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Nature Communications Oct 2023Tumor growth requires elevated ribosome biogenesis. Targeting ribosomes is an important strategy for cancer therapy. The ribosome inhibitor, homoharringtonine (HHT), is...
Tumor growth requires elevated ribosome biogenesis. Targeting ribosomes is an important strategy for cancer therapy. The ribosome inhibitor, homoharringtonine (HHT), is used for the clinical treatment of leukemia, yet it is ineffective for the treatment of solid tumors, the reasons for which remain unclear. Here we show that Snail1, a key factor in the regulation of epithelial-to-mesenchymal transition, plays a pivotal role in cellular surveillance response upon ribotoxic stress. Mechanistically, ribotoxic stress activates the JNK-USP36 signaling to stabilize Snail1 in the nucleolus, which facilitates ribosome biogenesis and tumor cell survival. Furthermore, we show that HHT activates the JNK-USP36-Snail1 axis in solid tumor cells, but not in leukemia cells, resulting in solid tumor cell resistance to HHT. Importantly, a combination of HHT with the inhibition of the JNK-USP36-Snail1 axis synergistically inhibits solid tumor growth. Together, this study provides a rationale for targeting the JNK-USP36-Snail1 axis in ribosome inhibition-based solid tumor therapy.
Topics: Humans; Cell Survival; Ribosomes; Cell Nucleolus; Neoplasms; Leukemia; Ubiquitin Thiolesterase
PubMed: 37833415
DOI: 10.1038/s41467-023-42257-8 -
Biomedicine & Pharmacotherapy =... Oct 2023Neuroblastoma, a childhood cancer affecting the sympathetic nervous system, continues to challenge the development of potent treatments due to the limited availability...
Neuroblastoma, a childhood cancer affecting the sympathetic nervous system, continues to challenge the development of potent treatments due to the limited availability of druggable targets for this aggressive illness. Recent investigations have uncovered that phosphoglycerate dehydrogenase (PHGDH), an essential enzyme for de novo serine synthesis, serves as a non-oncogene dependency in high-risk neuroblastoma. In this study, we show that homoharringtonine (HHT) acts as a PHGDH inhibitor, inducing intricate alterations in cellular metabolism, and thus providing an efficient treatment for neuroblastoma. We have experimentally verified the reliance of neuroblastoma on PHGDH and employed molecular docking, thermodynamic evaluations, and X-ray crystallography techniques to determine the bond interactions between HHT and PHGDH. Administering HHT to treat neuroblastoma resulted in effective cell elimination in vitro and tumor reduction in vivo. Metabolite and functional assessments additionally disclosed that HHT treatment suppressed de novo serine synthesis, initiating intricate metabolic reconfiguration and oxidative stress in neuroblastoma. Collectively, these discoveries highlight the potential of targeting PHGDH using HHT as a potent approach for managing high-risk neuroblastoma.
Topics: Humans; Child; Phosphoglycerate Dehydrogenase; Homoharringtonine; Molecular Docking Simulation; Enzyme Inhibitors; Neuroblastoma; Serine
PubMed: 37673018
DOI: 10.1016/j.biopha.2023.115429 -
Frontiers in Oncology 2023Refractory/relapsed acute myeloid leukemia (R/R AML) has unsatisfactory outcomes even after allogeneic hematopoietic stem cell transplantation. Long-term survival is...
Effectiveness of chemotherapy using bortezomib combined with homoharringtonine and cytarabine in refractory or relapsed acute myeloid leukemia: a phase II, multicenter, prospective clinical trial.
BACKGROUND
Refractory/relapsed acute myeloid leukemia (R/R AML) has unsatisfactory outcomes even after allogeneic hematopoietic stem cell transplantation. Long-term survival is mainly influenced by complete remission (CR) rates after induction therapies.
OBJECTIVES
To investigate CR/CR with incomplete hematologic recovery (CRi) rates and adverse events with a new induction therapy (bortezomib, homoharringtonine, and cytarabine [BHA]) for patients with R/R AML.
METHODS
We enrolled 21 patients with R/R AML (median age, 42 [range, 30-62] years), who received BHA for remission induction (bortezomib, 1.3 mg/m/day on days 1 and 4; homoharringtonine, 4 mg/m/day for 5 days, and cytarabine, 1.5 g/m/day for 5 days). CR and adverse events were assessed.
RESULTS
After one course of BHA, the CR/CRi and partial remission rates were 38.1% and 14.3%, respectively, with an overall response rate (ORR) of 52.4% in 21 patients. 9 of 21 patients harbored FLT3-ITD or FLT3-TKD mutations, and achieved either CR/CRi or ORR of 66.7% (=0.03) by comparison with that in R/R AML without FLT3 mutation. After induction therapy, consolidation chemotherapy or allogeneic hematopoietic stem cell transplantation led to a one-year overall survival of 27.8% in all patients. One-year relapse-free survival was 50% in 8 patients who had achieved CR/CRi after one course of BHA. During induction, non-hematologic adverse events (grade 3/4) commonly were infection (90.5%), hypokalemia (14.4%), hypocalcemia (14.3%), and mucositis (9.5%). In patients achieving CR, the median time to neutrophil count >0.5×10/L and time to platelet count >20×10/L were 15 (13-17) days and 13 (13-18) days, respectively.
CONCLUSION
BHA chemotherapy regimen was safe and tolerable to serve as an induction therapy for R/R AML, particularly with FLT3 mutation. The higher CR/CRi rate will give a clue to determine a potentialeffectiveness of BHA for AML patients carrying FLT3 mutation in a further investigation.
CLINICAL TRIAL REGISTRATION
https://www.chictr.org.cn/, identifier ChiCTR2000029841.
PubMed: 37664023
DOI: 10.3389/fonc.2023.1142449 -
Journal of Clinical Oncology : Official... Nov 2023Homoharringtonine (HHT) is commonly used for the treatment of Chinese adult AML, and all-trans retinoic acid (ATRA) has been verified in acute promyelocytic leukemia... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Homoharringtonine (HHT) is commonly used for the treatment of Chinese adult AML, and all-trans retinoic acid (ATRA) has been verified in acute promyelocytic leukemia (APL). However, the efficacy and safety of HHT-based induction therapy have not been confirmed for childhood AML, and ATRA-based treatment has not been evaluated among patients with non-APL AML.
PATIENTS AND METHODS
This open-label, multicenter, randomized Chinese Children's Leukemia Group-AML 2015 study was performed across 35 centers in China. Patients with newly diagnosed childhood AML were first randomly assigned to receive an HHT-based (H arm) or etoposide-based (E arm) induction regimen and then randomly allocated to receive cytarabine-based (AC arm) or ATRA-based (AT arm) maintenance therapy. The primary end points were the complete remission (CR) rate after induction therapy, and the secondary end points were the overall survival (OS) and event-free survival (EFS) at 3 years.
RESULTS
We enrolled 1,258 patients, of whom 1,253 were included in the intent-to-treat analysis. The overall CR rate was significantly higher in the H arm than in the E arm (79.9% 73.9%, = .014). According to the intention-to-treat analysis, the 3-year OS was 69.2% (95% CI, 65.1 to 72.9) in the H arm and 62.8% (95% CI, 58.7 to 66.6) in the E arm ( = .025); the 3-year EFS was 61.1% (95% CI, 56.8 to 65.0) in the H arm and 53.4% (95% CI, 49.2 to 57.3) in the E arm ( = .022). Among the per-protocol population, who received maintenance therapy, the 3-year EFS did not differ significantly across the four arms (H + AT arm: 70.7%, 95% CI, 61.1 to 78.3; H + AC arm: 74.8%, 95% CI, 67.0 to 81.0, = .933; E + AC arm: 72.9%, 95% CI, 65.1 to 79.2, = .789; E + AT arm: 66.2%, 95% CI, 56.8 to 74.0, = .336).
CONCLUSION
HHT is an alternative combination regimen for childhood AML. The effects of ATRA-based maintenance are comparable with those of cytarabine-based maintenance therapy.
Topics: Child; Humans; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; East Asian People; Homoharringtonine; Leukemia, Promyelocytic, Acute; Multicenter Studies as Topic; Remission Induction; Survival Rate; Treatment Outcome; Tretinoin
PubMed: 37531592
DOI: 10.1200/JCO.22.02836 -
Biochemical and Biophysical Research... Oct 2023Acute myeloid leukemia (AML) is a heterogeneous disease and about one third of AML patients carry nucleophosmin (NPM1) mutation. Because 95% mutations give NPM1 an...
Acute myeloid leukemia (AML) is a heterogeneous disease and about one third of AML patients carry nucleophosmin (NPM1) mutation. Because 95% mutations give NPM1 an additional nuclear export signaling (NES) and dislocate NPM1 in cytoplasm (NPMc), relocating NPM1 in nucleus provide an innovative strategy for treating this type of AML. The nuclear export of NPM1 depends on the nuclear protein export receptor XPO1, which recognizes the NES sequence on NPM1. Homoharringtonine (HHT) is a first-line chemotherapy drug of AML, yet the exact mechanism of its anti-AML activity is elusive. In this study, we found that HHT can directly target XPO1 to its NES-binding cleft, bind to Cys528 of XPO1, and inhibits its nuclear transport function. In addition, HHT can block NPMc proteins nuclear export and thus make NPMc AML cells much more sensitive to HHT treatment. Furthermore, the sensitivity of NPMc AML cells to HHT is a universal phenomenon irrespective of the different genetic lesions of AML. Taken together, our findings suggest that XPO1 is a new target of HHT and provide a novel strategy for NPMc AML treatment.
Topics: Humans; Homoharringtonine; Leukemia, Myeloid, Acute; Nuclear Proteins; Cell Nucleus; Cytoplasm; Mutation
PubMed: 37473530
DOI: 10.1016/j.bbrc.2023.07.027 -
Cell Transplantation 2023Allogeneic hematopoietic stem cell transplantation (HSCT) is an effective treatment for acute myeloid leukemia (AML). Pediatric patients with AML who relapse after HSCT...
Allogeneic hematopoietic stem cell transplantation (HSCT) is an effective treatment for acute myeloid leukemia (AML). Pediatric patients with AML who relapse after HSCT have an extremely poor prognosis. We performed a retrospective study of pediatric patients diagnosed with AML from August 2015 to October 2019 who were treated with HSCT. Kaplan-Meier analyses were used to evaluate overall survival (OS), event-free survival (EFS), and cumulative recurrence rate (CRR). Cox regression analysis was used to determine the association between the baseline characteristics and relapse. A total of 37 pediatric patients met the inclusion criteria. Twenty-eight (75.7%) patients survived, and 9 (24.3%) patients died. The OS rates of AML patients treated with HSCT were 89.2% ± 5.1%, 75.7% ± 7.1%, and 75.7% ± 7.1% at 1, 3, and 5 years, respectively, and the CRRs were 11.4% ± 5.4%, 24.7% ± 7.7%, and 33.1% ± 10.4% at 1, 3, and 5 years after HSCT, respectively; four of nine children who relapsed after transplantation died. Induction with etoposide rather than homoharringtonine and fungal infections could be high-risk factors for recurrence after transplantation. The association between homoharringtonine-based induction therapy and a low recurrence rate persisted after adjusting for age, sex, risk stratification, fusion genes, and fungal infections. This study clarifies the clinical features and poor prognosis of post-transplant relapse in pediatric AML and indicates the urgent need for effective therapy for patients who relapse after HSCT.
Topics: Humans; Child; Homoharringtonine; Induction Chemotherapy; Retrospective Studies; Hematopoietic Stem Cell Transplantation; Leukemia, Myeloid, Acute; Recurrence; Chronic Disease; Mycoses
PubMed: 37470325
DOI: 10.1177/09636897231183559 -
BioRxiv : the Preprint Server For... Apr 2023COVID-19 has claimed millions of lives since the emergence of SARS-CoV-2, and lung disease appears the primary cause of the death in COVID-19 patients. However, the...
UNLABELLED
COVID-19 has claimed millions of lives since the emergence of SARS-CoV-2, and lung disease appears the primary cause of the death in COVID-19 patients. However, the underlying mechanisms of COVID-19 pathogenesis remain elusive, and there is no existing model where the human disease can be faithfully recapitulated and conditions for the infection process can be experimentally controlled. Herein we report the establishment of an human precision-cut lung slice (hPCLS) platform for studying SARS-CoV-2 pathogenicity and innate immune responses, and for evaluating the efficacy of antiviral drugs against SARS-CoV-2. We show that while SARS-CoV-2 continued to replicate during the course of infection of hPCLS, infectious virus production peaked within 2 days, and rapidly declined thereafter. Although most proinflammatory cytokines examined were induced by SARS-CoV-2 infection, the degree of induction and types of cytokines varied significantly among hPCLS from individual donors, reflecting the heterogeneity of human populations. In particular, two cytokines (IP-10 and IL-8) were highly and consistently induced, suggesting a role in the pathogenesis of COVID-19. Histopathological examination revealed focal cytopathic effects late in the infection. Transcriptomic and proteomic analyses identified molecular signatures and cellular pathways that are largely consistent with the progression of COVID-19 in patients. Furthermore, we show that homoharringtonine, a natural plant alkaloid derived from , not only inhibited virus replication but also production of pro-inflammatory cytokines, and ameliorated the histopathological changes of the lungs caused by SARS-CoV-2 infection, demonstrating the usefulness of the hPCLS platform for evaluating antiviral drugs.
SIGNIFICANCE
Here we established an human precision-cut lung slice platform for assessing SARS-CoV-2 infection, viral replication kinetics, innate immune response, disease progression, and antiviral drugs. Using this platform, we identified early induction of specific cytokines, especially IP-10 and IL-8, as potential predictors for severe COVID-19, and uncovered a hitherto unrecognized phenomenon that while infectious virus disappears at late times of infection, viral RNA persists and lung histopathology commences. This finding may have important clinical implications for both acute and post-acute sequelae of COVID-19. This platform recapitulates some of the characteristics of lung disease observed in severe COVID-19 patients and is therefore a useful platform for understanding mechanisms of SARS-CoV-2 pathogenesis and for evaluating the efficacy of antiviral drugs.
PubMed: 37131640
DOI: 10.1101/2023.04.18.537373 -
IScience Apr 2023Chronic myeloid leukemia (CML) cells circulate between blood and bone marrow niche, representing different microenvironments. We studied the role of the two RNA-binding...
Chronic myeloid leukemia (CML) cells circulate between blood and bone marrow niche, representing different microenvironments. We studied the role of the two RNA-binding proteins, T-cell-restricted intracellular antigen (TIAR), and the fragile X mental retardation protein (FMRP) in the regulation of protein translation in CML cells residing in settings mimicking peripheral blood microenvironment (PBM) and bone marrow microenvironment (BMM). The outcomes showed how conditions shaped the translation process through TIAR and FMRP activity, considering its relevance in therapy resistance. The QuaNCAT mass-spectrometric approach revealed that TIAR and FMRP have a discrete modulatory effect on protein synthesis and thus affect distinct aspects of leukemic cells functioning in the hypoxic niche. In the BMM setup, FMRP impacted metabolic adaptation of cells and TIAR substantially supported the resistance of CML cells to translation inhibition by homoharringtonine. Overall, our results demonstrated that targeting post-transcriptional control should be considered when designing anti-leukemia therapeutic solutions.
PubMed: 37123244
DOI: 10.1016/j.isci.2023.106543 -
Journal of Hematology & Oncology Apr 2023Relapsed or refractory acute myeloid leukemia (R/R AML) has a dismal prognosis. The aim of this study was to investigate the activity and tolerability of venetoclax...
BACKGROUND
Relapsed or refractory acute myeloid leukemia (R/R AML) has a dismal prognosis. The aim of this study was to investigate the activity and tolerability of venetoclax combined with azacitidine plus homoharringtonine (VAH) regimen for R/R AML.
METHODS
This phase 2 trial was done at ten hospitals in China. Eligible patients were R/R AML (aged 18-65 years) with an Eastern Cooperative Oncology Group performance status of 0-2. Patients received venetoclax (100 mg on day 1, 200 mg on day 2, and 400 mg on days 3-14) and azacitidine (75 mg/m on days 1-7) and homoharringtonine (1 mg/m on days 1-7). The primary endpoint was composite complete remission rate [CRc, complete response (CR) plus complete response with incomplete blood count recovery (CRi)] after 2 cycles of treatment. The secondary endpoints include safety and survival.
RESULTS
Between May 27, 2020, and June 16, 2021, we enrolled 96 patients with R/R AML, including 37 primary refractory AML and 59 relapsed AML (16 relapsed after chemotherapy and 43 after allo-HSCT). The CRc rate was 70.8% (95% CI 60.8-79.2). In the patients with CRc, measurable residual disease (MRD)-negative was attained in 58.8% of CRc patients. Accordingly, overall response rate (ORR, CRc plus partial remission (PR)) was 78.1% (95% CI 68.6-85.4). At a median follow-up of 14.7 months (95% CI 6.6-22.8) for all patients, median overall survival (OS) was 22.1 months (95% CI 12.7-Not estimated), and event-free survival (EFS) was 14.3 months (95% CI 7.0-Not estimated). The 1-year OS was 61.5% (95% CI 51.0-70.4), and EFS was 51.0% (95% CI 40.7-60.5). The most common grade 3-4 adverse events were febrile neutropenia (37.4%), sepsis (11.4%), and pneumonia (21.9%).
CONCLUSIONS
VAH is a promising and well-tolerated regimen in R/R AML, with high CRc and encouraging survival. Further randomized studies are needed to be explored. Trial registration clinicaltrials.gov identifier: NCT04424147.
Topics: Humans; Azacitidine; Homoharringtonine; Leukemia, Myeloid, Acute; Bridged Bicyclo Compounds, Heterocyclic; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37120593
DOI: 10.1186/s13045-023-01437-1 -
Cancer Cell May 2023We uncover a tumor-suppressive process in urothelium called transcriptional-translational conflict caused by deregulation of the central chromatin remodeling component...
We uncover a tumor-suppressive process in urothelium called transcriptional-translational conflict caused by deregulation of the central chromatin remodeling component ARID1A. Loss of Arid1a triggers an increase in a nexus of pro-proliferation transcripts, but a simultaneous inhibition of the eukaryotic elongation factor 2 (eEF2), which results in tumor suppression. Resolution of this conflict through enhancing translation elongation speed enables the efficient and precise synthesis of a network of poised mRNAs resulting in uncontrolled proliferation, clonogenic growth, and bladder cancer progression. We observe a similar phenomenon in patients with ARID1A-low tumors, which also exhibit increased translation elongation activity through eEF2. These findings have important clinical implications because ARID1A-deficient, but not ARID1A-proficient, tumors are sensitive to pharmacologic inhibition of protein synthesis. These discoveries reveal an oncogenic stress created by transcriptional-translational conflict and provide a unified gene expression model that unveils the importance of the crosstalk between transcription and translation in promoting cancer.
Topics: Humans; Chromatin; Urinary Bladder Neoplasms
PubMed: 37084735
DOI: 10.1016/j.ccell.2023.03.021