RESUMEN
OBJECTIVE: TQB3602 is a novel orally bioavailable proteasome inhibitor. This study is the first-in-human phase I clinical trial to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of TQB3602 in relapsed/refractory multiple myeloma (RRMM). METHODS: This is a multicenter phase I clinical trial consisting of the 3+3 dose-escalation phase and dose expansion phase. Patients with MM who have received ≥2 prior antimyeloma therapies were enrolled. TQB3602 is administered at a dose of 0.5~7mg on days 1, 8, 15 in 28-day cycle. RESULTS: Twenty-five RRMM patients who relapsed or failed ≥2 lines of therapies were enrolled in the dose escalation phase. Two patients in the 7.0 mg dose group developed dose-limiting toxicity events (one with grade 2 peripheral neuropathy [PN] complicated by pain and one with diarrhea and abdominal pain), leading to a maximum tolerated dose of 6.0 mg. Any-grade adverse events (AEs) occurred in 24 (96.0%) patients, while grade ≥3 AEs occurred in 13 (52.0%). The most common grade ≥3 AEs was anemia (6, 24.0%). The incidence rate of PN was 16% with no grade ≥3 PN occurred. TQB3602 was rapidly absorbed, resulting in a time-to-plasma peak concentration of 0.8-1.5 h. The mean half-life was approximately 82 h. The AUClast and Cmax were approximately 1.9 times higher on day 15 than on day 1. Among 22 response-evaluable patients, 63.7% achieved stable disease or better. CONCLUSIONS: TQB3602 is well tolerated, with a favorable neurotoxicity profile, and has shown preliminary efficacy in patients with RRMM. The anticipated therapeutic dose was 6 mg and was adopted for an ongoing dose-expansion phase.
Asunto(s)
Mieloma Múltiple , Inhibidores de Proteasoma , Humanos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/patología , Masculino , Persona de Mediana Edad , Femenino , Anciano , Inhibidores de Proteasoma/uso terapéutico , Inhibidores de Proteasoma/farmacocinética , Inhibidores de Proteasoma/efectos adversos , Inhibidores de Proteasoma/administración & dosificación , Administración Oral , Dosis Máxima Tolerada , Resultado del Tratamiento , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adulto , Relación Dosis-Respuesta a Droga , Resistencia a AntineoplásicosRESUMEN
OBJECTIVE: To evaluate the effectiveness, safety, and convenience of in-class transition (iCT) from intravenous bortezomib-based induction to ixazomib-based oral regimens. METHODS: This retrospective real-world study was conducted in 16 Chinese hospitals between October 2017 and April 2023 and analyzed newly diagnosed (NDMM) and first-line relapsed multiple myeloma (FRMM) patients who attained at least a partial response from bortezomib-based induction therapy, followed by an ixazomib-based oral regimen for 2 year or until disease progression or intolerable toxicity. RESULTS: The study enrolled 199 patients, median age: 63 years old, male 55.4%, 53% as high risk (HR), and 47% as standard risk. Cytogenetic risk stratification by metaphase fluorescence in situ hybridization (M-FISH), based on the Mayo Clinic risk stratification system. The median duration of total PI therapy was 11 months, with ixazomib-based treatment spanning 6 months. At the 20-month median follow-up, 53% of patients remained on therapy. The 24-month PFS rate was 84.3% from the initiation of bortezomib-based induction and 83.4% from the start of ixazomib-based treatment. Overall response rate (ORR) was 100% post-bortezomib induction and 90% following 6 cycles of the ixazomib-based regimen. Based on the Sankey diagrams, 89.51% of patients maintained or improved their disease response after 2 cycles of iCT, 6 cycles (90.14%), and 12 cycles (80%). The HR level of Mayo was found to be a significant independent factor in a worse remission (hazard ratio (HR) 2.55; p = 0.033). Ixazomib's safety profile aligned with previous clinical trial data, with 49% of patients experiencing at least one AE of any grade. The most common AEs included peripheral neuropathy, nausea and vomiting, diarrhea, thrombocytopenia, and granulocytopenia. CONCLUSION: In the real-world Chinese MM population, NDMM and FRMM patients responded favorably to PI-based continuous therapy, demonstrating substantial response rates. The ixazomib-based iCT allows for sustained PI-based treatment, offering promising efficacy and tolerable AEs.
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Compuestos de Boro , Bortezomib , Glicina , Glicina/análogos & derivados , Mieloma Múltiple , Inhibidores de Proteasoma , Humanos , Compuestos de Boro/administración & dosificación , Compuestos de Boro/uso terapéutico , Compuestos de Boro/efectos adversos , Masculino , Glicina/administración & dosificación , Glicina/uso terapéutico , Glicina/efectos adversos , Mieloma Múltiple/tratamiento farmacológico , Persona de Mediana Edad , Femenino , Anciano , Estudios Retrospectivos , Inhibidores de Proteasoma/uso terapéutico , Inhibidores de Proteasoma/administración & dosificación , Inhibidores de Proteasoma/efectos adversos , Bortezomib/administración & dosificación , Bortezomib/uso terapéutico , Bortezomib/efectos adversos , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Administración Oral , China , Anciano de 80 o más AñosRESUMEN
OBJECTIVES: To characterize the impact of prior exposure and refractoriness to lenalidomide or proteasome inhibitors (PIs) on the effectiveness and safety of ixazomib-lenalidomide-dexamethasone (IRd) in relapsed/refractory multiple myeloma (RRMM). METHODS: INSURE is a pooled analysis of adult RRMM patients who had received IRd in ≥2 line of therapy from three studies: INSIGHT MM, UVEA-IXA, and REMIX. RESULTS: Overall, 391/100/68 were lenalidomide-naïve/-exposed/-refractory and 37/411/110 were PI-naïve/-exposed/-refractory. Median duration of therapy (DOT) was 15.3/15.6/4.7 months and median progression-free survival (PFS) was 21.6/25.8/5.6 months in lenalidomide-naïve/exposed/refractory patients. Median DOT and PFS in PI-naïve/exposed/refractory patients were 20.4/15.2/6.9 months and not reached/19.8/11.4 months, respectively. The proportion of lenalidomide-naïve/exposed/refractory patients in INSIGHT and UVEA-IXA who discontinued a study drug due to adverse events (AEs) was ixazomib, 31.6/28.2/28.0% and 18.6/6.7/10.5%; lenalidomide, 21.9/28.2/16.0% and 16.1/6.7/10.5%; dexamethasone, 18.4/20.5/16.0% and 10.6/0/10.5%, respectively. The proportion of PI-naïve/exposed/refractory patients in INSIGHT and UVEA-IXA who discontinued a study drug due to AEs was: ixazomib, 44.4/28.8/27.8% and 22.2/16.7/15.7%; lenalidomide, 33.3/22.0/19.4% and 16.7/15.9/11.8%; dexamethasone, 33.3/17.4/16.7% and 16.7/9.5/7.8%, respectively. REMIX AE discontinuation rates were unavailable. CONCLUSION: IRd appeared to be effective in RRMM patients in routine clinical practice regardless of prior lenalidomide or PI exposure, with better outcomes seen in lenalidomide- and/or PI-nonrefractory versus refractory patients.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Compuestos de Boro , Dexametasona , Resistencia a Antineoplásicos , Glicina , Lenalidomida , Mieloma Múltiple , Inhibidores de Proteasoma , Humanos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/mortalidad , Mieloma Múltiple/diagnóstico , Compuestos de Boro/administración & dosificación , Compuestos de Boro/efectos adversos , Compuestos de Boro/uso terapéutico , Glicina/análogos & derivados , Glicina/administración & dosificación , Glicina/efectos adversos , Glicina/uso terapéutico , Lenalidomida/administración & dosificación , Lenalidomida/efectos adversos , Lenalidomida/uso terapéutico , Dexametasona/administración & dosificación , Dexametasona/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Masculino , Inhibidores de Proteasoma/administración & dosificación , Inhibidores de Proteasoma/uso terapéutico , Inhibidores de Proteasoma/efectos adversos , Anciano , Femenino , Persona de Mediana Edad , Resultado del Tratamiento , Adulto , Anciano de 80 o más Años , Recurrencia , RetratamientoRESUMEN
Nitazoxanide and related thiazolides are a novel class of anti-infectious agents against protozoan parasites, bacteria and viruses. In recent years, it is demonstrated that thiazolides can also induce cell cycle arrest and apoptotic cell death in cancer cells. Due to their fast proliferating nature, cancer cells highly depend on the proteasome system to remove aberrant proteins. Many of these aberrant proteins are regulators of cell cycle progression and apoptosis, such as the cyclins, BCL2 family members and nuclear factor of κB (NF-κB). Here, we demonstrate at both molecular and cellular levels that the 20S proteasome is a direct target of NTZ and related thiazolides. By concurrently inhibiting the multiple catalytic subunits of 20S proteasome, NTZ promotes cell cycle arrest and triggers cell death in colon cancer cells, either directly or as a sensitizer to other anti-tumor agents, especially doxorubicin. We further show that the binding mode of NTZ in the ß5 subunit of the 20S proteasome is different from that of bortezomib and other existing proteasome inhibitors. These findings provide new insights in the design of novel small molecular proteasome inhibitors as anti-tumor agents suitable for solid tumor treatment in an oral dosing form.
Asunto(s)
Antineoplásicos/metabolismo , Muerte Celular/efectos de los fármacos , Sistemas de Liberación de Medicamentos/métodos , Nitrocompuestos/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Inhibidores de Proteasoma/metabolismo , Tiazoles/metabolismo , Animales , Antineoplásicos/administración & dosificación , Células CACO-2 , Muerte Celular/fisiología , Relación Dosis-Respuesta a Droga , Células HCT116 , Células HEK293 , Células HeLa , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Nitrocompuestos/administración & dosificación , Complejo de la Endopetidasa Proteasomal/química , Inhibidores de Proteasoma/administración & dosificación , Unión Proteica/efectos de los fármacos , Unión Proteica/fisiología , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , Tiazoles/administración & dosificaciónRESUMEN
Multiple myeloma (MM) patients typically receive several lines of combination therapy and first-line treatment commonly includes lenalidomide. As patients age, they become less tolerant to treatment, requiring convenient/tolerable/lenalidomide-free options. Carfilzomib and/or bortezomib-exposed/intolerant, lenalidomide-refractory MM patients with ≥2 prior lines of therapy were randomized 3:2 to ixazomib-dexamethasone (ixa-dex) (n = 73) or pomalidomide-dexamethasone (pom-dex) (n = 49) until progression/toxicity. Median progression-free survival (mPFS) was 7.1 vs 4.8 months with ixa-dex vs pom-dex (HR 0.847, 95% CI 0.535-1.341, P = 0.477; median follow-up: 15.3 vs 17.3 months); there was no statistically significant difference between arms. In patients with 2 and ≥3 prior lines of therapy, respectively, mPFS was 11.0 vs 5.7 months (HR 1.083, 95% CI 0.547-2.144) and 5.7 vs 3.7 months (HR 0.686, 95% CI 0.368-1.279). Among ixa-dex vs pom-dex patients, 69% vs 81% had Grade ≥3 treatment-emergent adverse events (TEAEs), 51% vs 53% had serious TEAEs, 39% vs 36% had TEAEs leading to drug discontinuation, 44% vs 32% had TEAEs leading to dose reduction, and 13% vs 13% died on study. Quality of life was similar between arms and maintained during treatment. Ixa-dex represents an important lenalidomide-free, oral option for this heavily pretreated, lenalidomide-refractory, proteasome inhibitor-exposed population.Trial registration: ClinicalTrials.gov number, NCT03170882.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Compuestos de Boro/uso terapéutico , Dexametasona/uso terapéutico , Glicina/análogos & derivados , Lenalidomida/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Inhibidores de Proteasoma/uso terapéutico , Talidomida/análogos & derivados , Administración Oral , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Compuestos de Boro/administración & dosificación , Compuestos de Boro/efectos adversos , Dexametasona/administración & dosificación , Dexametasona/efectos adversos , Supervivencia sin Enfermedad , Femenino , Glicina/administración & dosificación , Glicina/efectos adversos , Glicina/uso terapéutico , Humanos , Lenalidomida/administración & dosificación , Lenalidomida/efectos adversos , Masculino , Persona de Mediana Edad , Supervivencia sin Progresión , Inhibidores de Proteasoma/administración & dosificación , Inhibidores de Proteasoma/efectos adversos , Talidomida/administración & dosificación , Talidomida/efectos adversos , Talidomida/uso terapéuticoRESUMEN
PURPOSE: Proteasome inhibitors are effective in Waldenström's macroglobulinemia (WM) but require parenteral administration and are associated with polyneuropathy. We investigated efficacy and toxicity of the less neurotoxic oral proteasome inhibitor ixazomib combined with rituximab, in patients with relapsed WM. METHODS: We conducted a multicenter phase I/II trial with ixazomib, rituximab, and dexamethasone (IRD). Induction consisted of eight cycles IRD wherein rituximab was started in cycle 3, followed by rituximab maintenance. Phase I showed feasibility of 4 mg ixazomib. Primary end point for phase II was overall response rate (ORR [≥ minimal response]) after induction. RESULTS: A total of 59 patients were enrolled (median age, 69 years; range, 46-91 years). Median number of prior treatments was 2 (range, 1-7); 70% had an intermediate or high WM-IPSS (International Prognostic Scoring System for WM) score. After eight cycles, ORR was 71% (42 out of 59) (14% very good partial response [PR], 37% PR, and 20% minor response). Depth of response improved until month 12 (best ORR 85% [50 out of 59]: 15% very good PR, 46% PR, and 24% minor response). Median duration of response was 36 months. The average hematocrit level increased significantly (0.33-0.38 L/L) after induction (P < .001). After two cycles of ixazomib and dexamethasone, immunoglobulin M levels decreased significantly (median 3,700-2,700 mg/dL, P < .0001). Median time to first response was 4 months. Median progression-free survival and overall survival were not reached. After median follow-up of 24 months (range, 7.4-54.3 months), progression-free survival and overall survival were 56% and 88%, respectively. Toxicity included mostly grade 2 or 3 cytopenias, grade 1 or 2 neurotoxicity, and grade 2 or 3 infections. No infusion-related reactions or immunoglobulin M flare occurred with use of subcutaneous rituximab. Quality of life improved significantly after induction. In total, 48 patients (81%) completed at least six cycles of IRD. CONCLUSION: Combination of IRD shows promising efficacy with manageable toxicity in patients with relapsed or refractory WM.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Compuestos de Boro/administración & dosificación , Dexametasona/administración & dosificación , Glicina/análogos & derivados , Inhibidores de Proteasoma/administración & dosificación , Rituximab/administración & dosificación , Macroglobulinemia de Waldenström/tratamiento farmacológico , Administración Oral , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Compuestos de Boro/efectos adversos , Dexametasona/efectos adversos , Europa (Continente) , Estudios de Factibilidad , Femenino , Glicina/administración & dosificación , Glicina/efectos adversos , Humanos , Infusiones Subcutáneas , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Inhibidores de Proteasoma/efectos adversos , Rituximab/efectos adversos , Factores de Tiempo , Resultado del Tratamiento , Macroglobulinemia de Waldenström/diagnósticoRESUMEN
The Plasmodium falciparum proteasome is a potential antimalarial drug target. We have identified a series of amino-amide boronates that are potent and specific inhibitors of the P. falciparum 20S proteasome (Pf20S) ß5 active site and that exhibit fast-acting antimalarial activity. They selectively inhibit the growth of P. falciparum compared with a human cell line and exhibit high potency against field isolates of P. falciparum and Plasmodium vivax They have a low propensity for development of resistance and possess liver stage and transmission-blocking activity. Exemplar compounds, MPI-5 and MPI-13, show potent activity against P. falciparum infections in a SCID mouse model with an oral dosing regimen that is well tolerated. We show that MPI-5 binds more strongly to Pf20S than to human constitutive 20S (Hs20Sc). Comparison of the cryo-electron microscopy (EM) structures of Pf20S and Hs20Sc in complex with MPI-5 and Pf20S in complex with the clinically used anti-cancer agent, bortezomib, reveal differences in binding modes that help to explain the selectivity. Together, this work provides insights into the 20S proteasome in P. falciparum, underpinning the design of potent and selective antimalarial proteasome inhibitors.
Asunto(s)
Compuestos de Boro/farmacología , Malaria Falciparum/tratamiento farmacológico , Plasmodium falciparum/efectos de los fármacos , Complejo de la Endopetidasa Proteasomal/química , Inhibidores de Proteasoma/farmacología , Administración Oral , Animales , Compuestos de Boro/administración & dosificación , Compuestos de Boro/química , Dominio Catalítico , Humanos , Malaria Falciparum/enzimología , Malaria Falciparum/parasitología , Ratones , Ratones Endogámicos NOD , Ratones SCID , Modelos Moleculares , Plasmodium falciparum/enzimología , Inhibidores de Proteasoma/administración & dosificación , Inhibidores de Proteasoma/químicaRESUMEN
Preclinical studies have demonstrated activity of the oral proteasome inhibitor (PI) ixazomib (IXA) in bortezomib-resistant multiple myeloma (MM) and synergy with immunomodulatory drugs. We therefore conducted a phase I/II study to establish the safety and preliminary efficacy of IXA with pomalidomide (POM) and dexamethasone (DEX) in lenalidomide (LEN)/PI-refractory MM. Dose escalation established a 4 mg dose of POM and IXA and 20/40 mg dose of DEX as the maximum tolerated dose. The phase II portion of the trial was redesigned and started anew after six patients had been randomized to IXA-POM-DEX due to a rapidly changing treatment landscape. Among the 29 evaluable LEN/PI-refractory patients treated with IXA-POM-DEX in phase I/II, the overall response rate (partial response or better) was 51.7% with a median duration of response of 16.8 months (range 56 days to 4.1 years), median progression-free survival of 4.4 months (95% confidence interval [CI]: 3.0-18.4), and median overall survival of 34.3 months (95% CI: 19.2 to not reached). Hematologic, gastrointestinal, and constitutional adverse events were common and consistent with the side-effect profiles of the individual agents. Our results support further evaluation of this all-oral regimen in relapsed/refractory MM.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Compuestos de Boro/uso terapéutico , Dexametasona/uso terapéutico , Glicina/análogos & derivados , Lenalidomida/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Inhibidores de Proteasoma/uso terapéutico , Talidomida/análogos & derivados , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Compuestos de Boro/administración & dosificación , Compuestos de Boro/efectos adversos , Dexametasona/administración & dosificación , Dexametasona/efectos adversos , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Glicina/administración & dosificación , Glicina/efectos adversos , Glicina/uso terapéutico , Humanos , Lenalidomida/administración & dosificación , Lenalidomida/efectos adversos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Inhibidores de Proteasoma/administración & dosificación , Inhibidores de Proteasoma/efectos adversos , Talidomida/administración & dosificación , Talidomida/efectos adversos , Talidomida/uso terapéuticoRESUMEN
M3258 is the first selective inhibitor of the immunoproteasome subunit LMP7 (Large multifunctional protease 7) in early clinical development with the potential to improve therapeutic utility in patients of multiple myeloma (MM) or other hematological malignancies. Safety pharmacology studies with M3258 did not reveal any functional impairments of the cardiovascular system in several in vitro tests employing human cardiomyocytes and cardiac ion channels (including hERG), guinea pig heart refractory period and force contraction, and rat aortic contraction as well as in cardiovascular function tests in dogs. Following single dose M3258 administration to rats, no changes were observed on respiratory function by using whole body plethysmography, nor did it change (neuro)behavioral parameters in a battery of tests. Based on pivotal 4-week toxicity studies with daily oral dosing of M3258, the identified key target organs of toxicity were limited to the lympho-hematopoietic system in rats and dogs, and to the intestine with its local lymphoid tissues in dogs only. Importantly, the stomach, nervous system, heart, lungs, and kidneys, that may be part of clinically relevant toxicities as reported for pan-proteasome inhibitors, were spared with M3258. Therefore, it is anticipated that by targeting highly selective and potent inhibition of LMP7, the resulting favorable safety profile of M3258 together with the maintained potent anti-tumor activity as previously reported in mouse MM xenograft models, may translate into an improved benefit-risk profile in MM patients.
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Ácidos Borónicos/toxicidad , Furanos/toxicidad , Complejo de la Endopetidasa Proteasomal/metabolismo , Inhibidores de Proteasoma/toxicidad , Administración Oral , Animales , Ácidos Borónicos/administración & dosificación , Células Cultivadas , Perros , Femenino , Furanos/administración & dosificación , Cobayas , Sistema Hematopoyético/efectos de los fármacos , Sistema Hematopoyético/patología , Humanos , Intestinos/efectos de los fármacos , Intestinos/patología , Sistema Linfático/efectos de los fármacos , Sistema Linfático/patología , Masculino , Inhibidores de Proteasoma/administración & dosificación , Ratas Wistar , Medición de Riesgo , Especificidad de la Especie , Pruebas de ToxicidadRESUMEN
The proteasome inhibitor bortezomib (BTZ) is a first-line antitumor drug, mainly used for multiple myeloma treatment. However, BTZ shows prominent toxicity in the peripheral nervous system, termed BTZ-induced peripheral neuropathy (BIPN). BIPN is characterized by neuropathic pain, resulting in a dose reduction or even treatment withdrawal. To date, the pathological mechanism of BIPN has not been elucidated. There is still no effective strategy to prevent or treat BIPN. This review summarizes the pathological mechanisms of BIPN, which involves the pathological changes of Schwann cells, neurons, astrocytes and macrophages. A better knowledge of the pathological mechanisms of BIPN would provide new ideas for therapeutic interventions of BIPN patients.
Asunto(s)
Antineoplásicos/efectos adversos , Bortezomib/efectos adversos , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Animales , Antineoplásicos/administración & dosificación , Bortezomib/administración & dosificación , Humanos , Mieloma Múltiple/tratamiento farmacológico , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Inhibidores de Proteasoma/administración & dosificación , Inhibidores de Proteasoma/efectos adversosRESUMEN
Proteasome inhibitors bortezomib and carfilzomib are approved for the treatment of multiple myeloma and mantle cell lymphoma and have demonstrated clinical efficacy for the treatment of acute lymphoblastic leukemia (ALL). The t(4;11)(q21;q23) chromosomal translocation that leads to the expression of MLL-AF4 fusion protein and confers a poor prognosis, is the major cause of infant ALL. This translocation sensitizes tumor cells to proteasome inhibitors, but toxicities of bortezomib and carfilzomib may limit their use in pediatric patients. Many of these toxicities are caused by on-target inhibition of proteasomes in non-lymphoid tissues (e.g., heart muscle, gut, testicles). We found that MLL-AF4 cells express high levels of lymphoid tissue-specific immunoproteasomes and are sensitive to pharmacologically relevant concentrations of specific immunoproteasome inhibitor ONX-0914, even in the presence of stromal cells. Inhibition of multiple active sites of the immunoproteasomes was required to achieve cytotoxicity against ALL. ONX-0914, an inhibitor of LMP7 (ß5i) and LMP2 (ß1i) sites of the immunoproteasome, and LU-102, inhibitor of proteasome ß2 sites, exhibited synergistic cytotoxicity. Treatment with ONX-0914 significantly delayed the growth of orthotopic ALL xenograft tumors in mice. T-cell ALL lines were also sensitive to pharmacologically relevant concentrations of ONX-0914. This study provides a strong rationale for testing clinical stage immunoproteasome inhibitors KZ-616 and M3258 in ALL.
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Proteína de la Leucemia Mieloide-Linfoide/genética , Oligopéptidos/administración & dosificación , Proteínas de Fusión Oncogénica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Inhibidores de Proteasoma/administración & dosificación , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Ratones , Oligopéptidos/farmacología , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Inhibidores de Proteasoma/farmacología , Distribución Aleatoria , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The Revised International Staging System (R-ISS) stratifies patients affected by Multiple Myeloma (MM) into three distinct risk groups: R-ISS I [ISS Stage I, Standard-Risk cytogenetics and normal Lactase DeHydrogenase (LDH)], R-ISS III (ISS stage III and either high-risk cytogenetics or high LDH) and R-ISS II (any other characteristics). With the aim to verify whether the three R-ISS groups could be divided into subgroups with different prognostic factors based on the detection of Circulating Plasma Cells (CPCs) at diagnosis, in this retrospective analysis, we evaluated 161 patients with MM treated at our centre between 2005 and 2017. In all, 57 patients (33·9%) were staged as R-ISS III, 98 (58·3%) as R-ISS II and six (3·6%) as R-ISS I. CPCs were detected in 125 patients (74·4%), while in 43 patients (25·6%) no CPCs were seen. Our analysis revealed that Overall Survival (OS) and progression-free survival (PFS) rates in R-ISS II patients were higher in the subgroup without CPCs compared to the subgroup with ≥1 CPCs (OS: 44·7% vs. 16·3%, P = 0·0089; PFS: 27·8% vs. 8·1%, P = 0·0118). Our present findings suggest that the detection of CPCs at diagnosis may be used as a further prognostic biomarker to improve the risk stratification of patients with MM staged as R-ISS II.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Mieloma Múltiple , Células Neoplásicas Circulantes/metabolismo , Células Plasmáticas/metabolismo , Trasplante de Células Madre , Adulto , Anciano , Anciano de 80 o más Años , Autoinjertos , Dexametasona/administración & dosificación , Supervivencia sin Enfermedad , Femenino , Humanos , Factores Inmunológicos/administración & dosificación , Masculino , Persona de Mediana Edad , Mieloma Múltiple/sangre , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/mortalidad , Mieloma Múltiple/terapia , Estadificación de Neoplasias , Inhibidores de Proteasoma/administración & dosificación , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
Chemoresistance is the leading cause of limiting long-term treatment success in cancer cells. Anticancer drugs usually kill cells through apoptosis induction and defects in this signaling pathway lead to chemoresistance. Apoptotic protease activating factor 1 regulates cellular stress evoked by chemotherapeutic agents through facilitating apoptosome assembling but can be degraded by proteasome. This study examined the role of proteasome inhibitor Bortezomib in the cytotoxic effects of Docetaxel on MCF7 cells response and its correlation with Apaf-1 expression level. MTT assay, caspase 3/7 activity assay, propidium iodide staining, adenosine triphosphate and reactive oxygen species amount measurements were utilized to demonstrate the role of Bortezomib in Docetaxel efficacy with and without Apaf-1 overexpressing. Meanwhile, two-dimensional cell migration assay was performed by scratch wound assay. The combination of Docetaxel with Bortezomib was significantly more cytotoxic compared single drug, more effectively delayed cell growth, reduced ATP level and increased ROS production. In Apaf-1 overexpressing, Docetaxel was more efficient in preventing cell migration, however, Docetaxel plus Bortezomib were not significantly effective; and fluorescence images supported the interpretation. Our findings demonstrated MCF7 resistance to Docetaxel is due in part to low Apaf-1 level and Apaf-1 overexpression resulted in the increase of cell susceptibility to Docetaxel stimulus. We assume that proteasome inhibitor may restore apoptotic proteins like Apaf-1 and prevent the degradation of cytosolic cytochrome c released by Docetaxel, consequently triggering intrinsic apoptosis and promoting cancer cell death. Collectively, treating MCF7 breast cells with proteasome inhibitor sensitizes cells to Docetaxel-induced apoptosis and possibly overcomes chemoresistance.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Apoptosis/efectos de los fármacos , Bortezomib/farmacología , Inhibidores de Proteasoma/farmacología , Adenosina Trifosfato/metabolismo , Apoptosis/fisiología , Factor Apoptótico 1 Activador de Proteasas/genética , Factor Apoptótico 1 Activador de Proteasas/metabolismo , Bortezomib/administración & dosificación , Caspasa 3/metabolismo , Caspasa 7/metabolismo , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Fragmentación del ADN/efectos de los fármacos , Docetaxel/administración & dosificación , Activación Enzimática/efectos de los fármacos , Humanos , Células MCF-7 , Inhibidores de Proteasoma/administración & dosificación , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Although diverse antipsychotic drugs have been developed for the treatment of schizophrenia, most of their mechanisms of action remain elusive. Regulator of G-protein signaling 4 (RGS4) has been reported to be linked, both genetically and functionally, with schizophrenia and is a physiological substrate of the arginylation branch of the N-degron pathway (Arg/N-degron pathway). Here, we show that the atypical antipsychotic drug clozapine significantly inhibits proteasomal degradation of RGS4 proteins without affecting their transcriptional expression. In addition, the levels of Arg- and Phe-GFP (artificial substrates of the Arg/N-degron pathway) were significantly elevated by clozapine treatment. In silico computational model suggested that clozapine may interact with active sites of N-recognin E3 ubiquitin ligases. Accordingly, treatment with clozapine resulted in reduced polyubiquitylation of RGS4 and Arg-GFP in the test tube and in cultured cells. Clozapine attenuated the activation of downstream effectors of G protein-coupled receptor signaling, such as MEK1 and ERK1, in HEK293 and SH-SY5Y cells. Furthermore, intraperitoneal injection of clozapine into rats significantly stabilized the endogenous RGS4 protein in the prefrontal cortex. Overall, these results reveal an additional therapeutic mechanism of action of clozapine: this drug posttranslationally inhibits the degradation of Arg/N-degron substrates, including RGS4. These findings imply that modulation of protein post-translational modifications, in particular the Arg/N-degron pathway, may be a novel molecular therapeutic strategy against schizophrenia.
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Antipsicóticos/administración & dosificación , Arginina/metabolismo , Clozapina/administración & dosificación , Poliubiquitina/antagonistas & inhibidores , Inhibidores de Proteasoma/administración & dosificación , Proteolisis/efectos de los fármacos , Proteínas RGS/antagonistas & inhibidores , Animales , Línea Celular Tumoral , Células HEK293 , Humanos , Inyecciones Intraperitoneales , Masculino , Ratones , Poliubiquitina/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Estructura Terciaria de Proteína , Proteínas RGS/química , Proteínas RGS/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Ubiquitinación/efectos de los fármacos , Ubiquitinación/fisiologíaRESUMEN
Introduction: Waldenström macroglobulinemia (WM) is a rare subtype of non-Hodgkin lymphoma characterized by the presence of IgM-secreting clonal lymphocytes, plasma cells, and lymphoplasmacytic cells. Many well-established treatment options are available for patients with WM. However, a unique array of side effects may occur in patients during therapy related to the underlying disease, as well as the chosen treatment regimen.Areas covered: This review summarizes the most common adverse effects that occur during treatment of WM, as well as potential strategies to decrease the risk of toxicity.Expert opinion: There are multiple highly effective treatment options for patients with WM. All these treatment options, however, can be associated with a variety of adverse events. For example, chemotherapy has been associated with the development of myeloid neoplasms, anti-CD20 monoclonal antibodies with paradoxical IgM flares and infusion reactions, proteasome inhibitors with neuropathy, and BTK inhibitors with bleeding and cardiac arrhythmias. Dose reductions, lower number of cycles and changes in route of administration are some of the tools a clinician has available for managing and minimizing toxicity. Future research will focus on improving patient safety without sacrificing the efficacy of treatment.
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Antineoplásicos/administración & dosificación , Macroglobulinemia de Waldenström/tratamiento farmacológico , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Antineoplásicos/efectos adversos , Antineoplásicos/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Inhibidores de Proteasoma/administración & dosificación , Inhibidores de Proteasoma/efectos adversos , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Macroglobulinemia de Waldenström/patologíaRESUMEN
AIM: Nano drug delivery systems can provide the opportunity to reduce side effects and improve the therapeutic aspect of a variety of drugs. Bortezomib (BTZ) is a proteasome inhibitor approved for the treatment of multiple myeloma and mantle cell lymphoma. Severe side effects of BTZ are the major dose-limiting factor. Particulate drug delivery systems for BTZ are polymeric and lipidic drug delivery systems. This review focussed on lipidic-nano drug delivery systems (LNDDSs) for the delivery of BTZ. RESULTS: LNDDSs including liposomes, solid lipid nanoparticles, and self-nanoemulsifying drug delivery systems showed reduce systemic side effects, improved therapeutic efficacy, and increased intestinal absorption. Besides LNDDSs were used to target-delivery of BTZ to cancer. CONCLUSION: Overall, LNDDSs can be considered as a novel delivery system for BTZ to resolve the treatment-associated restrictions.
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Bortezomib/administración & dosificación , Sistemas de Liberación de Medicamentos , Lípidos/química , Nanopartículas , Inhibidores de Proteasoma/administración & dosificación , Animales , Antineoplásicos/administración & dosificación , Bortezomib/farmacocinética , Bortezomib/uso terapéutico , Composición de Medicamentos , Emulsiones , Humanos , Liposomas , Tamaño de la Partícula , Inhibidores de Proteasoma/farmacocinética , Inhibidores de Proteasoma/uso terapéutico , RatasRESUMEN
INTRODUCTION: In AL amyloidosis, a usually small plasma cell clone secretes unstable, amyloid-forming light chains, causing cytotoxicity and progressive (multi)organ function deterioration. Treatment aims at reducing/eradicating the underlying clone, to reduce/zero the supply of the amyloidogenic protein and halt the amyloidogenic cascade. AREAS COVERED: Safety data of alkylating agents, proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies from clinical trials are reviewed. EXPERT OPINION: Drugs used to treat AL amyloidosis are derived from experience with multiple myeloma or other B cell malignancies. However, treating AL amyloidosis is particularly challenging, as it implies delivering anti-neoplastic therapy to a hematologic malignancy directly causing (multi)organ function deterioration, often in elderly subjects with other comorbidities and polypharmacotherapy. This unique combination translates in increased patients' frailty and higher sensitivity toward treatment-related toxicities. Therefore, dose/schedule adjustments and special precautions are needed when translating treatment experience from multiple myeloma or other B cell malignancies to AL amyloidosis. Treatment of patients with AL amyloidosis should be risk adapted, tailored to individual patients' risk profile, considering the type and extent of organ involvement, and eventual comorbidity. As several classes of effective anti-plasma cell or B cell drugs are available, therapeutic choices are also influenced by individual drug's safety profile.
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Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/tratamiento farmacológico , Anciano , Alquilantes/administración & dosificación , Alquilantes/efectos adversos , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Relación Dosis-Respuesta a Droga , Humanos , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/fisiopatología , Factores Inmunológicos/administración & dosificación , Factores Inmunológicos/efectos adversos , Mieloma Múltiple/tratamiento farmacológico , Inhibidores de Proteasoma/administración & dosificación , Inhibidores de Proteasoma/efectos adversosRESUMEN
With the increasing overall survival of cancer patients due to recent discoveries in oncology, the incidence of side effects is also rising, and along with secondary malignancies, cardiotoxicity is one of the most concerning side effects, affecting the quality of life of cancer survivors. There are two types of cardiotoxicity associated with chemotherapy; the first one is acute, life-threatening but, fortunately, in most of the cases, reversible; and the second one is with late onset and mostly irreversible. The most studied drugs associated with cardiotoxicity are anthracyclines, but many new agents have demonstrated unexpected cardiotoxic effect, including those currently used in multiple myeloma treatment (proteasome inhibitors and immunomodulatory agents), tyrosine kinase inhibitors used in the treatment of chronic myeloid leukemia and some forms of acute leukemia, and immune checkpoint inhibitors recently introduced in treatment of refractory lymphoma patients. To prevent irreversible myocardial damage, early recognition of cardiac toxicity is mandatory. Traditional methods like echocardiography and magnetic resonance imaging are capable of detecting structural and functional changings, but unable to detect early myocardial damage; therefore, more sensible biomarkers like troponins and natriuretic peptides have to be introduced into the current practice. Baseline assessment of patients allows the identification of those with high risk for cardiotoxicity, while monitoring during and after treatment is important for early detection of cardiotoxicity and prompt intervention.
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Antraciclinas/efectos adversos , Antineoplásicos/efectos adversos , Cardiotoxicidad/prevención & control , Neoplasias Hematológicas/tratamiento farmacológico , Factores Inmunológicos/efectos adversos , Antraciclinas/administración & dosificación , Antineoplásicos/administración & dosificación , Biomarcadores/sangre , Supervivientes de Cáncer , Cardiotoxicidad/diagnóstico por imagen , Cardiotoxicidad/etiología , Ecocardiografía , Neoplasias Hematológicas/diagnóstico por imagen , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/inmunología , Humanos , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Factores Inmunológicos/administración & dosificación , Imagen por Resonancia Magnética , Péptidos Natriuréticos/sangre , Péptidos Natriuréticos/genética , Inhibidores de Proteasoma/administración & dosificación , Inhibidores de Proteasoma/efectos adversos , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Calidad de Vida/psicología , Troponina/sangre , Troponina/genéticaRESUMEN
The novel small molecule PTC596 inhibits microtubule polymerization and its clinical development has been initiated for some solid cancers. We herein investigated the preclinical efficacy of PTC596 alone and in combination with proteasome inhibitors in the treatment of multiple myeloma (MM). PTC596 inhibited the proliferation of MM cell lines as well as primary MM samples in vitro, and this was confirmed with MM cell lines in vivo. PTC596 synergized with bortezomib or carfilzomib to inhibit the growth of MM cells in vitro. The combination treatment of PTC596 with bortezomib exerted synergistic effects in a xenograft model of human MM cell lines in immunodeficient mice and exhibited acceptable tolerability. Mechanistically, treatment with PTC596 induced cell cycle arrest at G2/M phase followed by apoptotic cell death, associated with the inhibition of microtubule polymerization. RNA sequence analysis also revealed that PTC596 and the combination with bortezomib affected the cell cycle and apoptosis in MM cells. Importantly, endoplasmic reticulum stress induced by bortezomib was enhanced by PTC596, providing an underlying mechanism of action of the combination therapy. Our results indicate that PTC596 alone and in combination with proteasome inhibition are potential novel therapeutic options to improve outcomes in patients with MM.