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Journal of Hematology & Oncology Jan 2014Homoharringtonine (HHT), a plant alkaloid with antitumor properties originally identified nearly 40 years ago, has a unique mechanism of action by preventing the initial... (Review)
Review
Homoharringtonine (HHT), a plant alkaloid with antitumor properties originally identified nearly 40 years ago, has a unique mechanism of action by preventing the initial elongation step of protein synthesis. HHT has been used widely in China for the treatment of chronic myeloid leukemia (CML), acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Omacetaxine, a semisynthetic form of HHT, with excellent bioavailability by the subcutaneous route, has recently been approved by FDA of the United States for the treatment of CML refractory to tyrosine kinase inhibitors. This review summarized preclinical and clinical development of HHT and omacetaxine for myeloid hematological malignancies.
Topics: Acute Disease; Antineoplastic Agents, Phytogenic; Harringtonines; Homoharringtonine; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid; Myelodysplastic Syndromes; Treatment Outcome
PubMed: 24387717
DOI: 10.1186/1756-8722-7-2 -
OncoTargets and Therapy 2014In a significant proportion of patients with chronic myeloid leukemia, resistance to BCR-ABL tyrosine kinase inhibitors develops due to acquisition of BCR-ABL kinase... (Review)
Review
In a significant proportion of patients with chronic myeloid leukemia, resistance to BCR-ABL tyrosine kinase inhibitors develops due to acquisition of BCR-ABL kinase domain mutations and insensitivity of leukemia stem cells to tyrosine kinase inhibitors. Omacetaxine mepesuccinate (formerly called homoharringtonine) is a natural alkaloid that inhibits protein synthesis and induces cell death. Omacetaxine mepesuccinate has been recently approved by the US Food and Drug Administration to treat patients with chronic myeloid leukemia who failed to respond to multiple tyrosine kinase inhibitors and/or acquired the BCR-ABL-T315I mutation. In this review, we discuss the use and effectiveness of omacetaxine mepesuccinate in the treatment of chronic myeloid leukemia, with coverage of its pharmacology, mode of action, and pharmacokinetics. We believe that omacetaxine mepesuccinate will be beneficial to many patients with chronic myeloid leukemia who do not respond well to tyrosine kinase inhibitors.
PubMed: 24516334
DOI: 10.2147/OTT.S41786 -
Investigational New Drugs Oct 2016Background Omacetaxine mepesuccinate is indicated in adults with chronic myeloid leukemia resistant and/or intolerant to ≥ 2 tyrosine kinase inhibitor treatments....
Background Omacetaxine mepesuccinate is indicated in adults with chronic myeloid leukemia resistant and/or intolerant to ≥ 2 tyrosine kinase inhibitor treatments. This phase I study assessed the disposition, elimination, and safety of (14)C-omacetaxine in patients with solid tumors. Methods The study comprised a 7-days pharmacokinetic assessment followed by a treatment period of ≤ six 28-days cycles. A single subcutaneous dose of 1.25 mg/m(2) (14)C-omacetaxine was administered to six patients. Blood, urine, and feces were collected through 168 h or until radioactivity excreted within 24 h was <1 % of the dose. Total radioactivity (TRA) was measured in all matrices and concentrations of omacetaxine, 4'-desmethylhomoharringtonine (4'-DMHHT), and cephalotaxine were measured in plasma and urine. For each treatment cycle, patients received 1.25 mg/m(2) omacetaxine twice daily for 7 days. Results Mean TRA recovered was approximately 81 % of the dose, with approximately half of the radioactivity recovered in feces and half in urine. Approximately 20 % of the dose was excreted unchanged in urine; cephalotaxine (0.4 % of dose) and 4' DMHHT (9 %) were also present. Plasma concentrations of TRA were higher than the sum of omacetaxine and known metabolites, suggesting the presence of other (14)C-omacetaxine-derived compounds. Fatigue and anemia were common, consistent with the known toxicity profile of omacetaxine. Conclusion Renal and hepatic processes contribute to the elimination of (14)C-omacetaxine-derived radioactivity in cancer patients. In addition to omacetaxine and its known metabolites, other (14)C-omacetaxine-derived materials appear to be present in plasma and urine. Omacetaxine was adequately tolerated, with no new safety signals.
Topics: Adult; Aged; Antineoplastic Agents, Phytogenic; Carbon Radioisotopes; Feces; Female; Harringtonines; Homoharringtonine; Humans; Male; Middle Aged; Neoplasms
PubMed: 27221729
DOI: 10.1007/s10637-016-0360-9 -
Molecular Medicine Reports Apr 2016Clinical studies have demonstrated that omacetaxine mepesuccinate exerts beneficial effects on acute myelogenous leukemia. It has been suggested that omacetaxine...
Omacetaxine mepesuccinate induces apoptosis and cell cycle arrest, promotes cell differentiation, and reduces telomerase activity in diffuse large B‑cell lymphoma cells.
Clinical studies have demonstrated that omacetaxine mepesuccinate exerts beneficial effects on acute myelogenous leukemia. It has been suggested that omacetaxine mepesuccinate, used alone or with interferon‑α or cytarabine, induces remission in patients with chronic myelogenous leukemia. These effects are possibly mediated by its ability to induce apoptosis of leukemia cells and inhibit the activity of telomerase. To determine whether omacetaxine mepesuccinate is beneficial in diffuse large B‑cell lymphoma (DLBCL), two DLBCL cell lines [a germinal center B cell‑like subtype (GCB) and an activated B cell‑like subtype (ABC)] were treated with omacetaxine mepesuccinate at various concentrations for different durations. The present study indicated that omacetaxine mepesuccinate exerts proapoptotic effects in the two cell types in a dose‑ and time‑dependent manner. The ABC subtype demonstrated increased sensitivity compared with the GCB subtype. At 40 ng/ml, omacetaxine mepesuccinate exhibited a marked proapoptotic effect on DLBCL cells compared with the other tumor cells investigated. Furthermore, omacetaxine mepesuccinate induced cell cycle arrest at G0/G1 phase, and promoted cell terminal differentiation of pro‑B cells. The present study also demonstrated that omacetaxine mepesuccinate exerted its antitumor effect by reducing telomerase activity. In conclusion, the present study demonstrated that omacetaxine mepesuccinate may induce apoptosis and cell cycle arrest, promote cell differentiation, and reduce telomerase activity in DLBCL cells, thus aiding the development of omacetaxine mepesuccinate‑based DLBCL therapeutic strategies.
Topics: Antigens, Surface; Antineoplastic Agents, Phytogenic; Apoptosis; Cell Cycle Checkpoints; Cell Differentiation; Cell Line, Tumor; Harringtonines; Homoharringtonine; Humans; Immunophenotyping; Lymphoma, Large B-Cell, Diffuse; Telomerase
PubMed: 26935769
DOI: 10.3892/mmr.2016.4899 -
Clinical Cancer Research : An Official... Feb 2021The prognosis of patients with multiple myeloma who are resistant to proteasome inhibitors, immunomodulatory drugs (IMiD), and daratumumab is extremely poor. Even B-cell... (Observational Study)
Observational Study
PURPOSE
The prognosis of patients with multiple myeloma who are resistant to proteasome inhibitors, immunomodulatory drugs (IMiD), and daratumumab is extremely poor. Even B-cell maturation antigen-specific chimeric antigen receptor T-cell therapies provide only a temporary benefit before patients succumb to their disease. In this article, we interrogate the unique sensitivity of multiple myeloma cells to the alternative strategy of blocking protein translation with omacetaxine.
EXPERIMENTAL DESIGN
We determined protein translation levels ( = 17) and sensitivity to omacetaxine ( = 51) of primary multiple myeloma patient samples. Synergy was evaluated between omacetaxine and IMiDs , and . Underlying mechanism was investigated via proteomic analysis.
RESULTS
Almost universally, primary patient multiple myeloma cells exhibit >2.5-fold increased rates of protein translation compared with normal marrow cells. treatment with omacetaxine resulted in >50% reduction in viable multiple myeloma cells. In this cohort, high levels of translation serve as a biomarker for patient multiple myeloma cell sensitivity to omacetaxine. Unexpectedly, omacetaxine demonstrated synergy with IMiDs in multiple myeloma cell lines . In addition, in an IMiD-resistant relapsed patient sample, omacetaxine/IMiD combination treatment resensitized the multiple myeloma cells to the IMiD. Proteomic analysis found that the omacetaxine/IMiD combination treatment produced a double-hit on the IRF4/c-MYC pathway, which is critical to multiple myeloma survival.
CONCLUSIONS
Overall, protein translation inhibitors represent a potential new drug class for myeloma treatment and provide a rationale for conducting clinical trials with omacetaxine alone and in combination with IMiDs for patients with relapsed/refractory multiple myeloma.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Homoharringtonine; Humans; Immunomodulating Agents; Interferon Regulatory Factors; Mice; Multiple Myeloma; Primary Cell Culture; Protein Biosynthesis; Protein Synthesis Inhibitors; Proto-Oncogene Proteins c-myc; Signal Transduction; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
PubMed: 33109736
DOI: 10.1158/1078-0432.CCR-20-2246 -
Cancer Dec 2009Homoharringtonine (HHT) is a natural alkaloid that is obtained from various Cephalotaxus species. The mechanism of action by which HHT exerts its antitumor activity is... (Review)
Review
Homoharringtonine (HHT) is a natural alkaloid that is obtained from various Cephalotaxus species. The mechanism of action by which HHT exerts its antitumor activity is through inhibition of protein synthesis and promotion of apoptosis. In the 1990s, HHT proved to be significantly active as salvage therapy for patients with chronic myeloid leukemia (CML) after failure on interferon-alpha therapy. However, the remarkable success of imatinib mesylate in the treatment of CML relegated HHT to oblivion. The development of omacetaxine mepesuccinate, a subcutaneously bioavailable semisynthetic form of HHT, and its activity in imatinib-resistant CML has established this agent for the second time as a valuable option in the management of this disease. Preliminary results appear to support the use of this agent for patients who have imatinib-resistant CML, including those who carry the tyrosine kinase inhibitor-insensitive mutation that exchanges the amino acids threonine and isoleucine at position 315 (the T315I mutation). In this article, the authors discuss the current data on omacetaxine and the prospects of this agent to be integrated into the state-of-the-art treatment algorithms for CML.
Topics: Algorithms; Antineoplastic Agents, Phytogenic; Benzamides; Clinical Trials as Topic; Drug Discovery; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Harringtonines; Homoharringtonine; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Piperazines; Pyrimidines
PubMed: 19739234
DOI: 10.1002/cncr.24601 -
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 -
JCI Insight Jun 2021Hepatocellular carcinoma (HCC) is the sixth most common and the fourth most deadly cancer worldwide. The development cost of new therapeutics is a major limitation in...
Hepatocellular carcinoma (HCC) is the sixth most common and the fourth most deadly cancer worldwide. The development cost of new therapeutics is a major limitation in patient outcomes. Importantly, there is a paucity of preclinical HCC models in which to test new small molecules. Herein, we implemented potentially novel patient-derived organoid (PDO) and patient-derived xenografts (PDX) strategies for high-throughput drug screening. Omacetaxine, an FDA-approved drug for chronic myelogenous leukemia (CML), was found to be a top effective small molecule in HCC PDOs. Next, omacetaxine was tested against a larger cohort of 40 human HCC PDOs. Serial dilution experiments demonstrated that omacetaxine is effective at low (nanomolar) concentrations. Mechanistic studies established that omacetaxine inhibits global protein synthesis, with a disproportionate effect on short-half-life proteins. High-throughput expression screening identified molecular targets for omacetaxine, including key oncogenes, such as PLK1. In conclusion, by using an innovative strategy, we report - for the first time to our knowledge - the effectiveness of omacetaxine in HCC. In addition, we elucidate key mechanisms of omacetaxine action. Finally, we provide a proof-of-principle basis for future studies applying drug screening PDOs sequenced with candidate validation in PDX models. Clinical trials could be considered to evaluate omacetaxine in patients with HCC.
Topics: Adult; Aged; Animals; Antineoplastic Agents, Phytogenic; Carcinoma, Hepatocellular; Cell Proliferation; Cells, Cultured; Female; Homoharringtonine; Humans; Liver; Liver Neoplasms; Male; Mice; Middle Aged; Organoids; Protein Synthesis Inhibitors; Young Adult
PubMed: 34003798
DOI: 10.1172/jci.insight.138197 -
Cancer Chemotherapy and Pharmacology Jan 2013Omacetaxine mepesuccinate is a first-in-class cephalotaxine demonstrating clinical activity in chronic myeloid leukemia. A subcutaneous (SC) formulation demonstrated... (Clinical Trial)
Clinical Trial
PURPOSE
Omacetaxine mepesuccinate is a first-in-class cephalotaxine demonstrating clinical activity in chronic myeloid leukemia. A subcutaneous (SC) formulation demonstrated efficacy and safety in phase 1/2 trials in patients previously treated with ≥1 tyrosine kinase inhibitor. This study assessed pharmacokinetics and safety of SC omacetaxine in patients with advanced cancers.
METHODS
Omacetaxine 1.25 mg/m(2) SC was administered BID, days 1-14 every 28 days for 2 cycles, until disease progression or unacceptable toxicity. Blood and urine were collected to measure omacetaxine concentrations and inactive metabolites. Adverse events, including QT interval prolongation, were recorded. Tumor response was assessed at cycle 2 completion.
RESULTS
Pharmacokinetic parameters were estimated from cycle 1, day 1 data in 21 patients with solid tumors or hematologic malignancies and cycle 1, day 11 data in 10 patients. Omacetaxine was rapidly absorbed, with mean peak plasma concentrations observed within 1 h, and widely distributed, as evidenced by an apparent volume of distribution of 126.8 L/m(2). Plasma concentration versus time data demonstrated biexponential decay; mean steady-state terminal half-life was 7 h. Concentrations of inactive metabolites 4'-DMHHT and cephalotaxine were approximately 10 % of omacetaxine and undetectable in most patients, respectively. Urinary excretion of unchanged omacetaxine accounted for <15 % of the dose. Grade 3/4 drug-related adverse events included thrombocytopenia (48 %) and neutropenia (33 %). Two grade 2 increases in QTc interval (>470 ms) were observed and were not correlated with omacetaxine plasma concentration. No objective responses were observed.
CONCLUSIONS
Omacetaxine is well absorbed after SC administration. Therapeutic plasma concentrations were achieved with 1.25 mg/m(2) BID, supporting clinical development of this dose and schedule.
Topics: Adult; Aged; Antineoplastic Agents, Phytogenic; Female; Half-Life; Harringtonines; Hematologic Neoplasms; Homoharringtonine; Humans; Injections, Subcutaneous; Long QT Syndrome; Male; Middle Aged; Neoplasms; Neutropenia; Thrombocytopenia; Tissue Distribution
PubMed: 23053254
DOI: 10.1007/s00280-012-1963-2 -
Leukemia & Lymphoma 2016Omacetaxine mepesuccinate (Synribo) is an inhibitor of protein synthesis indicated for the treatment of patients with chronic- or accelerated-phase chronic myeloid...
Omacetaxine mepesuccinate (Synribo) is an inhibitor of protein synthesis indicated for the treatment of patients with chronic- or accelerated-phase chronic myeloid leukemia (CML) with resistance and/or intolerance to two or more tyrosine kinase inhibitors. Myelosuppression is the most common and clinically significant toxicity experienced by patients treated with omacetaxine. Here, we further examine the patterns of hematologic toxicity observed in clinical trials and describe the approach to management as well as resolution of events. Omacetaxine-related myelosuppression typically occurs more frequently during induction cycles. In general, the myelosuppression observed with omacetaxine treatment is manageable and reversible, and long-term administration is feasible. Careful monitoring, dose delays and reduction in administration days, and appropriate supportive care are critical for successful management of hematologic toxicity. Concerns regarding myelosuppression, observed with many cancer treatments, should not prevent eligible patients from receiving omacetaxine, particularly CML patients with unsatisfactory responses to multiple lines of prior treatment.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Blood Transfusion; Disease Management; Female; Harringtonines; Homoharringtonine; Humans; Incidence; Leukemia, Myeloid, Accelerated Phase; Leukemia, Myeloid, Chronic-Phase; Leukocyte Count; Male; Middle Aged; Pancytopenia; Treatment Outcome; Young Adult
PubMed: 26436949
DOI: 10.3109/10428194.2015.1071486