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Journal of Internal Medicine Nov 2020Senolytics are a class of drugs that selectively clear senescent cells (SC). The first senolytic drugs Dasatinib, Quercetin, Fisetin and Navitoclax were discovered using... (Review)
Review
Senolytics are a class of drugs that selectively clear senescent cells (SC). The first senolytic drugs Dasatinib, Quercetin, Fisetin and Navitoclax were discovered using a hypothesis-driven approach. SC accumulate with ageing and at causal sites of multiple chronic disorders, including diseases accounting for the bulk of morbidity, mortality and health expenditures. The most deleterious SC are resistant to apoptosis and have up-regulation of anti-apoptotic pathways which defend SC against their own inflammatory senescence-associated secretory phenotype (SASP), allowing them to survive, despite killing neighbouring cells. Senolytics transiently disable these SCAPs, causing apoptosis of those SC with a tissue-destructive SASP. Because SC take weeks to reaccumulate, senolytics can be administered intermittently - a 'hit-and-run' approach. In preclinical models, senolytics delay, prevent or alleviate frailty, cancers and cardiovascular, neuropsychiatric, liver, kidney, musculoskeletal, lung, eye, haematological, metabolic and skin disorders as well as complications of organ transplantation, radiation and cancer treatment. As anticipated for agents targeting the fundamental ageing mechanisms that are 'root cause' contributors to multiple disorders, potential uses of senolytics are protean, potentially alleviating over 40 conditions in preclinical studies, opening a new route for treating age-related dysfunction and diseases. Early pilot trials of senolytics suggest they decrease senescent cells, reduce inflammation and alleviate frailty in humans. Clinical trials for diabetes, idiopathic pulmonary fibrosis, Alzheimer's disease, COVID-19, osteoarthritis, osteoporosis, eye diseases and bone marrow transplant and childhood cancer survivors are underway or beginning. Until such studies are done, it is too early for senolytics to be used outside of clinical trials.
Topics: Betacoronavirus; COVID-19; Cellular Senescence; Coronavirus Infections; Drug Development; Drug Discovery; Humans; Pandemics; Pneumonia, Viral; SARS-CoV-2; Translational Research, Biomedical; COVID-19 Drug Treatment
PubMed: 32686219
DOI: 10.1111/joim.13141 -
Cancer Discovery Jun 2021Combining venetoclax, a selective BCL2 inhibitor, with low-dose navitoclax, a BCL-X/BCL2 inhibitor, may allow targeting of both BCL2 and BCL-X without dose-limiting...
Combining venetoclax, a selective BCL2 inhibitor, with low-dose navitoclax, a BCL-X/BCL2 inhibitor, may allow targeting of both BCL2 and BCL-X without dose-limiting thrombocytopenia associated with navitoclax monotherapy. The safety and preliminary efficacy of venetoclax with low-dose navitoclax and chemotherapy was assessed in this phase I dose-escalation study (NCT03181126) in pediatric and adult patients with relapsed/refractory (R/R) acute lymphoblastic leukemia or lymphoblastic lymphoma. Forty-seven patients received treatment. A recommended phase II dose of 50 mg navitoclax for adults and 25 mg for patients <45 kg with 400 mg adult-equivalent venetoclax was identified. Delayed hematopoietic recovery was the primary safety finding. The complete remission rate was 60%, including responses in patients who had previously received hematopoietic cell transplantation or immunotherapy. Thirteen patients (28%) proceeded to transplantation or CAR T-cell therapy on study. Venetoclax with navitoclax and chemotherapy was well tolerated and had promising efficacy in this heavily pretreated patient population. SIGNIFICANCE: In this phase I study, venetoclax with low-dose navitoclax and chemotherapy was well tolerated and had promising efficacy in patients with relapsed/refractory acute lymphoblastic leukemia or lymphoblastic lymphoma. Responses were observed in patients across histologic and genomic subtypes and in those who failed available therapies including stem cell transplant...
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aniline Compounds; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Child; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction; Sulfonamides; Treatment Outcome; Young Adult
PubMed: 33593877
DOI: 10.1158/2159-8290.CD-20-1465 -
Critical Reviews in Oncology/hematology Dec 2022Myelofibrosis (MF) is a clonal hematologic malignancy with progressive bone marrow fibrosis. Clinical manifestations of MF include splenomegaly, constitutional symptoms,... (Review)
Review
Myelofibrosis (MF) is a clonal hematologic malignancy with progressive bone marrow fibrosis. Clinical manifestations of MF include splenomegaly, constitutional symptoms, and anemia, whose pathogenesis is multifactorial and largely due to ineffective erythropoiesis and is clinically associated with poor quality of life and reduced overall survival. The only curative treatment for MF is allogenic stem cell transplantation; however, few patients are eligible. Disease management strategies for MF-related anemia have limited effectiveness, and Janus kinase (JAK) inhibitors may induce or worsen related anemia. Thus, there is a significant unmet need for the treatment of patients with MF-related anemia. This review summarizes current and emerging treatments for anemia in MF, including luspatercept and KER-050 (transforming growth factor-β ligand traps), momelotinib and pacritinib (JAK inhibitors), pelabresib (a bromodomain extra-terminal domain inhibitor), PRM-151 (an antifibrotic agent), imetelstat (a telomerase inhibitor), and navitoclax (a BCL-2/BCL-xL inhibitor). Therapeutic combinations with ruxolitinib may offer another treatment approach.
Topics: Humans; Primary Myelofibrosis; Janus Kinase 2; Quality of Life; Nitriles; Anemia; Antineoplastic Agents; Protein Kinase Inhibitors
PubMed: 36332787
DOI: 10.1016/j.critrevonc.2022.103862 -
EBioMedicine Jul 2017Cellular senescence entails essentially irreversible replicative arrest, apoptosis resistance, and frequently acquisition of a pro-inflammatory, tissue-destructive... (Review)
Review
Cellular senescence entails essentially irreversible replicative arrest, apoptosis resistance, and frequently acquisition of a pro-inflammatory, tissue-destructive senescence-associated secretory phenotype (SASP). Senescent cells accumulate in various tissues with aging and at sites of pathogenesis in many chronic diseases and conditions. The SASP can contribute to senescence-related inflammation, metabolic dysregulation, stem cell dysfunction, aging phenotypes, chronic diseases, geriatric syndromes, and loss of resilience. Delaying senescent cell accumulation or reducing senescent cell burden is associated with delay, prevention, or alleviation of multiple senescence-associated conditions. We used a hypothesis-driven approach to discover pro-survival Senescent Cell Anti-apoptotic Pathways (SCAPs) and, based on these SCAPs, the first senolytic agents, drugs that cause senescent cells to become susceptible to their own pro-apoptotic microenvironment. Several senolytic agents, which appear to alleviate multiple senescence-related phenotypes in pre-clinical models, are beginning the process of being translated into clinical interventions that could be transformative.
Topics: Aging; Animal Experimentation; Animals; Apoptosis; Biomarkers; Cellular Senescence; Chronic Disease; Disease Susceptibility; Drug Discovery; Humans; Phenotype; Secretory Pathway; Signal Transduction; Translational Research, Biomedical
PubMed: 28416161
DOI: 10.1016/j.ebiom.2017.04.013 -
Cells Apr 2021Myelofibrosis is a myeloproliferative neoplasm characterized by splenomegaly, constitutional symptoms, bone marrow fibrosis, and a propensity towards transformation to... (Review)
Review
Myelofibrosis is a myeloproliferative neoplasm characterized by splenomegaly, constitutional symptoms, bone marrow fibrosis, and a propensity towards transformation to acute leukemia. JAK inhibitors are the only approved therapy for myelofibrosis and have been successful in reducing spleen and symptom burden. However, they do not significantly impact disease progression and many patients are ineligible due to coexisting cytopenias. Patients who are refractory to JAK inhibition also have a dismal survival. Therefore, non-JAK inhibitor-based therapies are being explored in pre-clinical and clinical settings. In this review, we discuss novel treatments in development for myelofibrosis with targets outside of the JAK-STAT pathway. We focus on the mechanism, preclinical rationale, and available clinical efficacy and safety information of relevant agents including those that target apoptosis (navitoclax, KRT-232, LCL-161, imetelstat), epigenetic modulation (CPI-0610, bomedemstat), the bone marrow microenvironment (PRM-151, AVID-200, alisertib), signal transduction pathways (parsaclisib), and miscellaneous agents (tagraxofusp. luspatercept). We also provide commentary on the future of therapeutic development in myelofibrosis.
Topics: Apoptosis; Epigenesis, Genetic; Humans; Janus Kinases; Primary Myelofibrosis; Protein Kinase Inhibitors; Signal Transduction
PubMed: 33925695
DOI: 10.3390/cells10051034 -
Cell Death & Disease Apr 2020Many chemotherapy treatments induce apoptosis or pyroptosis through BAK/BAX-dependent mitochondrial pathway. BAK/BAX activation causes the mitochondrial outer membrane...
Many chemotherapy treatments induce apoptosis or pyroptosis through BAK/BAX-dependent mitochondrial pathway. BAK/BAX activation causes the mitochondrial outer membrane permeabilization (MOMP), which induces the activation of pro-apoptotic caspase cascade. GSDME cleavage by the pro-apoptotic caspases determines whether chemotherapy drug treatments induce apoptosis or pyroptosis, however, its regulation mechanisms are not clear. In this study, we showed that TNFα+CHX and navitoclax-induced cancer cell pyroptosis through a BAK/BAX-caspase-3-GSDME signaling pathway. GSDME knockdown inhibited the pyroptosis, suggesting the essential role of GSDME in this process. Interestingly, GSDME was found to be palmitoylated on its C-terminal (GSDME-C) during chemotherapy-induced pyroptosis, while 2-bromopalmitate (2-BP) could inhibit the GSDME-C palmitoylation and chemotherapy-induced pyroptosis. Mutation of palmitoylation sites on GSDME also diminished the pyroptosis induced by chemotherapy drugs. Moreover, 2-BP treatment increased the interaction between GSDME-C and GSDME-N, providing a potential mechanism of this function. Further studies indicated several ZDHHC proteins including ZDHHC-2,7,11,15 could interact with and palmitoylate GSDME. Our findings offered new targets to achieve the transformation between chemotherapy-induced pyroptosis and apoptosis.
Topics: Antineoplastic Agents; Caspase 3; HeLa Cells; Humans; Palmitates; Pyroptosis; Transfection
PubMed: 32332857
DOI: 10.1038/s41419-020-2476-2 -
Nature Oct 2018Cellular senescence, which is characterized by an irreversible cell-cycle arrest accompanied by a distinctive secretory phenotype, can be induced through various...
Cellular senescence, which is characterized by an irreversible cell-cycle arrest accompanied by a distinctive secretory phenotype, can be induced through various intracellular and extracellular factors. Senescent cells that express the cell cycle inhibitory protein p16 have been found to actively drive naturally occurring age-related tissue deterioration and contribute to several diseases associated with ageing, including atherosclerosis and osteoarthritis. Various markers of senescence have been observed in patients with neurodegenerative diseases; however, a role for senescent cells in the aetiology of these pathologies is unknown. Here we show a causal link between the accumulation of senescent cells and cognition-associated neuronal loss. We found that the MAPTPS19 mouse model of tau-dependent neurodegenerative disease accumulates p16-positive senescent astrocytes and microglia. Clearance of these cells as they arise using INK-ATTAC transgenic mice prevents gliosis, hyperphosphorylation of both soluble and insoluble tau leading to neurofibrillary tangle deposition, and degeneration of cortical and hippocampal neurons, thus preserving cognitive function. Pharmacological intervention with a first-generation senolytic modulates tau aggregation. Collectively, these results show that senescent cells have a role in the initiation and progression of tau-mediated disease, and suggest that targeting senescent cells may provide a therapeutic avenue for the treatment of these pathologies.
Topics: Aniline Compounds; Animals; Astrocytes; Cellular Senescence; Cognitive Dysfunction; Cyclin-Dependent Kinase Inhibitor p16; Female; Gliosis; Humans; Male; Mice; Mice, Transgenic; Neurofibrillary Tangles; Neuroglia; Phosphorylation; Solubility; Sulfonamides; Transgenes; tau Proteins
PubMed: 30232451
DOI: 10.1038/s41586-018-0543-y -
Nature Medicine Jan 2016Senescent cells (SCs) accumulate with age and after genotoxic stress, such as total-body irradiation (TBI). Clearance of SCs in a progeroid mouse model using a...
Senescent cells (SCs) accumulate with age and after genotoxic stress, such as total-body irradiation (TBI). Clearance of SCs in a progeroid mouse model using a transgenic approach delays several age-associated disorders, suggesting that SCs play a causative role in certain age-related pathologies. Thus, a 'senolytic' pharmacological agent that can selectively kill SCs holds promise for rejuvenating tissue stem cells and extending health span. To test this idea, we screened a collection of compounds and identified ABT263 (a specific inhibitor of the anti-apoptotic proteins BCL-2 and BCL-xL) as a potent senolytic drug. We show that ABT263 selectively kills SCs in culture in a cell type- and species-independent manner by inducing apoptosis. Oral administration of ABT263 to either sublethally irradiated or normally aged mice effectively depleted SCs, including senescent bone marrow hematopoietic stem cells (HSCs) and senescent muscle stem cells (MuSCs). Notably, this depletion mitigated TBI-induced premature aging of the hematopoietic system and rejuvenated the aged HSCs and MuSCs in normally aged mice. Our results demonstrate that selective clearance of SCs by a pharmacological agent is beneficial in part through its rejuvenation of aged tissue stem cells. Thus, senolytic drugs may represent a new class of radiation mitigators and anti-aging agents.
Topics: Aniline Compounds; Animals; Antineoplastic Agents; Antiviral Agents; Apoptosis; B-Lymphocytes; Blotting, Western; Cell Cycle; Cell Line; Cell Survival; Cellular Senescence; Colony-Forming Units Assay; Cyclin-Dependent Kinase Inhibitor p16; DNA Damage; Ganciclovir; Gene Knockdown Techniques; Hematopoietic Stem Cells; Humans; Mice; Microscopy; Muscle, Skeletal; Myoblasts; Proto-Oncogene Proteins c-bcl-2; RNA, Messenger; Rejuvenation; Sulfonamides; Whole-Body Irradiation; bcl-X Protein
PubMed: 26657143
DOI: 10.1038/nm.4010 -
Cancer Research Dec 2021Glioblastomas (GBM) are routinely treated with ionizing radiation (IR) but inevitably recur and develop therapy resistance. During treatment, the tissue surrounding...
Glioblastomas (GBM) are routinely treated with ionizing radiation (IR) but inevitably recur and develop therapy resistance. During treatment, the tissue surrounding tumors is also irradiated. IR potently induces senescence, and senescent stromal cells can promote the growth of neighboring tumor cells by secreting factors that create a senescence-associated secretory phenotype (SASP). Here, we carried out transcriptomic and tumorigenicity analyses in irradiated mouse brains to elucidate how radiotherapy-induced senescence of non-neoplastic brain cells promotes tumor growth. Following cranial irradiation, widespread senescence in the brain occurred, with the astrocytic population being particularly susceptible. Irradiated brains showed an altered transcriptomic profile characterized by upregulation of CDKN1A (p21), a key enforcer of senescence, and several SASP factors, including HGF, the ligand of the receptor tyrosine kinase (RTK) Met. Preirradiation of mouse brains increased Met-driven growth and invasiveness of orthotopically implanted glioma cells. Importantly, irradiated p21 mouse brains did not exhibit senescence and consequently failed to promote tumor growth. Senescent astrocytes secreted HGF to activate Met in glioma cells and to promote their migration and invasion , which could be blocked by HGF-neutralizing antibodies or the Met inhibitor crizotinib. Crizotinib also slowed the growth of glioma cells implanted in preirradiated brains. Treatment with the senolytic drug ABT-263 (navitoclax) selectively killed senescent astrocytes , significantly attenuating growth of glioma cells implanted in preirradiated brains. These results indicate that SASP factors in the irradiated tumor microenvironment drive GBM growth via RTK activation, underscoring the potential utility of adjuvant senolytic therapy for preventing GBM recurrence after radiotherapy. SIGNIFICANCE: This study uncovers mechanisms by which radiotherapy can promote GBM recurrence by inducing senescence in non-neoplastic brain cells, suggesting that senolytic therapy can blunt recurrent GBM growth and aggressiveness.
Topics: Aniline Compounds; Animals; Antineoplastic Agents; Astrocytes; Brain; Cellular Senescence; Gamma Rays; Glioblastoma; Humans; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Neoplasm Recurrence, Local; Senescence-Associated Secretory Phenotype; Sulfonamides; Tumor Microenvironment
PubMed: 34580063
DOI: 10.1158/0008-5472.CAN-21-0752 -
Nature Medicine Dec 2019B-cell lymphoma extra large (BCL-X) is a well-validated cancer target. However, the on-target and dose-limiting thrombocytopenia limits the use of BCL-X inhibitors, such...
B-cell lymphoma extra large (BCL-X) is a well-validated cancer target. However, the on-target and dose-limiting thrombocytopenia limits the use of BCL-X inhibitors, such as ABT263, as safe and effective anticancer agents. To reduce the toxicity of ABT263, we converted it into DT2216, a BCL-X proteolysis-targeting chimera (PROTAC), that targets BCL-X to the Von Hippel-Lindau (VHL) E3 ligase for degradation. We found that DT2216 was more potent against various BCL-X-dependent leukemia and cancer cells but considerably less toxic to platelets than ABT263 in vitro because VHL is poorly expressed in platelets. In vivo, DT2216 effectively inhibits the growth of several xenograft tumors as a single agent or in combination with other chemotherapeutic agents, without causing appreciable thrombocytopenia. These findings demonstrate the potential to use PROTAC technology to reduce on-target drug toxicities and rescue the therapeutic potential of previously undruggable targets. Furthermore, DT2216 may be developed as a safe first-in-class anticancer agent targeting BCL-X.
Topics: Aniline Compounds; Animals; Antineoplastic Agents; Blood Platelets; Gene Expression Regulation, Neoplastic; Heterografts; Humans; Mice; Proteolysis; Sulfonamides; Thrombocytopenia; Von Hippel-Lindau Tumor Suppressor Protein; bcl-X Protein
PubMed: 31792461
DOI: 10.1038/s41591-019-0668-z