas, diseases marked by BCL2 overexpression. In this review, we discuss the rationale behind targeting BCL2, highlight the recent findings from clinical trials, and pinpoint the next steps in the clinical development of this interesting and promising class of targeted agents, particularly for the treatment of lymphoid malignancies. Topics: Aniline Compounds; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Gossypol; Hematologic Neoplasms; Humans; Indoles; Leukemia, Lymphocytic, Chronic, B-Cell; Peptide Fragments; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Pyrroles; Sulfonamides | 2014 |
BH3 mimetics: status of the field and new developments.
Targeting apoptosis is an attractive approach in cancer therapy. The BH3-only proteins of the BCL-2 family (having only the BCL-2 homology domain BH3) can trigger apoptosis by binding to the prosurvival members of this family and neutralizing their functional activity (sequestration of the proapoptotic Bcl-2 family members). The "BH3 mimetic" concept has prompted the development of small molecules capable of mimicking BH3-only proteins and thus inducing apoptosis. The prototype BH3 mimetic ABT-737 selectively targets the three prosurvival proteins BCL-XL, BCL-2, and BCL-W (but not MCL-1 or A1) and its oral derivative ABT-263 has proved promising in clinical trials. Some putative BH3 mimetics are also tested clinically while others are still being characterized. This article recapitulates the various known BH3 mimetics and presents the recent developments in the field. The latter include (i) the identification of molecular determinants responsible for the specific interactions between BH3 motifs and the binding grooves of prosurvival proteins and (ii) the characterization of new compounds and particularly BH3 mimetics that antagonize either selectively MCL-1 or BCL-2 or a broad range of prosurvival proteins. These data are critical advances toward the discovery of novel anticancer agents. Topics: Amino Acid Motifs; Aniline Compounds; Antineoplastic Agents; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials as Topic; Drug Design; Drug Screening Assays, Antitumor; Gossypol; Humans; Indoles; Molecular Mimicry; Neoplasms; Peptide Fragments; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Pyrroles; Sulfonamides | 2013 |
28 other study(ies) available for abt-199 and navitoclax
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Venetoclax-based salvage therapy for adult patients with relapsed/refractory acute lymphoblastic leukemia.
Dysregulation of BCL-2 family members has been reported in acute lymphocytic leukemia (ALL), with various BH3-dependencies of the leukemic clone. We conducted a multicenter retrospective cohort of patients with relapsed/refractory B or T ALL, with ven-chemotherapy or ven-navitoclax combinations, to assess efficacy and safety.. Seventeen patients were included in the analysis, median age was 32 years, with 6 B-ALL and 11 T-ALL patients. Nine patients received venetoclax combined with chemotherapy, and 13 patients received venetoclax in combination with navitoclax, vincristine and asparaginase, of which 5 were already exposed to venetoclax in previous lines.. ORR was 55% and 46% among the ven-chemotherapy and the ven-navitoclax-chemotherapy, respectively. Most of the responders proceeded to an allogenic bone marrow transplant in both cohorts. The most common adverse effects of the ven-navitoclax combination were infectious complications and hepatotoxicity.. Our data demonstrated the possible efficacy of ven-chemotherapy and ven-navitoclax in r/r ALL with moderate toxicity. Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Humans; Leukemia, Myeloid, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Retrospective Studies; Salvage Therapy | 2023 |
Successful treatment of a chemotherapy-resistant t(17;19) paediatric ALL with a combination of inotuzumab, venetoclax and navitoclax.
Topics: Aniline Compounds; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Child; Humans; Sulfonamides | 2023 |
Senescence-Independent Anti-Inflammatory Activity of the Senolytic Drugs Dasatinib, Navitoclax, and Venetoclax in Zebrafish Models of Chronic Inflammation.
Topics: Aniline Compounds; Animals; Anti-Inflammatory Agents; Bridged Bicyclo Compounds, Heterocyclic; Cellular Senescence; Dasatinib; Inflammation; Non-alcoholic Fatty Liver Disease; Senotherapeutics; Serine Proteinase Inhibitors; Sulfonamides; Zebrafish | 2022 |
Dynamic BH3 profiling identifies active BH3 mimetic combinations in non-small cell lung cancer.
Conventional chemotherapy is still of great utility in oncology and rationally constructing combinations with it remains a top priority. Drug-induced mitochondrial apoptotic priming, measured by dynamic BH3 profiling (DBP), has been shown in multiple cancers to identify drugs that promote apoptosis in vivo. We therefore hypothesized that we could use DBP to identify drugs that would render cancers more sensitive to conventional chemotherapy. We found that targeted agents that increased priming of non-small cell lung cancer (NSCLC) tumor cells resulted in increased sensitivity to chemotherapy in vitro. To assess whether targeted agents that increase priming might enhance the efficacy of cytotoxic agents in vivo as well, we carried out an efficacy study in a PC9 xenograft mouse model. The BH3 mimetic navitoclax, which antagonizes BCL-xL, BCL-w, and BCL-2, consistently primed NSCLC tumors in vitro and in vivo. The BH3 mimetic venetoclax, which electively antagonizes BCL-2, did not. Combining navitoclax with etoposide significantly reduced tumor burden compared to either single agent, while adding venetoclax to etoposide had no effect on tumor burden. Next, we assessed priming of primary patient NSCLC tumor cells on drugs from a clinically relevant oncology combination screen (CROCS). Results confirmed for the first time the utility of BCL-xL inhibition by navitoclax in priming primary NSCLC tumor cells and identified combinations that primed further. This is a demonstration of the principle that DBP can be used as a functional precision medicine tool to rationally construct combination drug regimens that include BH3 mimetics in solid tumors like NSCLC. Topics: Aniline Compounds; Animals; Antineoplastic Agents; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Female; Humans; Lung Neoplasms; Mice, SCID; Mitochondria; Mitochondrial Membranes; Sulfonamides | 2021 |
Overcoming the acquired resistance to gefitinib in lung cancer brain metastasis in vitro and in vivo.
In our previous work, PC-9-Br, a PC-9 brain seeking line established via a preclinical animal model of lung cancer brain metastasis (LCBM), exhibited not only resistance to epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) gefitinib in vitro, but also chemotherapy regimens of cisplatin plus etoposide in vivo. Using this cell line, we investigated novel potential targeted therapeutics for treating LCBM in vitro and in vivo to combat drug resistance. Significant increases in mRNA and protein expression levels of Bcl-2 were found in PC-9-Br compared with parental PC-9 (PC-9-P), but no significant changes of Bcl-XL were observed. A remarkable synergistic effect between EGFR-TKI gefitinib and Bcl-2 inhibitors ABT-263 (0.17 ± 0.010 µM at 48 h and 0.02 ± 0.004 µM at 72 h), or ABT-199 (0.22 ± 0.008 µM at 48 h and 0.02 ± 0.001 µM at 72 h) to overcome acquired resistance to gefitinib (> 0.5 µM at 48 h and 0.10 ± 0.007 µM at 72 h) in PC-9-Br was observed in MTT assays. AZD9291 was also shown to overcome acquired resistance to gefitinib in PC-9-Br in MTT assays (0.23 ± 0.031 µM at 48 h and 0.03 ± 0.008 µM at 72 h). Western blot showed significantly decreased phospho-Erk1/2 and increased cleaved-caspase-3 expressions were potential synergistic mechanisms for gefitinib + ABT263/ABT199 in PC-9-Br. Significantly decreased protein expressions of phospho-EGFR, phospho-Akt, p21, and survivin were specific synergistic mechanism for gefitinib + ABT199 in PC-9-Br. In vivo studies demonstrated afatinib (30 mg/kg) and AZD9291 (25 mg/kg) could significantly reduce the LCBM in vivo and increase survival percentages of treated mice compared with mice treated with vehicle and gefitinib (6.25 mg/kg). In conclusion, our study demonstrated gefitinib + ABT263/ABT199, afatinib, and AZD9291 have clinical potential to treat LCBM. Topics: Acrylamides; Aniline Compounds; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Drug Resistance, Neoplasm; Female; Gefitinib; Lung Neoplasms; Mice; Mice, Nude; Proto-Oncogene Proteins c-bcl-2; Sulfonamides | 2021 |
Bcl-2/Bcl-xL inhibitor navitoclax increases the antitumor effect of Chk1 inhibitor prexasertib by inducing apoptosis in pancreatic cancer cells via inhibition of Bcl-xL but not Bcl-2.
In our previous study, we showed that prexasertib, a checkpoint kinase 1 (Chk1) inhibitor, enhances the effects of standard drugs for pancreatic cancer, including gemcitabine (GEM), S-1, and the combination of GEM and S-1 (GS). The combination of prexasertib and GS has a strong antitumor effect and induces apoptosis in pancreatic cancer cells by downregulating anti-apoptotic protein Bcl-2. In the present study, we investigated the combined effect of GEM, S-1, and prexasertib with a selective Bcl-2 inhibitor (venetoclax) and a non-selective Bcl-2 inhibitor (navitoclax) in SUIT-2 pancreatic cancer cells. An MTT assay revealed that the combination of prexasertib with navitoclax showed a synergistic effect but the combination with venetoclax did not. Investigation of the pancreatic cancer cell lines SUIT-2, MIA PaCa-2, and BxPC-3 revealed that BxPC-3 also showed a high synergistic effect when combined with prexasertib and navitoclax but not venetoclax. Mechanistic analysis of the combined effect showed that apoptosis was induced. Bcl-2 knockdown with siRNA and prexasertib treatment did not induce apoptosis, whereas Bcl-xL knockdown with siRNA and prexasertib treatment resulted in strong induction of apoptosis. In addition, among the three cell lines, the combined effect of prexasertib and navitoclax resulted in increased apoptotic cell death because the protein expression levels of Bcl-xL and Chk1 were higher. Our results demonstrate that the combination of prexasertib and navitoclax has a strong antitumor effect and induces apoptosis in pancreatic cancer cells by downregulating Bcl-xL. Simultaneous inhibition of Chk1 and Bcl-xL could be a new strategy for treating pancreatic cancer. Topics: Aniline Compounds; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; bcl-X Protein; Bridged Bicyclo Compounds, Heterocyclic; Cell Proliferation; Drug Synergism; Gene Expression Regulation, Neoplastic; Humans; Pancreatic Neoplasms; Proto-Oncogene Proteins c-bcl-2; Pyrazines; Pyrazoles; Sulfonamides; Tumor Cells, Cultured | 2020 |
DT2216-a Bcl-xL-specific degrader is highly active against Bcl-xL-dependent T cell lymphomas.
Patients with advanced T cell lymphomas (TCLs) have limited therapeutic options and poor outcomes in part because their TCLs evade apoptosis through upregulation of anti-apoptotic Bcl-2 proteins. Subsets of TCL cell lines, patient-derived xenografts (PDXs), and primary patient samples depend on Bcl-xL for survival. However, small molecule Bcl-xL inhibitors such as ABT263 have failed during clinical development due to on-target and dose-limiting thrombocytopenia.. We have developed DT2216, a proteolysis targeting chimera (PROTAC) targeting Bcl-xL for degradation via Von Hippel-Lindau (VHL) E3 ligase, and shown that it has better anti-tumor activity but is less toxic to platelets compared to ABT263. Here, we examined the therapeutic potential of DT2216 for TCLs via testing its anti-TCL activity in vitro using MTS assay, immunoblotting, and flow cytometry and anti-TCL activity in vivo using TCL cell xenograft and PDX model in mice.. The results showed that DT2216 selectively killed various Bcl-xL-dependent TCL cells including MyLa cells in vitro. In vivo, DT2216 alone was highly effective against MyLa TCL xenografts in mice without causing significant thrombocytopenia or other toxicity. Furthermore, DT2216 combined with ABT199 (a selective Bcl-2 inhibitor) synergistically reduced disease burden and improved survival in a TCL PDX mouse model dependent on both Bcl-2 and Bcl-xL.. These findings support the clinical testing of DT2216 in patients with Bcl-xL-dependent TCLs, both as a single agent and in rational combinations. Topics: Aniline Compounds; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; bcl-X Protein; Blood Platelets; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Drug Design; Drug Screening Assays, Antitumor; Drug Synergism; Female; Graft Survival; Humans; Liver; Lymphoma, T-Cell; Mice; Mice, Inbred NOD; Mice, SCID; Neoplasm Proteins; Neoplasm Transplantation; Piperazines; Proto-Oncogene Proteins c-bcl-2; Random Allocation; Spleen; Sulfonamides; Ubiquitin-Protein Ligases; Xenograft Model Antitumor Assays | 2020 |
Heterogeneous Pattern of Dependence on Anti-Apoptotic BCL-2 Family Proteins upon CHOP Treatment in Diffuse Large B-Cell Lymphoma.
Expression of the anti-apoptotic B-cell lymphoma 2 (BCL-2) protein in patients with diffuse large B-cell lymphoma (DLBCL) strongly correlates with resistance to standard therapy with cyclophosphamide, vincristine, doxorubicin, prednisolone, and rituximab (R-CHOP). Although studies focus mainly on the contribution of BCL-2, here we also investigate the contribution of other anti-apoptotic proteins to CHOP-therapy resistance in DLBCL. Functional dynamic BCL-2 homology (BH)3 profiling was applied to DLBCL cell lines upon CHOP treatment or single CHOP compounds. Cell-specific anti-apoptotic dependencies were validated with corresponding BH3-mimetics. We found high expression of anti-apoptotic BCL-2, MCL-1, and BCL-XL in DLBCL cell lines and patients. CHOP treatment resulted in both enhanced and altered anti-apoptotic dependency. Enhanced sensitivity to different BH3-mimetics after CHOP treatment was confirmed in specific cell lines, indicating heterogeneity of CHOP-induced resistance in DLBCL. Analysis of single CHOP compounds demonstrated that similar changes could also be induced by doxorubicin or vincristine, providing evidence for clinical combination therapies of doxorubicin or vincristine with BH3-mimetics in DLBCL. In conclusion, we show for the first time that CHOP treatment induces increased anti-apoptotic dependency on MCL-1 and BCL-XL, and not just BCL-2. These results provide new perspectives for the treatment of CHOP-resistant DLBCL and underline the potential of BH3 profiling in predicting therapy outcomes. Topics: Aniline Compounds; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bcl-2-Like Protein 11; bcl-X Protein; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Cell Survival; Cyclophosphamide; Doxorubicin; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Lymphoma, Large B-Cell, Diffuse; Myeloid Cell Leukemia Sequence 1 Protein; Prednisone; Prognosis; Proto-Oncogene Proteins c-bcl-2; Pyrimidines; Rituximab; Signal Transduction; Sulfonamides; Thiophenes; Treatment Outcome; Vincristine | 2019 |
Wnt5a and ROR1 activate non-canonical Wnt signaling via RhoA in TCF3-PBX1 acute lymphoblastic leukemia and highlight new treatment strategies via Bcl-2 co-targeting.
B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with TCF3-PBX1 fusion gene expression has constitutively elevated levels of Wnt16b and ROR1 (receptor tyrosine kinase-like orphan receptor), a ligand and a receptor from the Wnt signaling pathway, respectively. Although survival rate is usually high after the initial chemotherapy, many TCF3-PBX1 BCP-ALL patients relapse and subsequently develop treatment resistance, resulting in poor prognosis. Here, we aimed to investigate the molecular signaling associated with Wnt16b and ROR1 overexpression in TCF3-PBX1 cell lines and primary samples, and to identify effective treatment options via ROR1 targeting. We detected higher ROR1 expression on TCF3-PBX1 leukemic cells even at a later stage of patient relapse, providing a strong rationale for the use of ROR1-targeted therapy. We found that Wnt5a-ROR1 signaling enhances proliferation of TCF3-PBX1 cells via RhoA/Rac1 GTPases activation and STAT3 upregulation. Wnt16b also activated the RhoA/Rac1 signaling cascade suggesting the activation of a non-canonical Wnt pathway in TCF3-PBX1 cells. Wnt16 could interact with ROR1 but not in TCF3-PBX1 cells, suggesting that Wnt5a is the ligand signaling via ROR1 in TCF3-PBX1 cells. By high throughput drug-sensitivity testing of TCF3-PBX1 cells before and after ROR1 knockdown we found that targeting ROR1 significantly improves the therapeutic efficacy of Bcl-2 family inhibitors venetoclax and navitoclax, and this synergism was confirmed ex vivo using a drug-resistant primary sample from a relapsed TCF3-PBX1 patient. Our work underlines a new type of targeted combination therapy that could be clinically advantageous for patients with TCF3-PBX1 BCP-ALL. Topics: Aniline Compounds; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Humans; Oncogene Proteins, Fusion; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Proto-Oncogene Proteins c-bcl-2; Receptor Tyrosine Kinase-like Orphan Receptors; rhoA GTP-Binding Protein; Sulfonamides; Survival Rate; Translocation, Genetic; Up-Regulation; Wnt Signaling Pathway; Wnt-5a Protein | 2019 |
Allosteric modulation of sigma receptors by BH3 mimetics ABT-737, ABT-263 (Navitoclax) and ABT-199 (Venetoclax).
Topics: Allosteric Regulation; Aniline Compounds; Animals; Antineoplastic Agents; Biphenyl Compounds; Brain; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Guinea Pigs; Humans; Male; Nitrophenols; Piperazines; Proto-Oncogene Proteins c-bcl-2; Radioligand Assay; Receptors, sigma; Sigma-1 Receptor; Sulfonamides | 2019 |
BH3 mimetics efficiently induce apoptosis in mouse basophils and mast cells.
Basophil granulocytes and mast cells are recognized for their roles in immunity and are central effectors of diverse immunological disorders. Despite their similarities, there is emerging evidence for non-redundant roles of the circulating yet scarce basophils and tissue-resident mast cells, respectively. Because of their importance in allergic pathogenesis, specific induction of apoptosis in basophils and mast cells may represent an interesting novel treatment strategy. The pro-inflammatory cytokine interleukin-3 serves as a key factor for basophil and mouse mast cell survival. Interleukin-3 increases the expression of anti-apoptotic BCL-2 family members, such as BCL-2, BCL-X Topics: Aniline Compounds; Animals; Apoptosis; Apoptosis Regulatory Proteins; Basophils; bcl-X Protein; Bridged Bicyclo Compounds, Heterocyclic; Caspase 3; Cell Survival; Humans; Interleukin-3; Mast Cells; Mice; Mice, Inbred C57BL; Myeloid Cell Leukemia Sequence 1 Protein; Proto-Oncogene Proteins c-bcl-2; Sulfonamides | 2018 |
Clinically relevant interactions of anti-apoptotic Bcl-2 protein inhibitors with ABC transporters.
In this work we studied clinically relevant interactions between the BH3 mimetics and the ABCB1 and ABCG2 transporters. We observed that the intracellular levels of ABT-263 and ABT-199, but not ABT-737, might be reduced by ABCB1 or ABCG2. Importantly, this effect was proportional to the transporter expression level. High transporter expression levels decreased the intracellular levels of ABT-263 and ABT-199 substantially. Low transporter expression levels, which are clinically relevant, affected the intracellular level of ABT-263 slightly but significantly, however, they failed to decrease the intracellular level of ABT-199 below the control level in parental cells. Our results further revealed that ABT-263 did not inhibit the ABCB1 mediated transport, however, it partially inhibited the ABCG2 mediated transport at clinically relevant concentrations. In contrast, ABT-199 inhibited partially the ABCB1 mediated transport and it fully inhibited the ABCG2 mediated transport at clinically relevant concentrations. Importantly, cells expressing higher drug transporters levels required higher concentrations of ABT-263 or ABT-199 to achieve certain inhibition of substrate efflux.. Antiproliferative effects of ABT-263 and ABT-199 might be reduced by ABCB1 or ABCG2, however, this effect depends on transporter expression levels. Since the expression levels of ABCB1 and ABCG2 are rarely high in clinical samples, their contribution to the overall resistance to ABT-263 or ABT-199 is probably low. Inhibition study revealed that ABT-199, but not ABT-263, fully inhibited low expression level of ABCG2. Our data suggest that ABT-199 should be evaluated beyond its original application as an inhibitor of the ABCG2 transporter in clinical settings. Topics: Aniline Compounds; Antineoplastic Agents; Apoptosis; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily G, Member 2; Biological Transport; Biphenyl Compounds; Bridged Bicyclo Compounds, Heterocyclic; Gene Expression Regulation; Humans; K562 Cells; Neoplasm Proteins; Nitrophenols; Piperazines; Proto-Oncogene Proteins c-bcl-2; Sulfonamides | 2017 |
HOX gene expression predicts response to BCL-2 inhibition in acute myeloid leukemia.
Inhibitors of B-cell lymphoma-2 (BCL-2) such as venetoclax (ABT-199) and navitoclax (ABT-263) are clinically explored in several cancer types, including acute myeloid leukemia (AML), to selectively induce apoptosis in cancer cells. To identify robust biomarkers for BCL-2 inhibitor sensitivity, we evaluated the ex vivo sensitivity of fresh leukemic cells from 73 diagnosed and relapsed/refractory AML patients, and then comprehensively assessed whether the responses correlated to specific mutations or gene expression signatures. Compared with samples from healthy donor controls (nonsensitive) and chronic lymphocytic leukemia (CLL) patients (highly sensitive), AML samples exhibited variable responses to BCL-2 inhibition. Strongest CLL-like responses were observed in 15% of the AML patient samples, whereas 32% were resistant, and the remaining exhibited intermediate responses to venetoclax. BCL-2 inhibitor sensitivity was associated with genetic aberrations in chromatin modifiers, WT1 and IDH1/IDH2. A striking selective overexpression of specific HOXA and HOXB gene transcripts were detected in highly BCL-2 inhibitor sensitive samples. Ex vivo responses to venetoclax showed significant inverse correlation to β2-microglobulin expression and to a lesser degree to BCL-XL and BAX expression. As new therapy options for AML are urgently needed, the specific HOX gene expression pattern can potentially be used as a biomarker to identify venetoclax-sensitive AML patients for clinical trials. Topics: Aniline Compounds; Antineoplastic Agents; beta 2-Microglobulin; Biopsy; Bone Marrow; Bridged Bicyclo Compounds, Heterocyclic; Case-Control Studies; Cell Line, Tumor; Cluster Analysis; Drug Resistance, Neoplasm; Exome; Gene Expression Profiling; Gene Expression Regulation, Leukemic; Genes, Homeobox; High-Throughput Nucleotide Sequencing; Humans; Isocitrate Dehydrogenase; Leukemia, Myeloid, Acute; Multigene Family; Mutation; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; WT1 Proteins | 2017 |
BH3 profiling identifies heterogeneous dependency on Bcl-2 family members in multiple myeloma and predicts sensitivity to BH3 mimetics.
Topics: Aged; Aged, 80 and over; Aniline Compounds; Antineoplastic Agents; bcl-X Protein; Biological Assay; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Cytochromes c; Female; Gene Expression Regulation, Neoplastic; Humans; Male; Middle Aged; Mitochondria; Multiple Myeloma; Myeloid Cell Leukemia Sequence 1 Protein; Organ Specificity; Peptides; Plasma Cells; Proto-Oncogene Proteins c-bcl-2; Recurrence; Sulfonamides | 2016 |
Bcl-2 phosphorylation confers resistance on chronic lymphocytic leukaemia cells to the BH3 mimetics ABT-737, ABT-263 and ABT-199 by impeding direct binding.
Although the ongoing clinical trials of ABT-263 and ABT-199 in chronic lymphocytic leukaemia (CLL) have indicated that BH3 mimetics hold considerable promise, understanding the mechanism of CLL resistance to BH3 mimetics remains a challenge.. The LD50 values of ABT-737, ABT-263 and ABT-199 in a number of primary CLL cells from 40 patients, were determined. The levels of Bcl-2 family proteins, including phosphorylated Bcl-2 (pBcl-2) and their interactions were measured by immunoblotting and co-immunoprecipitation. In vitro binding assays were performed by isothermal titration calorimetry and ELISA. BH3 profiling in isolated mitochondria was analysed.. The ratio of (Mcl-1 + pBcl-2) to Bcl-2 expression provided the most significant predictive marker for the cytotoxic potential of ABT-737, ABT-263 and ABT-199 in the panel of CLL samples. Mechanistically, pBcl-2 inhibited the effects of the ABT compounds on the displacement of Bax and Bim from Bcl-2, thereby suppressing mitochondrial apoptosis. The ABT compounds exhibited 100-300-fold lower binding affinity to the glutamic acid, phosphomimetic, mutant of Bcl-2 (T69E, S70E and S87E; EEE-Bcl-2). BH3 peptides exhibited different rank orders of binding affinities to full-length WT-Bcl-2 and full-length EEE-Bcl-2.. Our study suggested that a structural alteration in the BH3-binding groove was induced by phosphorylation of Bcl-2. Our data also provided a framework to overcome resistance of CLL cells to the ABT compounds by combining pBcl-2 kinase inhibitors with the ABT compounds. Topics: Aniline Compounds; Antineoplastic Agents; Apoptosis; Biphenyl Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cell Line; Cell Survival; Cells, Cultured; Drug Resistance, Neoplasm; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Mitochondria; Nitrophenols; Peptide Fragments; Phosphorylation; Piperazines; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Sulfonamides | 2016 |
Select Bcl-2 antagonism restores chemotherapy sensitivity in high-risk neuroblastoma.
Pediatric patients with high-risk neuroblastoma (HR NB) often fail to respond to upfront intensive multimodal therapy. Tumor-acquired suppression of apoptosis contributes to therapy resistance. Many HR NB tumors depend on the anti-apoptotic protein Bcl-2 for survival, through Bcl-2 sequestration and inhibition of the pro-apoptotic protein, Bim. Bcl-2 dependent xenografts derived from aggressive human NB tumors are cured with a combination of cyclophosphamide and ABT-737, a Bcl-2/Bcl-XL/Bcl-w small molecule antagonist. The oral analogue to ABT-737, Navitoclax (ABT-263), clinically causes an immediate drop in peripheral platelet counts as mature platelets depend on Bcl-xL for survival. This led to the creation of a Bcl-2 selective inhibitor, ABT-199 (Venetoclax). A Phase I trial of ABT-199 in CLL showed remarkable antitumor activity and stable patient platelet counts. Given Bcl-XL does not play a role in HR NB survival, we hypothesized that ABT-199 would be equally potent against HR NB.. Cytotoxicity and apoptosis were measured in human derived NB cell lines exposed to ABT-199 combinations. Co-Immunoprecipitation evaluated Bim displacement from Bcl-2, following ABT-199. Murine xenografts of NB cell lines were grown and then exposed to a 14-day course of ABT-199 alone and with cyclophosphamide.. Bcl-2 dependent NB cell lines are exquisitely sensitive to ABT-199 (IC50 1.5-5 nM) in vitro, where Mcl-1 dependent NBs are completely resistant. Treatment with ABT-199 displaces Bim from Bcl-2 in NB to activate caspase 3, confirming the restoration of mitochondrial apoptosis. Murine xenografts of Mcl-1 and Bcl-2 dependent NBs were treated with a two-week course of ABT-199, cyclophosphamide, or ABT-199/cyclophosphamide combination. Mcl-1 dependent tumors did not respond to ABT-199 alone and showed no significant difference in time to tumor progression between chemotherapy alone or ABT-199/cyclophosphamide combination. In contrast, Bcl-2 dependent xenografts responded to ABT-199 alone and had sustained complete remission (CR) to the ABT-199/cyclophosphamide combination, with one recurrent tumor maintaining Bcl-2 dependence and obtaining a second CR after a second course of therapy.. HR NB patients are often thrombocytopenic at relapse, raising concerns for therapies like ABT-263 despite its HR NB tumor targeting potential. Our data confirms that Bcl-2 selective inhibitors like ABT-199 are equally potent in HR NB in vitro and in vivo and given their lack of platelet toxicity, should be translated into the clinic for HR NB. Topics: Aniline Compounds; Apoptosis; Apoptosis Regulatory Proteins; Bcl-2-Like Protein 11; bcl-X Protein; Bridged Bicyclo Compounds, Heterocyclic; Caspase 3; Cell Line, Tumor; Cyclophosphamide; Drug Resistance, Neoplasm; Humans; Membrane Proteins; Neuroblastoma; Platelet Count; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Risk Assessment; Sulfonamides; Xenograft Model Antitumor Assays | 2016 |
Human Pluripotent Stem Cells and Derived Neuroprogenitors Display Differential Degrees of Susceptibility to BH3 Mimetics ABT-263, WEHI-539 and ABT-199.
Human embryonic stem cells (hESCs) are hypersensitive to genotoxic stress and display lower survival ability relative to their differentiated progeny. Herein, we attempted to investigate the source of this difference by comparing the DNA damage responses triggered by the topoisomerase I inhibitor camptothecin, in hESCs, human induced pluripotent stem cells (hiPSCs) and hESCs-derived neuroprogenitors (NP). We observed that upon camptothecin exposure pluripotent stem cells underwent apoptosis more swiftly and at a higher rate than differentiated cells. However, the cellular response encompassing ataxia-telangiectasia mutated kinase activation and p53 phosphorylation both on serine 15 as well as on serine 46 resulted very similar among the aforementioned cell types. Importantly, we observed that hESCs and hiPSCs express lower levels of the anti-apoptotic protein Bcl-2 than NP. To assess whether Bcl-2 abundance could account for this differential response we treated cells with ABT-263, WEHI-539 and ABT-199, small molecules that preferentially target the BH3-binding pocket of Bcl-xL and/or Bcl-2 and reduce their ability to sequester pro-apoptotic factors. We found that in the absence of stress stimuli, NP exhibited a higher sensitivity to ABT- 263 and WEHI-539 than hESCs and hiPSCs. Conversely, all tested cell types appeared to be highly resistant to the Bcl-2 specific inhibitor, ABT-199. However, in all cases we determined that ABT-263 or WEHI-539 treatment exacerbated camptothecin-induced apoptosis. Importantly, similar responses were observed after siRNA-mediated down-regulation of Bcl-xL or Bcl-2. Taken together, our results suggest that Bcl-xL contrary to Bcl-2 contributes to ensure cell survival and also functions as a primary suppressor of DNA double-strand brake induced apoptosis both in pluripotent and derived NP cells. The emerging knowledge of the relative dependence of pluripotent and progenitor cells on Bcl-2 and Bcl-xL activities may help to predict cellular responses and potentially manipulate these cells for therapeutic purposes in the near future. Topics: Aniline Compounds; Ataxia Telangiectasia Mutated Proteins; bcl-X Protein; Bridged Bicyclo Compounds, Heterocyclic; Camptothecin; Cell Line; Human Embryonic Stem Cells; Humans; Induced Pluripotent Stem Cells; Neural Stem Cells; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; Tumor Suppressor Protein p53 | 2016 |
BAX-BAK1-independent LC3B lipidation by BH3 mimetics is unrelated to BH3 mimetic activity and has only minimal effects on autophagic flux.
Inhibition of prosurvival BCL2 family members can induce autophagy, but the mechanism is controversial. We have provided genetic evidence that BCL2 family members block autophagy by inhibiting BAX and BAK1, but others have proposed they instead inhibit BECN1. Here we confirm that small molecule BH3 mimetics can induce BAX- and BAK1-independent MAP1LC3B/LC3B lipidation, but this only occurred at concentrations far greater than required to induce apoptosis and dissociate canonical BH3 domain-containing proteins that bind more tightly than BECN1. Because high concentrations of a less-active enantiomer of ABT-263 also induced BAX- and BAK1-independent LC3B lipidation, induction of this marker of autophagy appears to be an off-target effect. Indeed, robust autophagic flux was not induced by BH3 mimetic compounds in the absence of BAX and BAK1. Therefore at concentrations that are on target and achievable in vivo, BH3 mimetics only induce autophagy in a BAX- and BAK1-dependent manner. Topics: Aniline Compounds; Animals; Apoptosis; Autophagy; bcl-2 Homologous Antagonist-Killer Protein; bcl-2-Associated X Protein; Biphenyl Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cells, Cultured; Mice; Microtubule-Associated Proteins; Nitrophenols; Piperazines; Proto-Oncogene Proteins c-bcl-2; Sulfonamides | 2016 |
BH3 Inhibitor Sensitivity and Bcl-2 Dependence in Primary Acute Lymphoblastic Leukemia Cells.
BH3 mimetic drugs may be useful to treat acute lymphoblastic leukemia (ALL) but the sensitivity of primary tumor cells has not been fully evaluated. Here, B-lineage ALL cell cultures derived from a set of primary tumors were studied with respect to sensitivity to the BH3 mimetics ABT-263 and ABT-199 and to Bcl-2 dependence and function. These ALL cells each expressed high levels of Bcl-2 and exhibited great sensitivity to ABT-263 and ABT-199, which induced rapid apoptotic cell death. BH3 profiling indicated that the ALL cultures were Bcl-2 dependent. Coimmunoprecipitation studies revealed a multifaceted role for Bcl-2 in binding proapoptotic partners including Bax, Bak, Bik, and Bim. ABT-263 disrupted Bcl-2:Bim interaction in cells. Mcl-1 overexpression rendered ALL cells resistant to ABT-263 and ABT-199, with Mcl-1 assuming the role of Bcl-2 in binding Bim. Freshly isolated pediatric ALL blasts also expressed high levels of Bcl-2 and exhibited high sensitivity to Bcl-2 inhibition by the BH3 mimetic compounds. Overall, our results showed that primary ALL cultures were both more sensitive to BH3 mimetics and more uniform in their response than established ALL cell lines that have been evaluated previously. Furthermore, the primary cell model characterized here offers a powerful system for preclinical testing of novel drugs and drug combinations to treat ALL. Topics: Aniline Compounds; Antineoplastic Agents; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Cell Survival; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; HeLa Cells; Humans; Inhibitory Concentration 50; Myeloid Cell Leukemia Sequence 1 Protein; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Proto-Oncogene Proteins c-bcl-2; Sulfonamides | 2015 |
Exploiting selective BCL-2 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapy.
The BCL-2/BCL-XL/BCL-W inhibitor ABT-263 (navitoclax) has shown promising clinical activity in lymphoid malignancies such as chronic lymphocytic leukemia. However, its efficacy in these settings is limited by thrombocytopenia caused by BCL-XL inhibition. This prompted the generation of the BCL-2-selective inhibitor venetoclax (ABT-199/GDC-0199), which demonstrates robust activity in these cancers but spares platelets. Navitoclax has also been shown to enhance the efficacy of docetaxel in preclinical models of solid tumors, but clinical use of this combination has been limited by neutropenia. We used venetoclax and the BCL-XL-selective inhibitors A-1155463 and A-1331852 to assess the relative contributions of inhibiting BCL-2 or BCL-XL to the efficacy and toxicity of the navitoclax-docetaxel combination. Selective BCL-2 inhibition suppressed granulopoiesis in vitro and in vivo, potentially accounting for the exacerbated neutropenia observed when navitoclax was combined with docetaxel clinically. By contrast, selectively inhibiting BCL-XL did not suppress granulopoiesis but was highly efficacious in combination with docetaxel when tested against a range of solid tumors. Therefore, BCL-XL-selective inhibitors have the potential to enhance the efficacy of docetaxel in solid tumors and avoid the exacerbation of neutropenia observed with navitoclax. These studies demonstrate the translational utility of this toolkit of selective BCL-2 family inhibitors and highlight their potential as improved cancer therapeutics. Topics: Administration, Oral; Aniline Compounds; Animals; Antineoplastic Agents; bcl-X Protein; Benzothiazoles; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Cell Survival; Docetaxel; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Granulocytes; Humans; Isoquinolines; Kinetics; Mice; Neoplasm Transplantation; Neoplasms; Neutropenia; Neutrophils; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; Taxoids; Thrombocytopenia | 2015 |
A synthetic peptide targeting the BH4 domain of Bcl-2 induces apoptosis in multiple myeloma and follicular lymphoma cells alone or in combination with agents targeting the BH3-binding pocket of Bcl-2.
Bcl-2 inhibits apoptosis by two distinct mechanisms but only one is targeted to treat Bcl-2-positive malignancies. In this mechanism, the BH1-3 domains of Bcl-2 form a hydrophobic pocket, binding and inhibiting pro-apoptotic proteins, including Bim. In the other mechanism, the BH4 domain mediates interaction of Bcl-2 with inositol 1,4, 5-trisphosphate receptors (IP3Rs), inhibiting pro-apoptotic Ca2+ signals. The current anti-Bcl-2 agents, ABT-263 (Navitoclax) and ABT-199 (Venetoclax), induce apoptosis by displacing pro-apoptotic proteins from the hydrophobic pocket, but do not inhibit Bcl-2-IP3R interaction. Therefore, to target this interaction we developed BIRD-2 (Bcl-2 IP3 Receptor Disruptor-2), a decoy peptide that binds to the BH4 domain, blocking Bcl-2-IP3R interaction and thus inducing Ca2+-mediated apoptosis in chronic lymphocytic leukemia, multiple myeloma, and follicular lymphoma cells, including cells resistant to ABT-263, ABT-199, or the Bruton's tyrosine kinase inhibitor Ibrutinib. Moreover, combining BIRD-2 with ABT-263 or ABT-199 enhances apoptosis induction compared to single agent treatment. Overall, these findings provide strong rationale for developing novel therapeutic agents that mimic the action of BIRD-2 in targeting the BH4 domain of Bcl-2 and disrupting Bcl-2-IP3R interaction. Topics: Aniline Compounds; Animals; Apoptosis; bcl-2-Associated X Protein; Bridged Bicyclo Compounds, Heterocyclic; Calcium Signaling; Cell Line, Tumor; Cell Survival; Drug Resistance, Neoplasm; HEK293 Cells; Humans; Hydrophobic and Hydrophilic Interactions; Immunohistochemistry; Inositol 1,4,5-Trisphosphate Receptors; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Follicular; Mice; Mice, Nude; Multiple Myeloma; Neoplasm Transplantation; NIH 3T3 Cells; Peptides; Protein Structure, Tertiary; Proto-Oncogene Proteins c-bcl-2; Sulfonamides | 2015 |
Loss in MCL-1 function sensitizes non-Hodgkin's lymphoma cell lines to the BCL-2-selective inhibitor venetoclax (ABT-199).
As a population, non-Hodgkin's lymphoma (NHL) cell lines positive for the t(14;18) translocation and/or possessing elevated BCL2 copy number (CN; BCL2(High)) are exquisitely sensitive to navitoclax or the B-cell lymphoma protein-2 (BCL-2)-selective inhibitor venetoclax. Despite this, some BCL2(High) cell lines remain resistant to either agent. Here we show that the MCL-1-specific inhibitor A-1210477 sensitizes these cell lines to navitoclax. Chemical segregation of this synergy with the BCL-2-selective inhibitor venetoclax or BCL-XL-selective inhibitor A-1155463 indicated that MCL-1 and BCL-2 are the two key anti-apoptotic targets for sensitization. Similarly, the CDK inhibitor flavopiridol downregulated MCL-1 expression and synergized with venetoclax in BCL2(High) NHL cell lines to a similar extent as A-1210477. A-1210477 also synergized with navitoclax in the majority of BCL2(Low) NHL cell lines. However, chemical segregation with venetoclax or A-1155463 revealed that synergy was driven by BCL-XL inhibition in this population. Collectively these data emphasize that BCL2 status is predictive of venetoclax potency in NHL not only as a single agent, but also in the adjuvant setting with anti-tumorigenic agents that inhibit MCL-1 function. These studies also potentially identify a patient population (BCL2(Low)) that could benefit from BCL-XL (navitoclax)-driven combination therapy. Topics: Aniline Compounds; Antineoplastic Agents; bcl-X Protein; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Drug Synergism; Humans; Indoles; Lymphoma, Non-Hodgkin; Myeloid Cell Leukemia Sequence 1 Protein; Proto-Oncogene Proteins c-bcl-2; Sulfonamides | 2015 |
The role of lymphatic transport on the systemic bioavailability of the Bcl-2 protein family inhibitors navitoclax (ABT-263) and ABT-199.
Navitoclax (ABT-263), a Bcl-2 family inhibitor and ABT-199, a Bcl-2 selective inhibitor, are high molecular weight, high logP molecules that show low solubility in aqueous media. While these properties are associated with low oral bioavailability (F), both navitoclax and ABT-199 showed moderate F in preclinical species. The objective of the described study was to determine if lymphatic transport contributes to the systemic availability of navitoclax and ABT-199 in dogs. The intravenous pharmacokinetics of navitoclax and ABT-199 were determined in intact (noncannulated) dogs. In oral studies, tablets (100 mg) of navitoclax and ABT-199 were administered to both intact and thoracic lymph duct-cannulated (TDC) dogs. The clearance of navitoclax and ABT-199 was low; 0.673 and 0.779 ml/min per kilogram, respectively. The volume of distribution of both compounds was low (0.5-0.7 l/kg). The half-lives of navitoclax and ABT-199 were 22.2 and 12.9 hours, respectively. The F of navitoclax and ABT-199 were 56.5 and 38.8%, respectively, in fed intact dogs. In fed TDC dogs, 13.5 and 4.67% of the total navitoclax and ABT-199 doses were observed in lymph with the % F of navitoclax and ABT-199 of 21.7 and 20.2%, respectively. The lower lymphatic transport of ABT-199 corresponds to the lower overall % F of ABT-199 versus navitoclax despite similar systemic availability via the portal vein (similar % F in TDC animals). This is consistent with the higher long chain triglyceride solubility of navitoclax (9.2 mg/ml) versus ABT-199 (2.2 mg/ml). In fasted TDC animals, lymph transport of navitoclax and ABT-199 decreased by 1.8-fold and 10-fold, respectively. Topics: Administration, Oral; Aniline Compounds; Animals; Antineoplastic Agents; Area Under Curve; Biological Availability; Bridged Bicyclo Compounds, Heterocyclic; Dogs; Fasting; Half-Life; Injections, Intravenous; Lymph; Male; Metabolic Clearance Rate; Models, Animal; Postprandial Period; Proto-Oncogene Proteins c-bcl-2; Solubility; Sulfonamides; Thoracic Duct | 2014 |
Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid leukemia.
B-cell leukemia/lymphoma 2 (BCL-2) prevents commitment to programmed cell death at the mitochondrion. It remains a challenge to identify those tumors that are best treated by inhibition of BCL-2. Here, we demonstrate that acute myeloid leukemia (AML) cell lines, primary patient samples, and murine primary xenografts are very sensitive to treatment with the selective BCL-2 antagonist ABT-199. In primary patient cells, the median IC50 was approximately 10 nmol/L, and cell death occurred within 2 hours. Our ex vivo sensitivity results compare favorably with those observed for chronic lymphocytic leukemia, a disease for which ABT-199 has demonstrated consistent activity in clinical trials. Moreover, mitochondrial studies using BH3 profiling demonstrate activity at the mitochondrion that correlates well with cytotoxicity, supporting an on-target mitochondrial mechanism of action. Our protein and BH3 profiling studies provide promising tools that can be tested as predictive biomarkers in any clinical trial of ABT-199 in AML. Topics: Aniline Compounds; Animals; Antineoplastic Agents; Biomarkers, Tumor; Biphenyl Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cell Death; Cell Line, Tumor; Drug Resistance, Neoplasm; Gene Expression Regulation, Leukemic; Humans; Leukemia, Myeloid, Acute; Mice; Mitochondria; Neoplasms, Experimental; Nitrophenols; Peptide Fragments; Piperazines; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; Xenograft Model Antitumor Assays | 2014 |
Platelet-derived growth factor primes cancer-associated fibroblasts for apoptosis.
Desmoplastic malignancies such as cholangiocarcinoma (CCA) are characterized by a dense stroma containing an abundance of myofibroblasts termed cancer-associated fibroblasts (CAF). The CAF phenotype represents an "activated state" in which cells are primed for cell death triggered by BH3 mimetics. Accordingly, this primed state may be therapeutically exploited. To elucidate the mechanisms underlying this poorly understood apoptotic priming, we examined the role of platelet-derived growth factor (PDGF) in CAF priming for cell death given its prominent role in CAF activation. PDGF isomers PDGF-B and PDGF-D are abundantly expressed in CCA cells derived from human specimens. Either isomer sensitizes myofibroblasts to cell death triggered by BH3 mimetics. Similar apoptotic sensitization was observed with co-culture of myofibroblasts and CCA cells. Profiling of Bcl-2 proteins expressed by PDGF-primed myofibroblasts demonstrated an increase in cellular levels of Puma. PDGF-mediated increases in cellular Puma levels induced proapoptotic changes in Bak, which resulted in its binding to Bcl-2. Short hairpin RNA-mediated down-regulation of Puma conferred resistance to PDGF-mediated apoptotic priming. Conversely, the BH3 mimetic navitoclax disrupted Bcl-2/Bak heterodimers, allowing Bak to execute the cell death program. Treatment with a Bcl-2-specific BH3 mimetic, ABT-199, reduced tumor formation and tumor burden in a murine model of cholangiocarcinoma. Collectively, these findings indicate that apoptotic priming of CAF by PDGF occurs via Puma-mediated Bak activation, which can be converted to active full-blown apoptosis by navitoclax or ABT-199 for therapeutic benefit. Topics: Aniline Compounds; Antineoplastic Agents; Apoptosis; bcl-2 Homologous Antagonist-Killer Protein; Bile Duct Neoplasms; Bridged Bicyclo Compounds, Heterocyclic; Cell Line; Cholangiocarcinoma; Fibroblasts; Humans; Peptide Fragments; Platelet-Derived Growth Factor; Proto-Oncogene Proteins; Sulfonamides | 2014 |
The BCL2 inhibitor ABT-199 significantly enhances imatinib-induced cell death in chronic myeloid leukemia progenitors.
BCR-ABL1-specific tyrosine kinase inhibitors prolong the life of patients with chronic myeloid leukemia (CML) but cannot completely eradicate CML progenitors. The BH3 mimetic, ABT-263, targets prosurvival BCL2 family members, and has activity against CML progenitors. However, the inhibitory effect of ABT-263 on BCL-XL, which mediates platelet survival, produces dose-limiting thrombocytopenia. A second-generation BH3 mimetic, ABT-199, has been developed to specifically bind BCL2 but not BCL-XL. We determined the activity of ABT-199 against CML cell lines, as well as primary CML and normal cord blood (NCB) progenitors. We find that BCL2 expression levels predict sensitivity to ABT-199 in CML and NCB progenitors, and that high NCB BCL2 levels may explain the reported hematologic toxicities in ABT-199-treated patients. Also, while single agent ABT-199 has modest activity against CML progenitors, when combined with imatinib, ABT-199 significantly enhances imatinib activity against CML progenitors at concentrations predicted to avoid hematologic toxicities. Topics: Aniline Compounds; Antineoplastic Agents; Apoptosis; Benzamides; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Drug Resistance, Neoplasm; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Neoplastic Stem Cells; Piperazines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-bcl-2; Pyrimidines; Sulfonamides; Tumor Stem Cell Assay | 2014 |
Bcl-2 family inhibition sensitizes human prostate cancer cells to docetaxel and promotes unexpected apoptosis under caspase-9 inhibition.
Docetaxel (DTX) is a useful chemotherapeutic drug for the treatment of hormone-refractory prostate cancer. However, emergence of DTX resistance has been a therapeutic hurdle. In this study, we investigated the effect of combining DTX with Bcl-2 family inhibitors using human prostate cancer cell lines (PC3, LNCaP, and DU145 cells). PC3 cells were less sensitive to DTX than were the other two cell lines. In contrast to ABT-199, which inhibits Bcl-2 and Bcl-w, both ABT-263 and ABT-737, which inhibit Bcl-2, Bcl-xL, and Bcl-w, significantly augmented the antitumor effect of DTX on PC3 cells. ABT-263 also enhanced the antitumor effect of DTX on a DTX-resistant PC3 variant cell line. The antitumor effect of ABT-263 was due mainly to its inhibitory effect on Bcl-xL. In a xenograft mouse model, DTX and ABT-737 combination therapy significantly inhibited PC3 tumor growth. Interestingly, although ABT-263 activated caspase-9 in PC3 cells, inhibition of caspase-9 unexpectedly promoted ABT-263-induced apoptosis in a caspase-8-dependent manner. This augmented apoptosis was also observed in LNCaP cells. These findings indicate that Bcl-xL inhibition can sensitize DTX-resistant prostate cancer cells to DTX, and they reveal a unique apoptotic pathway in which antagonism of Bcl-2 family members in caspase-9-inhibited prostate cancer cells triggers caspase-8-dependent apoptosis. Topics: Aniline Compounds; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Biphenyl Compounds; Bridged Bicyclo Compounds, Heterocyclic; Caspase 9; Caspase Inhibitors; Cell Line, Tumor; Docetaxel; Drug Synergism; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Nitrophenols; Piperazines; Prostatic Neoplasms; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; Taxoids; Transfection; Xenograft Model Antitumor Assays | 2014 |
ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets.
Proteins in the B cell CLL/lymphoma 2 (BCL-2) family are key regulators of the apoptotic process. This family comprises proapoptotic and prosurvival proteins, and shifting the balance toward the latter is an established mechanism whereby cancer cells evade apoptosis. The therapeutic potential of directly inhibiting prosurvival proteins was unveiled with the development of navitoclax, a selective inhibitor of both BCL-2 and BCL-2-like 1 (BCL-X(L)), which has shown clinical efficacy in some BCL-2-dependent hematological cancers. However, concomitant on-target thrombocytopenia caused by BCL-X(L) inhibition limits the efficacy achievable with this agent. Here we report the re-engineering of navitoclax to create a highly potent, orally bioavailable and BCL-2-selective inhibitor, ABT-199. This compound inhibits the growth of BCL-2-dependent tumors in vivo and spares human platelets. A single dose of ABT-199 in three patients with refractory chronic lymphocytic leukemia resulted in tumor lysis within 24 h. These data indicate that selective pharmacological inhibition of BCL-2 shows promise for the treatment of BCL-2-dependent hematological cancers. Topics: Aniline Compounds; Animals; Antineoplastic Agents; Apoptosis; bcl-X Protein; Blood Platelets; Bridged Bicyclo Compounds, Heterocyclic; Cell Survival; Dogs; Female; HeLa Cells; Hematologic Neoplasms; Humans; Mice; Mice, SCID; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; Tumor Burden; Xenograft Model Antitumor Assays | 2013 |