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Experimental Hematology Apr 2021Minimal residual disease (MRD) levels monitored by polymerase chain reaction are associated with outcomes in acute myeloid leukemia with RUNX1-RUNX1T1. The objectives of...
Minimal residual disease (MRD) levels monitored by polymerase chain reaction are associated with outcomes in acute myeloid leukemia with RUNX1-RUNX1T1. The objectives of our study were to quantitatively compare the predictive value of MRD reduction and absolute copies and assess the influence of other prognostic factors on MRD. A total of 224 consecutive patients with RUNX1-RUNX1T1 aged ≤55 years were included in the MRD study. Patients received different induction regimens including conventional- or intermediate-dose cytarabine plus low-dose daunorubicin and omacetaxine mepesuccinate or daunorubicin at 60 mg/m/day on days 1-3. As continuous variables, both MRD reduction and absolute MRD level were significantly associated with cumulative incidence of relapse (CIR; hazard ratio [HR] = 1.610, 95% confidence interval [CI]: 1.370-1.890, p < 0.001, and HR = 1.170, 95% CI: 1.120-1.230, p < 0.001, respectively). For the CIR, the area under the curves (AUCs) of MRD reduction and absolute MRD level after the first consolidation chemotherapy were 0.629 and 0.629, respectively. Intermediate-dose cytarabine induction (HR = 0.494; p = 0.039 for CIR, HR, 0.451; p = 0.014 for RFS, and HR, 0.262; p = 0.006 for OS) remained significantly associated with outcomes after adjusting for MRD reduction after the first consolidation therapy (HR = 1.456, p < 0.001, for CIR; HR = 1.467, p = 0.001, for relapse-free survival; and HR = 1.468, p = 0.014, for overall survival) in multivariate analyses. In conclusion, the prognostic significance of MRD after the first consolidation therapy was influenced by the induction regimen in acute myeloid leukemia with RUNX1-RUNX1T1.
Topics: Adolescent; Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Core Binding Factor Alpha 2 Subunit; Cytarabine; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Neoplasm, Residual; Oncogene Proteins, Fusion; Prognosis; RUNX1 Translocation Partner 1 Protein; Young Adult
PubMed: 33524443
DOI: 10.1016/j.exphem.2021.01.007 -
Blood Oct 2013
Topics: Antineoplastic Agents; Drug Resistance, Neoplasm; Fusion Proteins, bcr-abl; Gene Expression Regulation, Leukemic; HSP90 Heat-Shock Proteins; Harringtonines; Homoharringtonine; Humans; Imidazoles; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Primary Cell Culture; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-bcl-2; Pyridazines; Signal Transduction
PubMed: 24159169
DOI: 10.1182/blood-2013-04-494773 -
Leukemia & Lymphoma Dec 2009Imatinib is considered standard therapy for patients with chronic myelogenous leukemia (CML), inducing a high rate of hematologic and cytogenetic responses. Despite... (Review)
Review
Imatinib is considered standard therapy for patients with chronic myelogenous leukemia (CML), inducing a high rate of hematologic and cytogenetic responses. Despite these excellent results, several patients develop resistance to imatinib. Mechanisms of resistance are varied and include BCR-ABL1 kinase domain mutations, decreased entry of imatinib into cells, acquisition of secondary genetic changes and activation of alternate signaling pathways. Second-generation tyrosine kinase inhibitors (TKI) (dasatinib, nilotinib) were developed as an alternative for patients that develop resistance or are intolerant to imatinib. Dasatinib is a dual Abl/Src kinase TKI that is structurally unrelated to imatinib and is approved for therapy of all phases of CML in patients who are resistant or intolerant to imatinib. Nilotinib is a compound related to imatinib that has greater specificity and improved binding characteristics, and has clinical activity in the setting of imatinib failure. Resistance to multiple TKIs does occur, particularly in patients with the T315I mutation. Several new agents are in development including new TKIs, aurora kinase inhibitors and homoharringtonine.
Topics: Antineoplastic Combined Chemotherapy Protocols; Benzamides; Clinical Trials as Topic; Dasatinib; Drug Resistance, Neoplasm; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Models, Biological; Piperazines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrimidines; Thiazoles
PubMed: 20017607
DOI: 10.3109/10428190903383427 -
Leukemia Jun 2011Chronic myeloid leukaemia (CML) is maintained by a rare population of tyrosine kinase inhibitor (TKI)-insensitive malignant stem cells. Our long-term aim is to find a...
Chronic myeloid leukaemia (CML) is maintained by a rare population of tyrosine kinase inhibitor (TKI)-insensitive malignant stem cells. Our long-term aim is to find a BcrAbl-independent drug that can be combined with a TKI to improve overall disease response in chronic-phase CML. Omacetaxine mepesuccinate, a first in class cetaxine, has been evaluated by clinical trials in TKI-insensitive/resistant CML. Omacetaxine inhibits synthesis of anti-apoptotic proteins of the Bcl-2 family, including (myeloid cell leukaemia) Mcl-1, leading to cell death. Omacetaxine effectively induced apoptosis in primary CML stem cells (CD34(+)38(lo)) by downregulation of Mcl-1 protein. In contrast to our previous findings with TKIs, omacetaxine did not accumulate undivided cells in vitro. Furthermore, the functionality of surviving stem cells following omacetaxine exposure was significantly reduced in a dose-dependant manner, as determined by colony forming cell and the more stringent long-term culture initiating cell colony assays. This stem cell-directed activity was not limited to CML stem cells as both normal and non-CML CD34(+) cells were sensitive to inhibition. Thus, although omacetaxine is not leukaemia stem cell specific, its ability to induce apoptosis of leukaemic stem cells distinguishes it from TKIs and creates the potential for a curative strategy for persistent disease.
Topics: Angiogenesis Inhibitors; Antineoplastic Agents, Phytogenic; Apoptosis; Down-Regulation; Harringtonines; Homoharringtonine; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Myeloid Cell Leukemia Sequence 1 Protein; Neoplastic Stem Cells; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-bcl-2; Tumor Cells, Cultured
PubMed: 21468038
DOI: 10.1038/leu.2011.55 -
Mediators of Inflammation 2022Homoharringtonine (HHT) exhibits an anti-inflammatory activity. The potential protective effects and mechanisms of HHT on dextran sulfate sodium- (DSS-) induced colitis...
Homoharringtonine (HHT) exhibits an anti-inflammatory activity. The potential protective effects and mechanisms of HHT on dextran sulfate sodium- (DSS-) induced colitis were investigated. DSS-induced colitis mice were intraperitoneally injected with HHT. Body weight, colon length, disease activity index (DAI), and histopathological change were examined. The relative contents of interleukin- (IL-) 1, tumor necrosis factor- (TNF-) , IL-6, and the chemokine (C-C motif) ligand 2 (CCL2) in the colon tissues and HHT-treated RAW264.7 cells were detected with the enzyme-linked immunosorbent assay. In the meantime, the levels of p-p65 and p-IB were detected by Western blot. The proportion of macrophages (CD11bF4/80) in the colon tissues was detected by flow cytometry. HHT alleviated DSS-induced colitis with downregulated TNF-, IL-1, IL-6, and CCL2 expression; reduced activation of nuclear factor-kappa B (NF-B) signaling; and diminished proportion of recruited macrophages in colon tissues. It was further testified that HHT inhibited lipopolysaccharide-induced macrophage activation with reduced activation of NF-B signaling. In addition, HHT inhibited the M1 polarization of both human and mouse macrophages, while HHT did not affect the differentiation of human CD4 T cells into Th17, Th1, or Treg cells and did not affect the proliferation and migration of human colon epithelial cells. In summary, HHT attenuates DSS-induced colitis by inhibiting macrophage-associated NF-B activation and M1 polarization, which could be an option for the treatment of ulcerative colitis.
Topics: Animals; Anti-Inflammatory Agents; Chemokine CCL2; Colitis; Colitis, Ulcerative; Colon; Dextran Sulfate; Homoharringtonine; Humans; Interleukin-6; Lipopolysaccharides; Mice; Mice, Inbred C57BL; NF-KappaB Inhibitor alpha; NF-kappa B; Tumor Necrosis Factor-alpha
PubMed: 36211988
DOI: 10.1155/2022/3441357 -
Annals of Translational Medicine Apr 2022To evaluate whether homoharringtonine (HHT) combined with venetoclax could produce a synergistic anti-acute myeloid leukemia (AML) effect and determine the underlying...
BACKGROUND
To evaluate whether homoharringtonine (HHT) combined with venetoclax could produce a synergistic anti-acute myeloid leukemia (AML) effect and determine the underlying mechanisms.
METHODS
The effect of HHT and venetoclax combination on cell viability, apoptosis, and mitochondrial membrane potential was investigated using AML cell lines and primary cells. High-throughput mRNA sequencing was used to analyze mRNA level changes after the application of HHT and venetoclax on OCI-AML3 cells. Western blotting was used to verify the changes in protein expression within the mitogen-activated protein kinases/extracellular signal-regulated kinase (MAPK/ERK), phosphatidylinositiol 3-kinase (PI3K)/AKT and p53 pathway. The efficacy of HHT and venetoclax and their effects on survival time were evaluated in a xenograft model established in severe immunodeficiency (NOD/SCID) mice.
RESULTS
Venetoclax and HHT synergistically inhibited the proliferation of AML cells, decreased the mitochondrial membrane potential, and promoted AML cell apoptosis in a time- and concentration-dependent manner. Venetoclax combined with HHT increased the expression of the caspase-3, Poly (ADP-ribose) polymerase (PARP), and γH2AX proteins. HHT enhanced the proapoptotic effect of venetoclax by reducing the expression of myeloid cell leukemia sequence 1 (Mcl-1). HHT arrested AML cells in G1 phase of the cell cycle. HHT enhanced the proapoptotic effect of venetoclax by inhibiting the activation of the MAPK/ERK and PI3K/AKT pathways and activating the p53 pathway. experiments confirmed that the combination of HHT and venetoclax could inhibit the growth of tumors in AML xenotransplanted mice and prolong the survival time of tumor-bearing mice.
CONCLUSIONS
HHT combined with venetoclax synergistically promoted apoptosis in AML cell lines and primary cells by inhibiting the activation of the MAPK/ERK and PI3K/AKT pathways and activating the p53 pathway.
PubMed: 35571387
DOI: 10.21037/atm-22-1459 -
Journal of Oncology 2022The significance of vascular endothelial growth factor receptor (VEGFR)-2 in numerous solid tumors and acute myeloid leukemia (AML) has been demonstrated, but Apatinib...
PURPOSE
The significance of vascular endothelial growth factor receptor (VEGFR)-2 in numerous solid tumors and acute myeloid leukemia (AML) has been demonstrated, but Apatinib remains largely unexplored. In this study, whether Apatinib combined with homoharringtonine (HHT) kills AML cell lines and its possible mechanisms have been explored.
METHODS
AML cell lines were treated with Apatinib and HHT in different concentrations with control, Apatinib alone, HHT alone, and Apatinib combined with HHT. The changes of IC were measured by CCK8 assay, and apoptosis rate, cell cycle, and the mitochondrial membrane potential in each group were measured by flow cytometry. Finally, the possible cytotoxicity mechanism was analyzed by Western blotting.
RESULTS
Our results noted that Apatinib combined with HHT remarkably inhibited cell proliferation, reduced the capacity of colony-forming, and induced apoptosis and cell cycle arrest in AML cells. Mechanistically, Apatinib and HHT play a role as a suppressor in the expression of VEGFR-2 and the downstream signaling cascades, such as the PI3K, MAPK, and STAT3 pathways.
CONCLUSION
Our preclinical data demonstrate that Apatinib combined with HHT exerts a better antileukemia effect than Apatinib alone by inhibiting the VEGFR-2 signaling pathway, suggesting the potential role of Apatinib and HHT in the treatment of AML. This study provides clinicians with innovative combination therapies and new therapeutic targets for the treatment of AML.
PubMed: 36081666
DOI: 10.1155/2022/9005804 -
Drugs Nov 2015Through years of evolutionary selection pressures, organisms have developed potent toxins that coincidentally have marked antineoplastic activity. These natural products... (Review)
Review
Through years of evolutionary selection pressures, organisms have developed potent toxins that coincidentally have marked antineoplastic activity. These natural products have been vital for the development of multiagent treatment regimens currently employed in cancer chemotherapy, and are used in the treatment of a variety of malignancies. Therefore, this review catalogs recent advances in natural product-based drug discovery via the examination of mechanisms of action and available clinical data to highlight the utility of these novel compounds in the burgeoning age of precision medicine. The review also highlights the recent development of antibody-drug conjugates and other immunotoxins, which are capable of delivering highly cytotoxic agents previously deemed too toxic to elicit therapeutic benefit preferentially to neoplastic cells. Finally, the review examines natural products not currently used in the clinic that have novel mechanisms of action, and may serve to supplement current chemotherapeutic protocols.
Topics: Antineoplastic Agents; Biological Products; Cytochalasins; Dioxoles; Diphtheria Toxin; Drug Discovery; Epothilones; Furans; Harringtonines; Homoharringtonine; Humans; Immunoconjugates; Interleukin-2; Ketones; Recombinant Fusion Proteins; TOR Serine-Threonine Kinases; Tetrahydroisoquinolines; Trabectedin; Withanolides
PubMed: 26501980
DOI: 10.1007/s40265-015-0489-4 -
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 -
Biochemical Pharmacology Jan 2021The outbreak of a novel coronavirus (SARS-CoV-2) has caused a major public health concern across the globe. SARS-CoV-2 is the seventh coronavirus that is known to cause... (Review)
Review
The outbreak of a novel coronavirus (SARS-CoV-2) has caused a major public health concern across the globe. SARS-CoV-2 is the seventh coronavirus that is known to cause human disease. As of September 2020, SARS-CoV-2 has been reported in 213 countries and more than 31 million cases have been confirmed, with an estimated mortality rate of ∼3%. Unfortunately, a drug or vaccine is yet to be discovered to treat COVID-19. Thus, repurposing of existing cancer drugs will be a novel approach in treating COVID-19 patients. These drugs target viral replication cycle, viral entry and translocation to the nucleus. Some can enhance innate antiviral immune response as well. Hence this review focuses on comprehensive list of 22 drugs that work against COVID-19 infection. These drugs include fingolimod, colchicine, N4-hydroxycytidine, remdesivir, methylprednisone, oseltamivir, icatibant, perphanizine, viracept, emetine, homoharringtonine, aloxistatin, ribavirin, valrubicin, famotidine, almitrine, amprenavir, hesperidin, biorobin, cromolyn sodium, and antibodies- tocilzumab and sarilumab. Also, we provide a list of 31 drugs that are predicted to function against SARS-CoV-2 infection. In summary, we provide succinct overview of various therapeutic modalities. Among these 53 drugs, based on various clinical trials and literature, remdesivir, nelfinavir, methylpredinosolone, colchicine, famotidine and emetine may be used for COVID-19. SIGNIFICANCE: It is of utmost important priority to develop novel therapies for COVID-19. Since the effect of SARS-CoV-2 is so severe, slowing the spread of diseases will help the health care system, especially the number of visits to Intensive Care Unit (ICU) of any country. Several clinical trials are in works around the globe. Moreover, NCI developed a recent and robust response to COVID-19 pandemic. One of the NCI's goals is to screen cancer related drugs for identification of new therapies for COVID-19. https://www.cancer.gov/news-events/cancer-currents-blog/2020/covid-19-cancer-nci-response?cid=eb_govdel.
Topics: Adenosine Monophosphate; Alanine; Anti-Inflammatory Agents; Antioxidants; Antiviral Agents; Drug Repositioning; Humans; SARS-CoV-2; Treatment Outcome; Virus Internalization; COVID-19 Drug Treatment
PubMed: 33191206
DOI: 10.1016/j.bcp.2020.114296