-
International Journal of Molecular... Nov 2018This paper describes the substances of plant and marine origin that have anticancer properties. The chemical structure of the molecules of these substances, their... (Review)
Review
This paper describes the substances of plant and marine origin that have anticancer properties. The chemical structure of the molecules of these substances, their properties, mechanisms of action, their structure⁻activity relationships, along with their anticancer properties and their potential as chemotherapeutic drugs are discussed in this paper. This paper presents natural substances from plants, animals, and their aquatic environments. These substances include the vinca alkaloids, mistletoe plant extracts, podophyllotoxin derivatives, taxanes, camptothecin, combretastatin, and others including geniposide, colchicine, artesunate, homoharringtonine, salvicine, ellipticine, roscovitine, maytanasin, tapsigargin, and bruceantin. Compounds (psammaplin, didemnin, dolastin, ecteinascidin, and halichondrin) isolated from the marine plants and animals such as microalgae, cyanobacteria, heterotrophic bacteria, invertebrates (e.g., sponges, tunicates, and soft corals) as well as certain other substances that have been tested on cells and experimental animals and used in human chemotherapy.
Topics: Animals; Antineoplastic Agents; Aquatic Organisms; Biological Products; Humans; Plants
PubMed: 30423952
DOI: 10.3390/ijms19113533 -
Leukemia Aug 2009Omacetaxine mepesuccinate (formerly homoharringtonine) is a molecule with a mechanism of action that is different from tyrosine kinase inhibitors, and its activity in...
Omacetaxine mepesuccinate (formerly homoharringtonine) is a molecule with a mechanism of action that is different from tyrosine kinase inhibitors, and its activity in chronic myeloid leukemia (CML) seems to be independent of the BCR-ABL mutation status. Using BCR-ABL-expressing myelogenous and lymphoid cell lines and mouse models of CML and B-cell acute lymphoblastic leukemia (B-ALL) induced by wild-type BCR-ABL or T315I mutant-BCR-ABL, we evaluated the inhibitory effects of omacetaxine on CML and B-ALL. We showed that more than 90% of the leukemic stem cells were killed after treatment with omacetaxine in vitro. In contrast, less than 9 or 25% of the leukemic stem cells were killed after treating with imatinib or dasatinib, respectively. After 4 days of treatment of CML mice with omacetaxine, Gr-1(+)myeloid leukemia cells decreased in the peripheral blood of the treated CML mice. In the omacetaxine-treated B-ALL mice, only 0.8% of the B220(+)leukemia cells were found in peripheral blood, compared with 34% of the B220(+)leukemia cells in the placebo group. Treatment with omacetaxine decreased the number of leukemia stem cells and prolonged the survival of mice with BCR-ABL-induced CML or B-ALL.
Topics: Animals; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Fusion Proteins, bcr-abl; Gene Expression Regulation, Leukemic; HSP90 Heat-Shock Proteins; Harringtonines; Homoharringtonine; Humans; K562 Cells; Leukemia, B-Cell; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Neoplastic Stem Cells; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Radiation Chimera; Recombinant Fusion Proteins; Transduction, Genetic
PubMed: 19322212
DOI: 10.1038/leu.2009.52 -
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 -
American Journal of Hematology May 2013Omacetaxine mepesuccinate (omacetaxine) is a first-in-class cephalotaxine with a unique mode of action, independent of BCR-ABL, that has shown promising activity in...
Omacetaxine mepesuccinate (omacetaxine) is a first-in-class cephalotaxine with a unique mode of action, independent of BCR-ABL, that has shown promising activity in patients with chronic myeloid leukemia (CML). This multicenter, noncomparative, open-label phase 2 study evaluated the efficacy and safety of subcutaneous omacetaxine in CML patients with resistance or intolerance to two or more tyrosine kinase inhibitors (TKIs); results in patients in chronic phase are reported here. Patients received subcutaneous omacetaxine 1.25 mg/m² twice daily days 1-14 every 28 days until hematologic response (up to a maximum of six cycles), then days 1-7 every 28 days as maintenance. Primary endpoints were rates of hematologic response lasting >8 weeks and major cytogenetic response (MCyR). Forty-six patients were enrolled: all had received imatinib, 83% had received dasatinib, and 57% nilotinib. A median 4.5 cycles of omacetaxine were administered (range, 1-36). Hematologic response was achieved or maintained in 31 patients (67%); median response duration was 7.0 months. Ten patients (22%) achieved MCyR, including 2 (4%) complete cytogenetic responses. Median progression-free survival was 7.0 months [95% confidence interval (CI), 5.9-8.9 months], and overall survival was 30.1 months (95% CI, 20.3 months-not reached). Grade 3/4 hematologic toxicity included thrombocytopenia (54%), neutropenia (48%), and anemia (33%). Nonhematologic adverse events were predominantly grade 1/2 and included diarrhea (44%), nausea (30%), fatigue (24%), pyrexia (20%), headache (20%), and asthenia (20%). Subcutaneous omacetaxine may offer clinical benefit to patients with chronic-phase CML with resistance or intolerance to multiple TKI therapies.
Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Bone Marrow Cells; Drug Monitoring; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; Harringtonines; Hematopoiesis; Homoharringtonine; Humans; Induction Chemotherapy; Injections, Subcutaneous; Leukemia, Myeloid, Chronic-Phase; Maintenance Chemotherapy; Male; Middle Aged; Protein Kinase Inhibitors; Protein Synthesis Inhibitors; Protein-Tyrosine Kinases; Survival Analysis; Young Adult
PubMed: 23468307
DOI: 10.1002/ajh.23408 -
Phytotherapy Research : PTR Jul 2022Coronavirus disease 2019 (COVID-19) is caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which has a high mortality rate and transmissibility. In... (Review)
Review
Coronavirus disease 2019 (COVID-19) is caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which has a high mortality rate and transmissibility. In this context, medicinal plants have attracted attention due to the wide availability and variety of therapeutic compounds, such as alkaloids, a vast class with several proven pharmacological effects, like the antiviral and anti-inflammatory activities. Therefore, this scoping review aimed to summarize the current knowledge of the potential applicability of alkaloids for treating COVID-19. A systematic search was performed on PubMed and Scopus, from database inception to August 2021. Among the 63 eligible studies, 65.07% were in silico model, 20.63% in vitro and 14.28% clinical trials and observational studies. According to the in silico assessments, the alkaloids 10-hydroxyusambarensine, cryptospirolepine, crambescidin 826, deoxynortryptoquivaline, ergotamine, michellamine B, nigellidine, norboldine and quinadoline B showed higher binding energy with more than two target proteins. The remaining studies showed potential use of berberine, cephaeline, emetine, homoharringtonine, lycorine, narciclasine, quinine, papaverine and colchicine. The possible ability of alkaloids to inhibit protein targets and to reduce inflammatory markers show the potential for development of new treatment strategies against COVID-19. However, more high quality analyses/reviews in this field are necessary to firmly establish the effectiveness/safety of the alkaloids here described.
Topics: Alkaloids; Antiviral Agents; Humans; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 35355337
DOI: 10.1002/ptr.7442 -
Blood Cancer Journal Dec 2015
Prediction of response and survival in patients with chronic-phase chronic myeloid leukemia treated with omacetaxine mepesuccinate: logistic regression and landmark analyses.
Topics: Antineoplastic Agents, Phytogenic; Drug Resistance, Neoplasm; Harringtonines; Homoharringtonine; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Regression Analysis; Survival Analysis
PubMed: 26657200
DOI: 10.1038/bcj.2015.104 -
Clinical Lymphoma, Myeloma & Leukemia Oct 2021To evaluate the efficacy and safety of homoharringtonine (HHT) in acute myeloid leukemia (AML). (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
To evaluate the efficacy and safety of homoharringtonine (HHT) in acute myeloid leukemia (AML).
METHODS
PubMed, Cochrane Library, Embase, China National Knowledge of Infrastructure, and Wanfang data were systematically searched until October 31, 2020, for AML treatment with and without HHT. Fixed- and random-effect models were used to pool main outcomes, and between-study heterogeneity was assessed.
RESULTS
A total of 37 articles (2846 patients) fitting our criterion were included. The pooled overall response rate for the patients treated with HHT was 82% (CI, 77.9%-85.6%; I = 73.5%), and the complete response rate was 63.4% (CI, 58.8%-68%; I = 67.3%). Our study showed that patients treated with HHT have more overall response and complete response benefits and less cardiotoxicity and relapse rate. Subgroup analysis showed that patients with AML treated with HHT have significant overall response benefits in patients younger than 60 (odds ratio [OR], 1.63; CI, 1.33-2; I = 1.7%; P < .001), the newly diagnosed (OR, 1.59; CI, 1.15-2.21; I = 34.7%; P = .006), and relapsed/refractory patients (OR, 2.13; CI, 1.38-3.29; I = 32.3%; P = .001). Better complete remission benefits were observed in patients younger than 60 (OR, 1.32; CI, 1.1-1.59; I = 7%; P = .004), the newly diagnosed (OR, 1.32; CI, 1.08-1.62; I = 33.5%; P = .006), and relapsed/refractory patients (OR, 1.81; CI, 1.19-2.77; P = .006). For elderly patients, HHT treatment reduced relapse risk by 76.6% (OR, 0.23; CI, 0.09-0.63; I = 0%; P = .004).
CONCLUSIONS
HHT can be a reliable choice with less cardiotoxicity for patients with AML, especially for the newly diagnosed or patients younger than 60. For elderly intolerant patients, the use of HHT can reduce relapse.
Topics: Antineoplastic Agents, Phytogenic; Homoharringtonine; Humans; Leukemia, Myeloid, Acute
PubMed: 34301487
DOI: 10.1016/j.clml.2021.06.002 -
Pharmacological Research Feb 2023The application of immune checkpoint inhibitors and FGFR protein tyrosine kinase inhibitors have made a tremendous breakthrough in bladder cancer therapy. However,...
The application of immune checkpoint inhibitors and FGFR protein tyrosine kinase inhibitors have made a tremendous breakthrough in bladder cancer therapy. However, inadequate drug responses and drug resistance interfere with successful treatment outcomes. For a new drug to enter the market, there is a long development cycle with high costs and low success rates. Repurposing previously Food and Drug Administration (FDA)-approved medications and using novel drug discovery strategies may be an optimal approach. Homoharringtonine (HHT) has been used for hematologic malignancies for over 40 years in China and was approved by the FDA approximately 10 years ago. Many studies have demonstrated that HHT effectively inhibits the development of several types of solid tumors, although the underlying mechanisms of action are unclear. In this study, we investigated the mechanisms underlying HHT activity against bladder cancer growth. We first compared HTT with the drugs currently used clinically for bladder cancer treatment. HHT showed stronger inhibitory activity than cisplatin, carboplatin, and doxorubicin. Our in vitro and in vivo data demonstrated that HHT inhibited proliferation, colony formation, migration, and cell adhesion of bladder cancer cells and induced apoptosis and cell cycle arrest in the nanomolar concentration range. Furthermore, we revealed that HHT treatment could downregulate the MAPK/Erk and PI3k/Akt signaling pathways by inactivating the integrin α5/β1-FAK/Src axis. HHT-induced activity reduced cell-ECM interactions and cell migration, thus suppressing tumor metastasis progression. Altogether, HHT shows enormous potential as an anticancer agent and may be applied as a combination treatment strategy for bladder cancer.
Topics: Humans; Homoharringtonine; Integrin alpha5; Pharmaceutical Preparations; Phosphatidylinositol 3-Kinases; Integrin alpha5beta1; Cell Line, Tumor; Apoptosis; Urinary Bladder Neoplasms
PubMed: 36640858
DOI: 10.1016/j.phrs.2023.106654 -
Blood Cancer Journal Feb 2024Germline, mono-allelic mutations in RUNX1 cause familial platelet disorder (RUNX1-FPD) that evolves into myeloid malignancy (FPD-MM): MDS or AML. FPD-MM commonly harbors...
Germline, mono-allelic mutations in RUNX1 cause familial platelet disorder (RUNX1-FPD) that evolves into myeloid malignancy (FPD-MM): MDS or AML. FPD-MM commonly harbors co-mutations in the second RUNX1 allele and/or other epigenetic regulators. Here we utilized patient-derived (PD) FPD-MM cells and established the first FPD-MM AML cell line (GMR-AML1). GMR-AML1 cells exhibited active super-enhancers of MYB, MYC, BCL2 and CDK6, augmented expressions of c-Myc, c-Myb, EVI1 and PLK1 and surface markers of AML stem cells. In longitudinally studied bone marrow cells from a patient at FPD-MM vs RUNX1-FPD state, we confirmed increased chromatin accessibility and mRNA expressions of MYB, MECOM and BCL2 in FPD-MM cells. GMR-AML1 and PD FPD-MM cells were sensitive to homoharringtonine (HHT or omacetaxine) or mebendazole-induced lethality, associated with repression of c-Myc, EVI1, PLK1, CDK6 and MCL1. Co-treatment with MB and the PLK1 inhibitor volasertib exerted synergistic in vitro lethality in GMR-AML1 cells. In luciferase-expressing GMR-AML1 xenograft model, MB, omacetaxine or volasertib monotherapy, or co-treatment with MB and volasertib, significantly reduced AML burden and improved survival in the immune-depleted mice. These findings highlight the molecular features of FPD-MM progression and demonstrate HHT, MB and/or volasertib as effective agents against cellular models of FPD-MM.
Topics: Humans; Animals; Mice; Core Binding Factor Alpha 2 Subunit; Leukemia, Myeloid, Acute; Homoharringtonine; Blood Platelets; Blood Platelet Disorders; Proto-Oncogene Proteins c-bcl-2
PubMed: 38316746
DOI: 10.1038/s41408-024-00981-4 -
Internal Medicine (Tokyo, Japan) Apr 2002Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disorder molecularly defined by the BCR-ABL gene and its products. The protein encoded by this chimeric... (Review)
Review
Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disorder molecularly defined by the BCR-ABL gene and its products. The protein encoded by this chimeric gene is a constitutively activated tyrosine kinase that alters multiple signal transduction pathways inducing malignant transformation. Until recently, treatment options for patients with CML consisted of hydroxyurea, interferon-based therapies or allogeneic stem cell transplantation (alloSCT). Treatment decisions were generally based on the age of the patient and the phase of the disease. Recently, several new therapies have been developed that may change the natural history of CML and patient prognosis. In particular imatinib mesylate (ST1571, Gleevec) an oral Bcr-Abl kinase inhibitor, has demonstrated activity in all phases of CML, and may replace interferon and alloSCT as the initial therapy for this disease. Other agents and therapies with potential value, either alone or in combination, include polyethyleneglycol (PEG) interferon, homoharringtonine, decitabine, oral cytarabine, and growth factor modulation. In this article, we discuss the biological and clinical characteristics of CML, as well as the different therapeutic alternatives for patients with this disorder.
Topics: Antineoplastic Agents; Clinical Trials as Topic; Hematopoietic Stem Cell Transplantation; Humans; Immunotherapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive
PubMed: 11993784
DOI: 10.2169/internalmedicine.41.254