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Biomedicine & Pharmacotherapy =... Jul 2024The plant alkaloid homoharringtonine (HHT) is a Food and Drug Administration (FDA)-approved drug for the treatment of hematologic malignancies. In addition to its...
(Homo-)harringtonine prevents endothelial inflammation through IRF-1 dependent downregulation of VCAM1 mRNA expression and inhibition of cell adhesion molecule protein biosynthesis.
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.
Topics: Animals; Down-Regulation; Vascular Cell Adhesion Molecule-1; Inflammation; RNA, Messenger; Humans; Interferon Regulatory Factor-1; Mice; Homoharringtonine; Male; Human Umbilical Vein Endothelial Cells; Anti-Inflammatory Agents; Intercellular Adhesion Molecule-1; Endothelial Cells; Mice, Inbred C57BL; Cell Adhesion Molecules; Leukocytes
PubMed: 38865849
DOI: 10.1016/j.biopha.2024.116907 -
American Journal of Cancer Research 2024Heat shock factor 1 (HSF1), an essential transcription factor for stress response, is exploited by various tumors to facilitate their initiation, progression, invasion,...
Heat shock factor 1 (HSF1), an essential transcription factor for stress response, is exploited by various tumors to facilitate their initiation, progression, invasion, and migration. Amplification of HSF1 is widely regarded as an indicator in predicting cancer severity, the likelihood of treatment failure and reduced patient survival. Notably, HSF1 is markedly amplified in 40% of pancreatic cancer (PC), which typically have limited treatment options. HSF1 has been proven to be a promising therapeutic target for multiple cancers. However, a direct small molecule HSF1 inhibitor with sufficient bioactivity and reliable safety has not been developed clinically. In this study, we successfully established a high-throughput screening system utilizing luciferase reporter assay specifically designed for HSF1, which leads to the discovery of a potent small molecule inhibitor targeting HSF1. Homoharringtonine (HHT) selectively inhibited PC cell viability with high HSF1 expression and induced a markedly stronger tumor regression effect in the subcutaneous xenograft model than the comparator drug KRIBB11, known for its direct action on HSF1. Moreover, HHT shows promise in countering the resistance encountered with HSP90 inhibitors, which have been observed to increase heat shock response intensity in clinical trials. Mechanistically, HHT directly bound to HSF1, suppressing its expression and thereby inhibiting transcription of HSF1 target genes. In conclusion, our work presents a preclinical discovery and validation for HHT as a HSF1 inhibitor for PC treatment.
PubMed: 38859866
DOI: 10.62347/XFJH3424 -
IScience Jun 2024Homoharringtonine (HHT), an alkaloid isolated from , is an effective anti-leukemia agent and exhibits inhibitory effects in various solid tumors. However, the impacts of...
Homoharringtonine (HHT), an alkaloid isolated from , is an effective anti-leukemia agent and exhibits inhibitory effects in various solid tumors. However, the impacts of HHT treatment on thyroid cancer (TC) remain unclear. Our findings demonstrated that HHT exhibited remarkable anti-TC activity that involved inhibiting cell proliferation, invasion, and migration, as well as inducing apoptosis. Proteomics analysis revealed that the expression of the tissue inhibitor of metalloproteinase 1 (TIMP1) was downregulated in TC cells after HHT treatment. TIMP1 overexpression promoted TC progression and partially reversed the anti-TC effects of HHT, while TIMP1 downregulation inhibited TC progression and enhanced the anti-TC effects of HHT. Furthermore, TIMP1 re-expression attenuated the enhancement of anti-TC effects of HHT induced by TIMP1 knockdown. Mechanistically, HHT exerted anti-TC effects by downregulating TIMP1 expression and then inactivating the FAK/PI3K/AKT signaling pathway. Taken together, our study demonstrated that HHT could inhibit TC progression by inhibiting the TIMP1/FAK/PI3K/AKT signaling pathway.
PubMed: 38770133
DOI: 10.1016/j.isci.2024.109829 -
Blood Science (Baltimore, Md.) Apr 2024An accurate prognostic model for acute myeloid leukemia (AML) can guide personalized treatment. In our prospective cohort of 591 patients newly diagnosed with AML, we...
An accurate prognostic model for acute myeloid leukemia (AML) can guide personalized treatment. In our prospective cohort of 591 patients newly diagnosed with AML, we evaluated the prognostic significance of serum albumin levels. We recognized baseline serum albumin as a prognostic factor by univariate Cox regression analysis (albumin-high vs albumin-low: overall survival [OS]: hazard ratio [HR]: 0.679, 95% confidence interval [CI]: 0.529-0.870, = .002; cumulative incidence of relapse [CIR]: HR: 0.705, 95% CI: 0.530-0.938, = .017) and multivariate Cox regression analysis (OS: HR per g/L: 0.966, 95% CI: 0.940-0.993, = .014; CIR: HR per g/L: 0.959, 95% CI: 0.927-0.993, = .017). In the subgroup analysis, serum albumin was prognostic significant in patients who received intermediate-dose cytarabine combined with daunorubicin and omacetaxine mepesuccinate induction (albumin-high vs albumin-low: OS: HR: 0.585, 95% CI: 0.397-0.863, = .007; CIR: HR: 0.551, 95% CI: 0.353-0.861, = .009) rather than those receiving conventional-dose induction regimens. In addition, the impact of baseline serum albumin level was evident in patients with intermediate European LeukemiaNet risk (albumin-high vs albumin-low: OS: HR: 0.617, 95% CI: 0.424-0.896, = .011; CIR: HR: 0.617, 95% CI: 0.388-0.979, = .040). Gene set enrichment analysis revealed that leukemia stem cell signatures were enriched in patients with low serum albumin levels. Our study suggested that baseline serum albumin level was associated with the inherent properties of AML and correlated with patient outcomes.
PubMed: 38742239
DOI: 10.1097/BS9.0000000000000189 -
European Journal of Medical Research May 2024HHT has emerged as a notable compound in the realm of cancer treatment, particularly for hematological malignancies. Its multifaceted pharmacological properties extend... (Review)
Review
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.
Topics: Humans; Hematologic Neoplasms; Homoharringtonine; Neoplasms; Animals
PubMed: 38704602
DOI: 10.1186/s40001-024-01856-x -
BMC Cancer Apr 2024Acute myeloid leukaemia (AML) is a fatal haematopoietic malignancy and is treated with the conventional combination of cytarabine (Ara-C) and daunorubicin (Dau). The...
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.
Topics: Humans; Homoharringtonine; Cytarabine; Myeloid Cell Leukemia Sequence 1 Protein; Leukemia, Myeloid, Acute; Apoptosis; p38 Mitogen-Activated Protein Kinases; Animals; Mice; Xenograft Model Antitumor Assays; Histones; Cell Line, Tumor; Drug Synergism; Antineoplastic Combined Chemotherapy Protocols; Phosphorylation; Female
PubMed: 38658865
DOI: 10.1186/s12885-024-12286-7 -
Cancer Research May 2024Patients with triple-negative breast cancer (TNBC) have a poor prognosis due to the lack of effective molecular targets for therapeutic intervention. Here we found that...
UNLABELLED
Patients with triple-negative breast cancer (TNBC) have a poor prognosis due to the lack of effective molecular targets for therapeutic intervention. Here we found that the long noncoding RNA (lncRNA) MILIP supports TNBC cell survival, proliferation, and tumorigenicity by complexing with transfer RNAs (tRNA) to promote protein production, thus representing a potential therapeutic target in TNBC. MILIP was expressed at high levels in TNBC cells that commonly harbor loss-of-function mutations of the tumor suppressor p53, and MILIP silencing suppressed TNBC cell viability and xenograft growth, indicating that MILIP functions distinctively in TNBC beyond its established role in repressing p53 in other types of cancers. Mechanistic investigations revealed that MILIP interacted with eukaryotic translation elongation factor 1 alpha 1 (eEF1α1) and formed an RNA-RNA duplex with the type II tRNAs tRNALeu and tRNASer through their variable loops, which facilitated the binding of eEF1α1 to these tRNAs. Disrupting the interaction between MILIP and eEF1α1 or tRNAs diminished protein synthesis and cell viability. Targeting MILIP inhibited TNBC growth and cooperated with the clinically available protein synthesis inhibitor omacetaxine mepesuccinate in vivo. Collectively, these results identify MILIP as an RNA translation elongation factor that promotes protein production in TNBC cells and reveal the therapeutic potential of targeting MILIP, alone and in combination with other types of protein synthesis inhibitors, for TNBC treatment.
SIGNIFICANCE
LncRNA MILIP plays a key role in supporting protein production in TNBC by forming complexes with tRNAs and eEF1α1, which confers sensitivity to combined MILIP targeting and protein synthesis inhibitors.
Topics: Triple Negative Breast Neoplasms; Humans; Female; RNA, Transfer; Animals; Mice; Peptide Elongation Factor 1; RNA, Long Noncoding; Cell Proliferation; Protein Biosynthesis; Cell Line, Tumor; Xenograft Model Antitumor Assays; Mice, Nude; Gene Expression Regulation, Neoplastic
PubMed: 38593213
DOI: 10.1158/0008-5472.CAN-23-3046 -
Science Advances Apr 2024Histopathological heterogeneity is a hallmark of prostate cancer (PCa). Using spatial and parallel single-nucleus transcriptomics, we report an androgen receptor...
Histopathological heterogeneity is a hallmark of prostate cancer (PCa). Using spatial and parallel single-nucleus transcriptomics, we report an androgen receptor (AR)-positive but neuroendocrine-null primary PCa subtype with morphologic and molecular characteristics of small cell carcinoma. Such small cell-like PCa (SCLPC) is clinically aggressive with low AR, but high stemness and proliferation, activity. Molecular characterization prioritizes protein translation, represented by up-regulation of many ribosomal protein genes, and SP1, a transcriptional factor that drives SCLPC phenotype and overexpresses in castration-resistant PCa (CRPC), as two potential therapeutic targets in AR-indifferent CRPC. An SP1-specific inhibitor, plicamycin, effectively suppresses CRPC growth in vivo. Homoharringtonine, a Food And Drug Administration-approved translation elongation inhibitor, impedes CRPC progression in preclinical models and patients with CRPC. We construct an SCLPC-specific signature capable of stratifying patients for drug selectivity. Our studies reveal the existence of SCLPC in admixed PCa pathology, which may mediate tumor relapse, and establish SP1 and translation elongation as actionable therapeutic targets for CRPC.
Topics: Male; Humans; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Neoplasm Recurrence, Local; Transcription Factors; Protein Biosynthesis; Cell Line, Tumor; Gene Expression Regulation, Neoplastic
PubMed: 38569039
DOI: 10.1126/sciadv.adm7098 -
Zhonghua Xue Ye Xue Za Zhi = Zhonghua... Dec 2023This study aimed to explore the synergistic effect and underlying mechanism of azacitidine (AZA) in combination with homoharringtonine (HHT) in acute myeloid leukemia...
This study aimed to explore the synergistic effect and underlying mechanism of azacitidine (AZA) in combination with homoharringtonine (HHT) in acute myeloid leukemia (AML) . The synergistic effects of AZA and HHT were examined by cell proliferation, apoptosis, and colony formation assays. The synergistic effects were calculated using the combination index (CI) , and the underlying mechanisms were explored using RNA sequencing, pathway inhibitors, and gene knockdown approaches. Compared with the single-drug controls, AZA and HHT combination significantly induced cell proliferation arrest and showed a synergistic effect with CI < 0.9 in AML cells. In the combination group versus the single-drug controls, colony formation was significantly decreased, whereas apoptosis was significantly increased in U937 (<0.001) and MV4-11 (<0.001) cells. AZA and HHT combination activated the integrated stress response (ISR) signaling pathway and induced DDIT3-PUMA-dependent apoptosis in cells. Furthermore, it remarkably downregulated the expression of c-MYC. The combination also activated c-MYC/DDIT3/PUMA-mediated ISR signaling to induce synergy on apoptosis. The synergy of AZA+HHT on apoptosis was induced by activating c-MYC/DDIT3/PUMA-mediated ISR signaling. The combination of AZA and HHT exerts synergistic anti-AML effects by inhibiting cellular proliferation and promoting apoptosis through activation of the ISR signaling pathway via the c-MYC/DDIT3/PUMA axis.
Topics: Humans; Homoharringtonine; Azacitidine; Apoptosis Regulatory Proteins; Apoptosis; Leukemia, Myeloid, Acute; Cell Line, Tumor; Transcription Factor CHOP
PubMed: 38503523
DOI: 10.3760/cma.j.issn.0253-2727.2023.12.006 -
Translational Pediatrics Feb 2024
PubMed: 38455741
DOI: 10.21037/tp-23-536