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AbstractVenetoclax (VEN), a B-cell lymphoma 2 (BCL-2) selective inhibitor, is widely used for treating acute myeloid leukemia (AML) with promising results. However, the anti-leukemic effect of VEN in relapsed/refractory (R/R)- AML requires improvement. In this study, we observed that combining homoharringtonine (HHT) with VEN plus azacitidine resulted in a significantly higher response and better survival than VA alone in patients with R/R-AML. Basic research indicates that HHT combined with VEN has a highly synergistic effect against both resistant AML cells and primary cells with/without mesenchymal stem cell (MSC) co-culture in vivo, inhibiting proliferation and colony-forming capacity of AML cells associated with concomitant cell cycle arrest. Mechanistically, HHT sensitizes AML cells to VEN by downregulating the anti-apoptotic proteins MCL-1/BCL-xL, activating reactive oxygen species (ROS), leading to mitochondrial membrane potential loss, and attenuating fatty acid (FA) uptake. These findings adding HHT to VEN-based regimens may enhance outcomes in R/R-AML patients. [ABSTRACT FROM AUTHOR]

The knowledge of impurities is an important issue and the base of quality control in modern drugs. To date, the quality control of the antitumor drug homoharringtonine (HHT) is still not sufficiently solved and needs to be improved. Six main impurities, drupacine, cephalotaxine, desmethylcephalotaxinone, harringtonine, 3-O-acetyl-cephalotaxine and 2'R,3'S-isoharringtonine were traced during HHT drug production by HPLC and LC-MS analyses. Additionally, we were able to isolate and identify three undescribed key trace impurities, neohomoharringtonines A–C. Their structures were established by 1D-, and 2D NMR experiments combined with mass spectrometry. An improved quality inspection ability of HHT was constructed. [ABSTRACT FROM AUTHOR]

Purpose: T(8;21)(q22;q22.1)/AML1-ETO positive acute myeloid leukemia (AE-AML) is sensitive to conventional chemotherapy with a favorable prognosis. However, recent small case reports suggest the limited effectiveness of venetoclax (VEN) and hypomethylating agents (HMA) in treating AE-AML. The aim of this retrospective study was to evaluate the effectiveness of VEN plus AZA (VA) in AE-AML and explore whether adding homoharringtonine (HHT) to VA (VAH) could improve the response. Methods: Patients who received VEN plus AZA and HHT (VAH) or VEN plus AZA (VA) regimens were included in this retrospective study. The endpoints of this study were to evaluate the rate of composite complete remission (CRc), measurable residual disease (MRD), event-free survival (EFS), overall survival (OS), and relapse between VAH and VA groups. Results: A total of 32 AE-AML patients who underwent VA or VAH treatments (newly diagnosed with VA, ND-VA, n = 8; relapsed/refractory with VA, R/R-VA, n = 10; relapsed/refractory with VAH, R/R-VAH, n = 14) were included. The CR (complete remission) /CRi (CR with incomplete count recovery) rate of ND-VA, R/R-VA and R/R-VAH were 25%, 10%, and 64.3%, respectively. Measurable residual disease (MRD) negative was observed in 66.7% of R/R-VAH and none of VA-R/R patients. Co-occurring methylation mutations are associated with poor outcomes with VA but exhibit a more favorable response with VAH treatment. Additionally, patients with c-kit mutation presented inferior outcomes with both VEN-based regimens. All regimens were tolerated well by all patients. Conclusion: Our data confirmed the poor response of VA in AE-AML, whether used as frontline or salvage therapy. Adding HHT to VA may improve outcomes and enhance the efficacy of VEN in this population.Keypoints: 1. Patients with t(8;21) AML are unlikely to derive significant advantages from venetoclax (VEN) combined with hypomethylating agents (HMA) treatment, whether it is used in the initial induction phase or as salvage therapy. 2. Adding homoharringtonine to VEN + HMA may enhance the outcomes of patients with t(8;21) AML and is well tolerated, which warrants further study. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) induces cardiac inflammation and fibrosis and reduces survival. We previously demonstrated that G protein-coupled receptor 68 (GPR68) promotes cardiac inflammation and fibrosis in mice with 5/6 nephrectomy (5/6Nx) and patients with CKD. However, no method of GPR68 inhibition has been found that has potential for therapeutic application. Here, we report that Cephalotaxus harringtonia var. nana extract and homoharringtonine ameliorate cardiac inflammation and fibrosis under CKD by suppressing GPR68 function. Reagents that inhibit the function of GPR68 were explored by high-throughput screening using a medicinal plant extract library (8,008 species), and we identified an extract from Cephalotaxus harringtonia var. nana as a GPR68 inhibitor that suppresses inflammatory cytokine production in a GPR68 expression-dependent manner. Consumption of the extract inhibited inflammatory cytokine expression and cardiac fibrosis and improved the decreased survival attributable to 5/6Nx. Additionally, homoharringtonine, a cephalotaxane compound characteristic of C. harringtonia , inhibited inflammatory cytokine production. Homoharringtonine administration in drinking water alleviated cardiac fibrosis and improved heart failure and survival in 5/6Nx mice. A previously unknown effect of C. harringtonia extract and homoharringtonine was revealed in which GPR68-dependent inflammation and cardiac dysfunction were suppressed. Utilizing these compounds could represent a new strategy for treating GPR68-associated diseases, including CKD. [ABSTRACT FROM AUTHOR]

Abstract HHT has emerged as a notable compound in the realm of cancer treatment, particularly for hematological malignancies. Its multifaceted pharmacological properties extend beyond traditional applications, warranting an extensive review of its mechanisms and efficacy. This review aims to synthesize comprehensive insights into the efficacy of HHT in treating hematological malignancies, diverse cancers, and other biomedical applications. It focuses on elucidating the molecular mechanisms, therapeutic potential, and broader applications of HHT. A comprehensive search for peer-reviewed papers was conducted across various academic databases, including ScienceDirect, Web of Science, Scopus, American Chemical Society, Google Scholar, PubMed/MedLine, and Wiley. The review highlights HHT's diverse mechanisms of action, ranging from its role in leukemia treatment to its emerging applications in managing other cancers and various biomedical conditions. It underscores HHT's influence on cellular processes, its efficacy in clinical settings, and its potential to alter pathological pathways. HHT demonstrates significant promise in treating various hematological malignancies and cancers, offering a multifaceted approach to disease management. Its ability to impact various physiological pathways opens new avenues for therapeutic applications. This review provides a consolidated foundation for future research and clinical applications of HHT in diverse medical fields.

Abstract Acute myeloid leukaemia (AML) is a fatal haematopoietic malignancy and is treated with the conventional combination of cytarabine (Ara-C) and daunorubicin (Dau). The survival rate of AML patients is lower due to the cardiotoxicity of daunorubicin. Clinically, homoharringtonine (HHT) plus Ara-C has been reported to be equally effective as Dau plus Ara-C in some types of AML patients with less toxic effects. We utilized the clinical use of homoharringtonine in combination with Ara-C to test its combination mechanism. We found that the insensitivity of AML cells to cytarabine-induced apoptosis is associated with increased Mcl-1 stability and p38 inactivation. HHT downregulates Mcl-1, phosphorylates H2AX and induces apoptosis by activating p38 MAPK. Inactivation of p38 through inhibitors and siRNA blocks apoptosis, H2AX phosphorylation and Mcl-1 reduction. HHT enhances Ara-C activation of the p38 MAPK signalling pathway, overcoming Ara-C tolerance to cell apoptosis by regulating the p38/H2AX/Mcl-1 axis. The optimal ratio of HHT to Ara-C for synergistic lethality in AML cells is 1:4 (M/M). HHT synergistically induces apoptosis in combination with Ara-C in vitro and prolongs the survival of xenografts. We provide a new mechanism for AML treatment by regulating the p38 MAPK/H2AX/Mcl-1 axis to improve cytarabine therapy.

HHT has emerged as a notable compound in the realm of cancer treatment, particularly for hematological malignancies. Its multifaceted pharmacological properties extend beyond traditional applications, warranting an extensive review of its mechanisms and efficacy. This review aims to synthesize comprehensive insights into the efficacy of HHT in treating hematological malignancies, diverse cancers, and other biomedical applications. It focuses on elucidating the molecular mechanisms, therapeutic potential, and broader applications of HHT. A comprehensive search for peer-reviewed papers was conducted across various academic databases, including ScienceDirect, Web of Science, Scopus, American Chemical Society, Google Scholar, PubMed/MedLine, and Wiley. The review highlights HHT's diverse mechanisms of action, ranging from its role in leukemia treatment to its emerging applications in managing other cancers and various biomedical conditions. It underscores HHT's influence on cellular processes, its efficacy in clinical settings, and its potential to alter pathological pathways. HHT demonstrates significant promise in treating various hematological malignancies and cancers, offering a multifaceted approach to disease management. Its ability to impact various physiological pathways opens new avenues for therapeutic applications. This review provides a consolidated foundation for future research and clinical applications of HHT in diverse medical fields. [ABSTRACT FROM AUTHOR]

Mammary tumour is the most common type of tumour in dogs, especially in unneutered female dogs. Homoharringtonine (HHT) is a natural alkaloid that can be used to treat various types of human tumour. However, the inhibitory effect and mechanism of HHT on canine mammary carcinomas (CMC) remain unclear. This study aimed to evaluate the inhibitory effect of HHT on CMC in vitro and determine its underlying molecular mechanism. The effects of HHT on the cytotoxicity of CMC U27 cells were evaluated by the cell counting kit‐8, wound healing, and Transwell assays. HHT‐induced apoptosis of U27 cells was detected by JC‐1 and terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assay. Moreover, the gene expression of B‐cell lymphoma‐2 (Bcl‐2) and Bcl‐2 associated X protein (Bax) were analysed using quantitative reverse transcription‐polymerase chain reaction (RT‐qPCR), and the protein expression of protein kinase B/mammalian target of rapamycin (AKT/mTOR) and mitochondrial apoptosis proteins were determined by western blotting. Furthermore, mammary tumour‐bearing mouse models were established using 4T1 cells to evaluate the therapeutic effect of HHT. It was found that HHT could significantly down‐regulated the protein expression of p‐AKT, p‐mTOR, and Bcl‐2, and up‐regulated the protein expression of P53, Bax, cleaved caspase‐3, and cleaved caspase‐9. In addition, HHT significantly suppressed both tumour volume and mass in mammary tumour mice. In conclusion, HHT damages CMC cells by inhibiting the AKT/mTOR signalling pathway and inducing mitochondrial apoptosis. Such findings lay a theoretical foundation for the clinical treatment of CMC and provide more options for clinical medication. [ABSTRACT FROM AUTHOR]

The plant alkaloid homoharringtonine (HHT) is a Food and Drug Administration (FDA)-approved drug for the treatment of hematologic malignancies. In addition to its well-established antitumor activity, accumulating evidence attributes anti-inflammatory effects to HHT, which have mainly been studied in leukocytes to date. However, a potential influence of HHT on inflammatory activation processes in endothelial cells, which are a key feature of inflammation and a prerequisite for the leukocyte-endothelial cell interaction and leukocyte extravasation, remains poorly understood. In this study, the anti-inflammatory potential of HHT and its derivative harringtonine (HT) on the TNF-induced leukocyte-endothelial cell interaction was assessed, and the underlying mechanistic basis of these effects was elucidated. HHT affected inflammation in vivo in a murine peritonitis model by reducing leukocyte infiltration and proinflammatory cytokine expression as well as ameliorating abdominal pain behavior. In vitro, HT and HHT impaired the leukocyte-endothelial cell interaction by decreasing the expression of the endothelial cell adhesion molecules intracellular adhesion molecule −1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). This effect was mediated by a bipartite mechanism. While HHT did not affect the prominent TNF-induced pro-inflammatory NF-ĸB signaling cascade, the compound downregulated the VCAM1 mRNA expression in an IRF-1-dependent manner and diminished active ICAM1 mRNA translation as determined by polysome profiling. This study highlights HHT as an anti-inflammatory compound that efficiently hampers the leukocyte-endothelial cell interaction by targeting endothelial activation processes.

Background: Patients with relapsed or refractory acute myeloid leukemia (R/R AML) and FLT3‐internal tandem duplication (FLT3‐ITD) respond infrequently to salvage chemotherapy. Objective: To investigate the efficacy of sorafenib plus triplet therapy with venetoclax, azacitidine, and homoharringtonine (VAH) as a salvage therapy in this population. Methods: This multicenter, single‐arm, phase 2 study was conducted at 12 hospitals across China. Eligible patients had R/R AML with FLT3‐ITD (aged 18–65 years) who were treated with VAH. The primary endpoint was composite complete remission (CRc) after two cycles. Secondary outcomes included the overall response rate (ORR), safety, and survival. Results: Between July 9, 2020, and March 19, 2022, 58 patients were assessed for eligibility, 51 of whom were enrolled. The median patient age was 47 years (interquartile range [IQR] 31–57). CRc was 76.5% with ORR of 82.4%. At a median follow‐up of 17.7 months (IQR, 8.7–24.7), the median duration of CRc was not reached (NR), overall survival was 18.1 months (95% confidence interval [CI], 11.8‐NR) and event‐free survival was 11.4 months (95% CI, 5.6‐NR). Grade 3 or 4 adverse events occurring in ≥10% of patients included neutropenia in 47 (92.2%), thrombocytopenia in 41 (80.4%), anemia in 35 (68.6%), febrile neutropenia in 29 (56.9%), pneumonia in 13 (25.5%), and sepsis in 6 (11.8%) patients. Treatment‐related death occurred in two (3.9%) patients. Conclusions: The sorafenib plus VAH regimen was well tolerated and highly active against R/R AML with FLT3‐ITD. This regimen may be a suitable therapeutic option for this population, but larger population trials are needed to be explored. Trial registration: Clinical Trials Registry: NCT04424147 [ABSTRACT FROM AUTHOR]

Circadian-paced biological processes are key to physiology and required for metabolic, immunologic, and cardiovascular homeostasis. Core circadian clock components are transcription factors whose half-life is precisely regulated, thereby controlling the intrinsic cellular circadian clock. Genetic disruption of molecular clock components generally leads to marked pathological events phenotypically affecting behavior and multiple aspects of physiology. Using a transcriptional signature similarity approach, we identified anti-cancer protein synthesis inhibitors as potent modulators of the cardiomyocyte molecular clock. Eukaryotic protein translation inhibitors, ranging from translation initiation (rocaglates, 4-EGI1, etc.) to ribosomal elongation inhibitors (homoharringtonine, puromycin, etc.), were found to potently ablate protein abundance of REV-ERBα, a repressive nuclear receptor and component of the molecular clock. These inhibitory effects were observed both in vitro and in vivo and could be extended to PER2, another component of the molecular clock. Taken together, our observations suggest that the activity spectrum of protein synthesis inhibitors, whose clinical use is contemplated not only in cancers but also in viral infections, must be extended to circadian rhythm disruption, with potential beneficial or iatrogenic effects upon acute or prolonged administration. [ABSTRACT FROM AUTHOR]

Objectives To explore the effects of homoharringtonine (HHT) on the proliferation and apoptosis of melanoma cells. [Methods] Mouse melanoma cell line B16F10 was divided into 5 different dose groups, among which 0 µg/mL. HHT was as the negative blank group, and the remaining four groups were added with different concentrations of HHT (20, 40, 80 and 160 µg/ml.). After B16F10 cells were treated with HHT for 48 h, the growth inhibition rate of B16F10 cells was observed, and the cell cycle was detected. Cyclin D1, MMP-9 and VEGF mRNA and protein levels were detected by qRT-PCR and Western-blot. [Results] Compared with 0 µg/ml, group, after different concentrations of HHT treated B16F10 cells, the inhibition rate and apoptosis rate of B16F10 cells increased, and Cyclin D1, MMP-9 and VEGF mRNA and protein levels in all groups decreased significantly, with statistical significance (P<0.05). [Conclusions] HHT may be involved in the apoptosis of melanoma cells by regulating Cyclin D1 level, affecting cell cycle, and inhibiting VEGF and MMP-9 gene protein levels. [ABSTRACT FROM AUTHOR]

Venetoclax (VEN)-based regimens are the standard of care for elderly or unfit patients with newly diagnosed (ND) acute myeloid leukemia (AML). Some single-arm studies have implied that hypomethylating agents (HMAs) plus priming regimens may potentially provide an alternative therapeutic approach, owing to encouraging efficacy seen. However, no comparative data exists yet regarding these two treatment approaches. In this retrospective multi-center cohort study, we enrolled 294 ND AML patients, allocating 167 to the HMA + priming group and 127 to the VEN-based group. Treatment response and overall survival (OS) were compared between groups. Molecular subgroup analyses were also conducted. With a median of two cycles for HMA + priming group, the overall response (ORR) was 65.3%, including 55.1% complete remission (CR), 9.6% CR with incomplete hematologic recovery (CRi) and 0.6% morphologic leukemia-free state (MLFS). With a median of two cycles for VEN-based group, the ORR was 70.9%, including 46.5% CR, 18.9% CRi, and 5.5% MLFS. Response differences (ORR or CR/CRi) between groups were not significant (p > 0.05). With a median follow-up of 10.1 months, median OSs were similar between groups (20.9 vs 16.3 months, p = 0.41). However, VEN regimens demonstrated superior CR/CRi for patients with mutations in FLT3, IDH1/2, and NPM1 compared to HMA + priming (80.0% vs 35.0%, p = 0.01; 90.9% vs 65.5%, p = 0.02; 90.9% and 65.5%, p = 0.02, respectively). In conclusion, HMAs plus modified priming regimens might be a potential alternative therapeutic approach for patients with ND AML, but VEN-based regimens presented predominance in specific molecular subgroups. Molecular characteristics contribute to guiding choice of treatment. [ABSTRACT FROM AUTHOR]

Abstract Adverse‐risk acute myeloid leukemia (AML) has a dismal prognosis. We aimed to investigate the activity and tolerability of venetoclax combined with homoharringtonine (HHT) plus cytarabine (VHA) regimen for de novo adverse‐risk AML. Thirteen de novo AML patients with adverse‐risk factors were treated with venetoclax (100 mg day 1, 200 mg day 2, 400 mg days 3‐21), HHT (1 mg/m2 days 1‐5) and cytarabine (100 mg/m2 days 1‐5) (VHA regimen). Complete remission (CR) was achieved in 11/13 patient (84.6%), all of CR responders were measurable residual disease (MRD) negative detected by multi‐parameter flow cytometry (MFC). Grade 3‐4 neutropenia, anaemia, and thrombocytopenia occurred in most patients. Grade 3‐4 non haematological adverse events (AEs) included febrile neutropenia (4/13, 30.8%). With a median follow‐up of 10 months (range 4‐19), median overall survival and event‐free survival were not reached. VHA may be a promising and well‐tolerated regimen in de novo adverse‐risk AML.

Bromodomain‐containing protein 4 (BRD4) inhibitors have been clinically developed to treat acute myeloid leukemia (AML), but their application is limited by the possibility of drug resistance, which is reportedly associated with the activation of the WNT/β‐catenin pathway. Meanwhile, homoharringtonine (HHT), a classic antileukemia drug, possibly inhibits the WNT/β‐catenin pathway. In this study, we attempted to combine a novel BRD4 inhibitor (ACC010) and HHT to explore their synergistic lethal effects in treating AML. Here, we found that co‐treatment with ACC010 and HHT synergistically inhibited cell proliferation, induced apoptosis, and arrested the cell cycle in FMS‐like tyrosine kinase 3‐internal tandem duplication (FLT3‐ITD)–positive AML cells in vitro, and significantly inhibiting AML progression in vivo. Mechanistically, ACC010 and HHT cooperatively downregulated MYC and inhibited FLT3 activation. Further, when HHT was added, ACC010‐resistant cells demonstrated a good synergy. We also extended our study to the mouse BaF3 cell line with FLT3‐inhibitor‐resistant FLT3‐ITD/tyrosine kinase domain mutations and AML cells without FLT3‐ITD. Collectively, our results suggested that the combination treatment of ACC010 and HHT might be a promising strategy for AML patients, especially those carrying FLT3‐ITD.

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. • HHT inhibits NPMc + nuclear export by targeting XPO1. • HHT inhibits XPO1 by occupying the NES-binding cleft. • NPMc + mutation sensitize AML cells to HHT treatment. [ABSTRACT FROM AUTHOR]

Objectives: Pancreatic cancer (PC) is a very lethal malignancy with a scarcity of treatment options. Although erlotinib- and gemcitabine-based treatments have been approved for PC, their effectiveness is limited. The present study is aimed at exploring the molecular and epigenetic mechanisms of anticancer activities of homoharringtonine (HHT) and its interaction with erlotinib to develop a potential therapeutic strategy for PC. Methods: The RT-qPCR, western blotting, immunofluorescence and expression-vectors and oligonucleotide transfection were employed to determine the expression characteristics of onco-factors. Anticancer activities were determined by MTT, colony forming, and flowcytometric analysis. Dual luciferase assay was conducted to confirm putative target of miR-130b-3p. In-vivo experiments were followed by immunohistochemical assay. Key findings: The EphB4/JAK2/STAT3 pathway drives the growth and proliferation of PC through induction of prosurvival factors and cell cycle mediators. HHT directly and epigenetically via miR-130b-3p targets EphB4, leading to downregulation of JAK2/STAT3 pathway. The inactivation of STAT3 results in diminution of antiapoptotic factors and cell cycle mediators. HHT also enhances the anticancer activity of erlotinib. Conclusions: HHT demonstrates potential anticancer activities in PC by downregulating EphB4/JAK2/STAT3 signalling. HHT also produces synergistic effects with erlotinib. [ABSTRACT FROM AUTHOR]

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/m²/day on days 1 and 4; homoharringtonine, 4 mg/m²/day for 5 days, and cytarabine, 1.5 g/m2/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% (P=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 >0.5x109/L and time to platelet count >20x109/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. [ABSTRACT FROM AUTHOR]

Abstract 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/m2 on days 1–7) and homoharringtonine (1 mg/m2 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.

Background: Colorectal cancer (CRC) is the most common primary malignancy. Recently, antineoplastic attributes of homoharringtonine (HHT) have attracted lots of attention. This study investigated the molecular target and underlying mechanism of HHT in the CRC process by using a cellular and animal models. Methods: This study first detected the effects of HHT on the proliferation, cell cycle and apoptosis ability of CRC cells using CCK-8, Edu staining, flow cytometry and Western blotting assay. In vitro recovery experiment and in vivo tumorigenesis experiment were used to detect the targeted interaction between HHT and NKD1. After that, the downstream target and mechanism of action of HHT targeting NKD1 was determined using quantitative proteomics combined with co-immunoprecipitation/immunofluorescence assay. Results: HHT suppressed CRC cells proliferation by inducing cell cycle arrest and apoptosis in vitro and vivo. HHT inhibited NKD1 expression in a concentration and time dependent manner. NKD1 was overexpressed in CRC and its depletion enhanced the therapeutic sensitivity of HHT on CRC, which indicating that NKD1 plays an important role in the development of CRC as the drug delivery target of HHT. Furthermore, proteomic analysis revealed that PCM1 participated the process of NKD1-regulated cell proliferation and cell cycle. NKD1 interacted with PCM1 and promoted PCM1 degradation through the ubiquitin-proteasome pathway. The overexpression of PCM1 effectively reversed the inhibition of siNKD1 on cell cycle. Conclusions: The present findings revealed that HHT blocked NKD1 expression to participate in inhibiting cell proliferation and inducing cell apoptosis, ultimately leading to obstruction of CRC development through NKD1/PCM1 dependent mechanism. Our research provide evidence for clinical application of NKD1-targeted therapy in improving HHT sensitivity for CRC treatment. [ABSTRACT FROM AUTHOR]

Bromodomain‐containing protein 4 (BRD4) inhibitors have been clinically developed to treat acute myeloid leukemia (AML), but their application is limited by the possibility of drug resistance, which is reportedly associated with the activation of the WNT/β‐catenin pathway. Meanwhile, homoharringtonine (HHT), a classic antileukemia drug, possibly inhibits the WNT/β‐catenin pathway. In this study, we attempted to combine a novel BRD4 inhibitor (ACC010) and HHT to explore their synergistic lethal effects in treating AML. Here, we found that co‐treatment with ACC010 and HHT synergistically inhibited cell proliferation, induced apoptosis, and arrested the cell cycle in FMS‐like tyrosine kinase 3‐internal tandem duplication (FLT3‐ITD)–positive AML cells in vitro, and significantly inhibiting AML progression in vivo. Mechanistically, ACC010 and HHT cooperatively downregulated MYC and inhibited FLT3 activation. Further, when HHT was added, ACC010‐resistant cells demonstrated a good synergy. We also extended our study to the mouse BaF3 cell line with FLT3‐inhibitor‐resistant FLT3‐ITD/tyrosine kinase domain mutations and AML cells without FLT3‐ITD. Collectively, our results suggested that the combination treatment of ACC010 and HHT might be a promising strategy for AML patients, especially those carrying FLT3‐ITD. [ABSTRACT FROM AUTHOR]

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/m2 on days 1–7) and homoharringtonine (1 mg/m2 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. [ABSTRACT FROM AUTHOR]

Abstract Background Despite advances in targeted agent development, effective treatment of acute myeloid leukemia (AML) remains a major clinical challenge. The B-cell lymphoma-2 (BCL-2) inhibitor exhibited promising clinical activity in AML, acute lymphoblastic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL) treatment. APG-2575 is a novel BCL-2 selective inhibitor, which has demonstrated anti-tumor activity in hematologic malignancies. Homoharringtonine (HHT), an alkaloid, exhibited anti-AML activity. Methods The synergistic effects of APG-2575 and HHT were studied in AML cell lines and primary samples. MTS was used to measure the cell viability. Annexin V/propidium iodide staining was used to measure the apoptosis rate by flow cytometry. AML cell xenografted mouse models were established to evaluate the anti-leukemic effect of BCL-2 inhibitor, HHT and their combination in vivo. Western blot was used to determine the expression of related proteins. Results APG-2575 showed comparable anti-leukemic effect to the FDA-approved BCL-2 inhibitor ABT-199 in vitro and in vivo. Combined treatment of HHT with APG-2575 synergistically inhibited AML cell growth and engraftment. Mechanistically, HHT promoted degradation of myeloid cell leukemia-1 (MCL-1), which was reported to induce BCL-2 inhibitor resistant, through the PI3K/AKT/GSK3β signaling pathway. Conclusion Our results provide an effective AML treatment strategy through combination of APG-2575 and HHT, which is worthy of further clinical research.