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1.
Nat Commun ; 12(1): 1998, 2021 03 31.
Artículo en Inglés | MEDLINE | ID: mdl-33790302

RESUMEN

The heterogeneity of breast cancer plays a major role in drug response and resistance and has been extensively characterized at the genomic level. Here, a single-cell breast cancer mass cytometry (BCMC) panel is optimized to identify cell phenotypes and their oncogenic signalling states in a biobank of patient-derived tumour xenograft (PDTX) models representing the diversity of human breast cancer. The BCMC panel identifies 13 cellular phenotypes (11 human and 2 murine), associated with both breast cancer subtypes and specific genomic features. Pre-treatment cellular phenotypic composition is a determinant of response to anticancer therapies. Single-cell profiling also reveals drug-induced cellular phenotypic dynamics, unravelling previously unnoticed intra-tumour response diversity. The comprehensive view of the landscapes of cellular phenotypic heterogeneity in PDTXs uncovered by the BCMC panel, which is mirrored in primary human tumours, has profound implications for understanding and predicting therapy response and resistance.


Asunto(s)
Benzamidas/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Xenoinjertos/efectos de los fármacos , Morfolinas/farmacología , Piperazinas/farmacología , Piridinas/farmacología , Pirimidinas/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , Animales , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Femenino , Xenoinjertos/metabolismo , Humanos , Células MCF-7 , Ratones Endogámicos NOD , Ratones Noqueados , Ratones SCID , Inhibidores de Proteínas Quinasas/farmacología , Resultado del Tratamiento
2.
Anticancer Res ; 41(4): 1745-1751, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33813378

RESUMEN

BACKGROUND/AIM: Osteosarcoma is the most frequent malignant bone tumor. Failure of first-line therapy results in poor prognosis of osteosarcoma. In the present report, we examined the efficacy of the combination of oral recombinant methioninase (o-rMETase) and docetaxel (DOC) on an osteosarcoma patient-derived orthotopic xenograft (PDOX) mouse model. MATERIALS AND METHODS: Osteosarcoma-PDOX models were established by tumor insertion within the tibia of nude mice. The osteosarcoma PDOX models were randomized into four groups (4-5 mice per group): control; o-rMETae alone; DOC alone; o- rMETase combined with DOC. The treatment period was 3 weeks. RESULTS: The combination of o-rMETase and DOC showed significant efficacy compared to the control group (p=0.03). In contrast, there was no significant efficacy of o-rMETase alone or DOC alone (p=0.65, 0.60, respectively). CONCLUSION: o-rMETase converted an osteosarcoma PDOX from DOC-resistant to -sensitive. This combination therapy may be effective against recalcitrant osteosarcoma and other recalcitrant cancers.


Asunto(s)
Antineoplásicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias Óseas/tratamiento farmacológico , Liasas de Carbono-Azufre/administración & dosificación , Docetaxel/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Osteosarcoma/tratamiento farmacológico , Tibia/efectos de los fármacos , Administración Oral , Adolescente , Animales , Neoplasias Óseas/patología , Humanos , Masculino , Ratones Desnudos , Osteosarcoma/patología , Proteínas Recombinantes/administración & dosificación , Tibia/patología , Ensayos Antitumor por Modelo de Xenoinjerto
3.
Anticancer Res ; 41(4): 1937-1944, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33813399

RESUMEN

BACKGROUND/AIM: To assess the prognostic relevance of volume-based parameters [whole body (wb)-metabolic tumor volume (MTV) and wb-total lesion glycolysis (TLG)] of pretreatment PET/CT in patients with potentially platinum-responsive recurrent ovarian cancer. PATIENTS AND METHODS: This retrospective investigation analyzed 67 patients at first relapse. RESULTS: At univariate analysis, post-relapse survival and overall survival correlated with residual disease after primary surgery (RD) (p=0.015 and 0.049, respectively), time to recurrence (p=0.005 and p=0.0003), number of recurrence sites (p=0.001 and p=0.0005), treatment at recurrence (p=0.044 and 0.043) and wb-MTV (p=0.023 and 0.021) but not with wb-TLG. RD, time to recurrence and number of recurrence sites, but not wb-MTV, were independent prognostic variables for post-relapse survival, and time to recurrence and number of recurrence sites, but not wb-MTV, were independent prognostic factors for overall survival. CONCLUSION: Volume-based parameters of PET/CT are not independent predictors of clinical outcome in potentially platinum-responsive recurrent ovarian cancer.


Asunto(s)
Carcinoma Epitelial de Ovario/diagnóstico , Recurrencia Local de Neoplasia/diagnóstico , Neoplasias Ováricas/diagnóstico , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Carga Tumoral/fisiología , Adulto , Anciano , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Carcinoma Epitelial de Ovario/patología , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Fluorodesoxiglucosa F18 , Humanos , Italia , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/patología , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Compuestos de Platino/uso terapéutico , Valor Predictivo de las Pruebas , Pronóstico , Estudios Retrospectivos , Resultado del Tratamiento , Carga Tumoral/efectos de los fármacos
4.
Int J Mol Sci ; 22(6)2021 Mar 13.
Artículo en Inglés | MEDLINE | ID: mdl-33805656

RESUMEN

17ß-estradiol (E2) exerts its physiological effects through the estrogen receptor α (i.e., ERα). The E2:ERα signaling allows the regulation of cell proliferation. Indeed, E2 sustains the progression of ERα positive (ERα+) breast cancers (BCs). The presence of ERα at the BC diagnosis drives their therapeutic treatment with the endocrine therapy (ET), which restrains BC progression. Nonetheless, many patients develop metastatic BCs (MBC) for which a treatment is not available. Consequently, the actual challenge is to complement the drugs available to fight ERα+ primary and MBC. Here we exploited a novel anti-estrogen discovery platform to identify new Food and Drug Administration (FDA)-approved drugs inhibiting E2:ERα signaling to cell proliferation in cellular models of primary and MBC cells. We report that the anti-fungal drugs clotrimazole (Clo) and fenticonazole (Fenti) induce ERα degradation and prevent ERα transcriptional signaling and proliferation in cells modeling primary and metastatic BC. The anti-proliferative effects of Clo and Fenti occur also in 3D cancer models (i.e., tumor spheroids) and in a synergic manner with the CDK4/CDK6 inhibitors palbociclib and abemaciclib. Therefore, Clo and Fenti behave as "anti-estrogens"-like drugs. Remarkably, the present "anti-estrogen" discovery platform represents a valuable method to rapidly identify bioactive compounds with anti-estrogenic activity.


Asunto(s)
Aminopiridinas/farmacología , Antineoplásicos/farmacología , Bencimidazoles/farmacología , Clotrimazol/farmacología , Receptor alfa de Estrógeno/antagonistas & inhibidores , Imidazoles/farmacología , Piperazinas/farmacología , Piridinas/farmacología , Antifúngicos/farmacología , Ciclo Celular/efectos de los fármacos , Ciclo Celular/genética , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 4 Dependiente de la Ciclina/genética , Quinasa 4 Dependiente de la Ciclina/metabolismo , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/genética , Quinasa 6 Dependiente de la Ciclina/metabolismo , Aprobación de Drogas , Descubrimiento de Drogas , Reposicionamiento de Medicamentos , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Sinergismo Farmacológico , Estradiol/metabolismo , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Células MCF-7 , Proteolisis , Transducción de Señal , Esferoides Celulares/efectos de los fármacos , Esferoides Celulares/metabolismo , Esferoides Celulares/patología
5.
Int J Mol Sci ; 22(6)2021 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-33808900

RESUMEN

TNF-related apoptosis-inducing ligand (TRAIL) is a type II transmembrane protein capable of selectively inducing apoptosis in cancer cells by binding to its cognate receptors. Here, we examined the anticancer efficacy of a recently developed chimeric AD-O51.4 protein, a TRAIL fused to the VEGFA-originating peptide. We tested AD-O51.4 protein activity against human colorectal cancer (CRC) models and investigated the resistance mechanism in the non-responsive CRC models. The quantitative comparison of apoptotic activity between AD-O51.4 and the native TRAIL in nine human colorectal cancer cell lines revealed dose-dependent toxicity in seven of them; the immunofluorescence-captured receptor abundance correlated with the extent of apoptosis. AD-O51.4 reduced the growth of CRC patient-derived xenografts (PDXs) with good efficacy. Cell lines that acquired AD-O51.4 resistance showed a significant decrease in surface TRAIL receptor expression and apoptosis-related proteins, including Caspase-8, HSP60, and p53. These results demonstrate the effectiveness of AD-O51.4 protein in CRC preclinical models and identify the potential mechanism underlying acquired resistance. Progression of AD-O51.4 to clinical trials is expected.


Asunto(s)
Antineoplásicos/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Proteínas Recombinantes de Fusión/farmacología , Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Animales , Apoptosis/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Línea Celular Tumoral , Membrana Celular/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF/química , Ligando Inductor de Apoptosis Relacionado con TNF/genética , Factor A de Crecimiento Endotelial Vascular/química , Factor A de Crecimiento Endotelial Vascular/genética , Ensayos Antitumor por Modelo de Xenoinjerto
6.
Methods Mol Biol ; 2265: 591-620, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33704742

RESUMEN

Melanoma accounts for 4% of all skin cancer malignancies, with only 14% of diagnosed patients surviving for more than 5 years after diagnosis. Until now, there is no clear understanding of the detailed molecular contributors of melanoma pathogenesis. Accordingly, more research is needed to understand melanoma development and prognosis.All the treatment approaches that are currently applied have several significant limitations that prevent effective use in melanoma. One major limitation in the treatment of cancer is the acquisition of multidrug resistance (MDR). The MDR results in significant treatment failure and poor clinical outcomes in several cancers, including skin cancer. Treatment of melanoma is especially retarded by MDR. Despite the current advances in targeted and immune-mediated therapy, treatment arms of melanoma are severely limited and stand as a significant clinical challenge. Further, the poor pharmacokinetic profile of currently used chemotherapeutic agents is another reason for treatment failure. Therefore, more research is needed to develop novel drugs and carrier tools for more effective and targeted treatment.Nucleic acid therapy is based on nucleic acids or chemical compounds that are closely related, such as antisense oligonucleotides, aptamers, and small-interfering RNAs that are usually used in situations when a specific gene implicated in a disorder is deemed a therapeutically beneficial target for inhibition. However, the proper application for nucleic acid therapies is hampered by the development of an effective delivery system that can maintain their stability in the systemic circulation and enhance their uptake by the target cells. In this chapter, the prognosis of the different types of melanoma along with the currently used medications is highlighted, and the different types of nucleic acids along with the currently available nanoparticle systems for delivering these nucleic acids into melanoma cells are discussed. We also discuss recently conducted research on the use of different types of nanoparticles for nucleic acid delivery into melanoma cells and highlight the most significant outcomes.


Asunto(s)
Antineoplásicos , Sistemas de Liberación de Medicamentos , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Melanoma/tratamiento farmacológico , Nanopartículas , Ácidos Nucleicos , Neoplasias Cutáneas/tratamiento farmacológico , Antineoplásicos/química , Antineoplásicos/farmacología , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Resistencia a Múltiples Medicamentos/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Humanos , Melanoma/genética , Melanoma/metabolismo , Melanoma/patología , Nanopartículas/química , Nanopartículas/uso terapéutico , Ácidos Nucleicos/química , Ácidos Nucleicos/farmacología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología
7.
Int J Nanomedicine ; 16: 2173-2186, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33758505

RESUMEN

Background: Colon cancer is a top lethal cancer in man and women worldwide and drug resistance is the major cause of cancer-related death. Combinational therapy and drug delivery with nanoparticles have been shown to effectively overcome drug resistance in many cancers. We previously reported that nanoemulsion (NE) loaded paclitaxel (PTX) and BEZ235 could synergistically inhibit colon cancer cell growth. Purpose: To investigate whether NE loaded PTX and BEZ235 can overcome drug resistance and synergistically inhibit drug-resistant colon cancer cell growth in vitro and in vivo. Methods: The in vitro treatment effect on cell viability was assayed using CCK8 kit, cell morphological change was detected by ß-tubulin immunofluorescence staining, drug resistance-related proteins were analyzed by Western blotting, and in vivo tumor growth test was performed in nude mice xeno-transplanted with 2 drug-resistant colon cancer cell lines HCT116-LOHP and HT29-DDP. Results: Both cell lines were sensitive to PTX but relatively insensitive to BEZ235. PTX combined with BEZ235 synergistically inhibited the proliferation of both cell lines. Nanoemulsion loaded PTX (NE-PTX) reduced the IC50 of PTX to approximately 2/5 of free PTX, indicating a high inhibitory efficacy of NE-PTX. When NE-PTX combined with a low concentration of BEZ235 (50 nM), the IC50 was decreased to approximately 2/3 of free PTX. Moreover, NE-PTX+BEZ235 treatment increased apoptosis, decreased Pgp and ABCC1 expression, and reduced tumor weights compared to the single drug treatment and the control group. These results suggest that nanoemulsion loaded PTX+BEZ235 can overcome drug resistance and improve the inhibitory effect on cancer cell proliferation and tumor growth. Conclusion: Our study thus provides a possible new approach to treat colon cancer patients with drug resistance.


Asunto(s)
Apoptosis , Neoplasias del Colon/tratamiento farmacológico , Resistencia a Antineoplásicos , Imidazoles/uso terapéutico , Nanopartículas/química , Paclitaxel/uso terapéutico , Inhibidores de las Quinasa Fosfoinosítidos-3/uso terapéutico , Quinolinas/uso terapéutico , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Recuento de Células , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Forma de la Célula/efectos de los fármacos , Neoplasias del Colon/patología , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Emulsiones/química , Femenino , Humanos , Imidazoles/farmacología , Concentración 50 Inhibidora , Ratones Endogámicos BALB C , Ratones Desnudos , Proteínas de Neoplasias/metabolismo , Paclitaxel/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Quinolinas/farmacología , Serina-Treonina Quinasas TOR/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
8.
Medicine (Baltimore) ; 100(8): e24917, 2021 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-33663128

RESUMEN

RATIONALE: Patients with lung adenocarcinoma harboring EML4-ALK rearrangements respond well to multiple ALK tyrosine kinase inhibitors (TKIs). However, the tumor will invariably progress due to acquired resistance. Comprehensive genomic profiling appears to be a promising strategy to reveal the underlying molecular mechanisms of ALK-TKIs resistance. PATIENT CONCERNS: A patient with right lung adenocarcinoma harboring an ALK rearrangement received targeted therapy with multiple ALK-TKIs. He sought for follow-up treatment after his disease progressed again. DIAGNOSIS: The patient had a tumor diagnosed with stage I (T1bN0M0) lung adenocarcinoma. INTERVENTIONS: Due to the surgical contraindication, the patient did not undergo surgical resection. Instead, he received crizotinib as the first-line therapy with the progression-free survival of 20 months. Then he switched to alectinib treatment, however the disease rapidly progressed again. OUTCOMES: Next-generation sequencing was performed and revealed that 7 somatic mutations were identified. Among them, 2 mutations, ALK I1171T and BRAF V600E, may be responsible for the resistance of this patient to ALK-TKIs. BRAF V600E mutation may explain the patient's resistance to lorlatinib. LESSONS: We present a case of ALK-rearranged lung adenocarcinoma with acquired resistance to ALK inhibition, in which the BRAF V600E mutation is a novel resistance mechanism. This provides evidence that BRAF V600E mutation is one mechanism of ALK-TKI resistance.


Asunto(s)
Adenocarcinoma del Pulmón/genética , Neoplasias Óseas/secundario , Neoplasias Pulmonares/genética , Adenocarcinoma del Pulmón/tratamiento farmacológico , Quinasa de Linfoma Anaplásico/efectos de los fármacos , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/genética , Proteínas de Ciclo Celular , Crizotinib/farmacología , Crizotinib/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Resultado Fatal , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Masculino , Proteínas Asociadas a Microtúbulos , Persona de Mediana Edad , Mutación , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Serina Endopeptidasas
9.
Lancet Oncol ; 22(3): e105-e118, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33662288

RESUMEN

This Policy Review presents the International Myeloma Working Group's clinical practice recommendations for the treatment of relapsed and refractory multiple myeloma. Based on the results of phase 2 and phase 3 trials, these recommendations are proposed for the treatment of patients with relapsed and refractory disease who have received one previous line of therapy, and for patients with relapsed and refractory multiple myeloma who have received two or more previous lines of therapy. These recommendations integrate the issue of drug access in both low-income and middle-income countries and in high-income countries to help guide real-world practice and thus improve patient outcomes.


Asunto(s)
Antineoplásicos/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Mieloma Múltiple/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Guías de Práctica Clínica como Asunto/normas , Terapia Recuperativa , Humanos , Mieloma Múltiple/patología , Recurrencia Local de Neoplasia/patología
10.
Anticancer Res ; 41(3): 1429-1438, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33788734

RESUMEN

BACKGROUND/AIM: Clinical significance of antitumour drugs is limited by multidrug resistance (MDR). We examined the effect of bioreductive activation of the anthracyclines, doxorubicin (DOX) and pirarubicin (PIRA), by cytochrome P450 reductase (CPR) on triggering apoptosis of leukaemia HL60 cells and their MDR counterparts. MATERIALS AND METHODS: Cell cycle and FAS expression were investigated by flow cytometry. DNA fragmentation was examined by electrophoretic analysis and caspase-3/8 activities were determined colorimetrically. RESULTS: Non-activated and CPR-activated forms of DOX and PIRA (IC90) had similar efficacy in provoking G2/M arrest of sensitive HL60 as well as resistant HL60/VINC and HL60/DOX cells and in causing DNA degradation. Interestingly, HL60/VINC cells were more prone to apoptosis induced by all studied forms of these drugs. However, no change in Fas expression was observed. CONCLUSION: Bioreductive activation of DOX and PIRA does not affect their ability to induce apoptosis of sensitive and resistant HL60 leukaemia cells.


Asunto(s)
Apoptosis/efectos de los fármacos , Doxorrubicina/análogos & derivados , Doxorrubicina/farmacología , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Leucemia/patología , Antineoplásicos/farmacología , Caspasa 3/metabolismo , Caspasa 8/metabolismo , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Fragmentación del ADN/efectos de los fármacos , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Células HL-60 , Humanos , Leucemia/metabolismo , NADPH-Ferrihemoproteína Reductasa/metabolismo
11.
Nat Med ; 27(3): 426-433, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33664492

RESUMEN

Metastatic castration-resistant prostate cancer is typically lethal, exhibiting intrinsic or acquired resistance to second-generation androgen-targeting therapies and minimal response to immune checkpoint inhibitors1. Cellular programs driving resistance in both cancer and immune cells remain poorly understood. We present single-cell transcriptomes from 14 patients with advanced prostate cancer, spanning all common metastatic sites. Irrespective of treatment exposure, adenocarcinoma cells pervasively coexpressed multiple androgen receptor isoforms, including truncated isoforms hypothesized to mediate resistance to androgen-targeting therapies2,3. Resistance to enzalutamide was associated with cancer cell-intrinsic epithelial-mesenchymal transition and transforming growth factor-ß signaling. Small cell carcinoma cells exhibited divergent expression programs driven by transcriptional regulators promoting lineage plasticity and HOXB5, HOXB6 and NR1D2 (refs. 4-6). Additionally, a subset of patients had high expression of dysfunction markers on cytotoxic CD8+ T cells undergoing clonal expansion following enzalutamide treatment. Collectively, the transcriptional characterization of cancer and immune cells from human metastatic castration-resistant prostate cancer provides a basis for the development of therapeutic approaches complementing androgen signaling inhibition.


Asunto(s)
Antineoplásicos/farmacología , Neoplasias de la Próstata Resistentes a la Castración/terapia , Transcripción Genética/efectos de los fármacos , Biopsia , Linfocitos T CD8-positivos/inmunología , Resistencia a Antineoplásicos/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Humanos , Masculino , Neoplasias de la Próstata Resistentes a la Castración/inmunología , Neoplasias de la Próstata Resistentes a la Castración/patología , Receptores Androgénicos/metabolismo
12.
Int J Mol Sci ; 22(4)2021 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-33669837

RESUMEN

We established the following two variants of the MOLM-13 human acute myeloid leukemia (AML) cell line: (i) MOLM-13/DAC cells are resistant to 5-aza-2'-deoxycytidine (DAC), and (ii) MOLM-13/AZA are resistant to 5-azacytidine (AZA). Both cell variants were obtained through a six-month selection/adaptation procedure with a stepwise increase in the concentration of either DAC or AZA. MOLM-13/DAC cells are resistant to DAC, and MOLM-13/AZA cells are resistant to AZA (approximately 50-fold and 20-fold, respectively), but cross-resistance of MOLM-13/DAC to AZA and of MOLM-13/AZA to DAC was not detected. By measuring the cell retention of fluorescein-linked annexin V and propidium iodide, we showed an apoptotic mode of death for MOLM-13 cells after treatment with either DAC or AZA, for MOLM-13/DAC cells after treatment with AZA, and for MOLM-13/AZA cells after treatment with DAC. When cells progressed to apoptosis, via JC-1 (5,5',6,6'-tetrachloro-1,1',3,3'-tetraethyl-imidacarbocyanine iodide) assay, we detected a reduction in the mitochondrial membrane potential. Furthermore, we characterized promoter methylation levels for some genes encoding proteins regulating apoptosis and the relation of this methylation to the expression of the respective genes. In addition, we focused on determining the expression levels and activity of intrinsic and extrinsic apoptosis pathway proteins.


Asunto(s)
Apoptosis , Metilación de ADN/genética , Resistencia a Antineoplásicos , Transducción de Señal , Apoptosis/efectos de los fármacos , Apoptosis/genética , Azacitidina/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Metilación de ADN/efectos de los fármacos , Decitabina/farmacología , Progresión de la Enfermedad , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Modelos Biológicos , Necrosis , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Regiones Promotoras Genéticas , Transducción de Señal/efectos de los fármacos , Proteína X Asociada a bcl-2/metabolismo
13.
Int J Mol Sci ; 22(5)2021 Feb 26.
Artículo en Inglés | MEDLINE | ID: mdl-33652766

RESUMEN

Elevated activation of the autophagy pathway is currently thought to be one of the survival mechanisms allowing therapy-resistant cancer cells to escape elimination, including for cytarabine (AraC)-resistant acute myeloid leukemia (AML) patients. Consequently, the use of autophagy inhibitors such as chloroquine (CQ) is being explored for the re-sensitization of AraC-resistant cells. In our study, no difference in the activity of the autophagy pathway was detected when comparing AraC-Res AML cell lines to parental AraC-sensitive AML cell lines. Furthermore, treatment with autophagy inhibitors CQ, 3-Methyladenine (3-MA), and bafilomycin A1 (BafA1) did not re-sensitize AraC-Res AML cell lines to AraC treatment. However, in parental AraC-sensitive AML cells, treatment with AraC did activate autophagy and, correspondingly, combination of AraC with autophagy inhibitors strongly reduced cell viability. Notably, the combination of these drugs also yielded the highest level of cell death in a panel of patient-derived AML samples even though not being additive. Furthermore, there was no difference in the cytotoxic effect of autophagy inhibition during AraC treatment in matched de novo and relapse samples with differential sensitivity to AraC. Thus, inhibition of autophagy may improve AraC efficacy in AML patients, but does not seem warranted for the treatment of AML patients that have relapsed with AraC-resistant disease.


Asunto(s)
Antimetabolitos Antineoplásicos/farmacología , Autofagia/efectos de los fármacos , Cloroquina/farmacología , Citarabina/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Leucemia Mieloide Aguda/tratamiento farmacológico , Línea Celular Tumoral , Humanos , Células Tumorales Cultivadas
14.
Medicine (Baltimore) ; 100(10): e25046, 2021 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-33725888

RESUMEN

RATIONALE: Genotypic and histological evolution of non-small-cell lung cancer (NSCLC) into small-cell lung cancer (SCLC) has been described as a mechanism of acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy. However, the number of clinical cases is rare. PATIENT CONCERNS: Two lung adenocarcinoma patients with EGFR mutations who recurred after radical resection transformed into SCLC under treatment with the sequential first- and third-generation EGFR-TKIs. DIAGNOSIS: The 2 cases were both confirmed as SCLC by pathological rebiopsy after EGFR-TKIs resistance. INTERVENTIONS: Case 1 was treated with etoposide plus cisplatin (EP) regimen and erlotinib, while case 2 was treated with erlotinib and EP followed by oral etoposide. OUTCOMES: Case 1 treated with EP only achieved 3-month progression-free survival (PFS), which is the first case that reported T790 M/C797S cis-mutation for osimertinib resistance before the SCLC transformation. However, case 2 treated with erlotinib and EP followed by oral etoposide, PFS lasted for 8 months. LESSONS: The cases highlighted the importance of rebiopsy that identified pathologically SCLC transformation after EGFR-TKI resistance, and suggested the treatment of erlotinib plus EP followed by etoposide, which could provide a reference for such phenotype.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/terapia , Neoplasias Pulmonares/patología , Recurrencia Local de Neoplasia/terapia , Inhibidores de Proteínas Quinasas/farmacología , Carcinoma Pulmonar de Células Pequeñas/terapia , Acrilamidas/farmacología , Acrilamidas/uso terapéutico , Adulto , Compuestos de Anilina/farmacología , Compuestos de Anilina/uso terapéutico , Biopsia , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Cisplatino/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Epirrubicina/uso terapéutico , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Clorhidrato de Erlotinib/uso terapéutico , Resultado Fatal , Femenino , Humanos , Pulmón/diagnóstico por imagen , Pulmón/patología , Pulmón/cirugía , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Neumonectomía , Inhibidores de Proteínas Quinasas/uso terapéutico , Carcinoma Pulmonar de Células Pequeñas/diagnóstico , Carcinoma Pulmonar de Células Pequeñas/genética , Carcinoma Pulmonar de Células Pequeñas/patología , Tomografía Computarizada por Rayos X , Resultado del Tratamiento
15.
Carbohydr Polym ; 260: 117809, 2021 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-33712155

RESUMEN

Gene therapy is an emerging and promising strategy in cancer therapy where small interfering RNA (siRNA) system has been deployed for down-regulation of targeted gene and subsequent inhibition in cancer progression; some issues with siRNA, however, linger namely, its off-targeting property and degradation by enzymes. Nanoparticles can be applied for the encapsulation of siRNA thus enhancing its efficacy in gene silencing where chitosan (CS), a linear alkaline polysaccharide derived from chitin, with superb properties such as biodegradability, biocompatibility, stability and solubility, can play a vital role. Herein, the potential of CS nanoparticles has been discussed for the delivery of siRNA in cancer therapy; proliferation, metastasis and chemoresistance are suppressed by siRNA-loaded CS nanoparticles, especially the usage of pH-sensitive CS nanoparticles. CS nanoparticles can provide a platform for the co-delivery of siRNA and anti-tumor agents with their enhanced stability via chemical modifications. As pre-clinical experiments are in agreement with potential of CS-based nanoparticles for siRNA delivery, and these carriers possess biocompatibiliy and are safe, further studies can focus on evaluating their utilization in cancer patients.


Asunto(s)
Quitosano/química , Nanopartículas/química , Neoplasias/terapia , ARN Interferente Pequeño/uso terapéutico , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Portadores de Fármacos/química , Resistencia a Antineoplásicos/efectos de los fármacos , Silenciador del Gen , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , ARN Interferente Pequeño/química
16.
Int J Mol Sci ; 22(4)2021 Feb 16.
Artículo en Inglés | MEDLINE | ID: mdl-33669204

RESUMEN

Insulin-like Growth Factor (IGF)/IGF-1 Receptor (IGF-1R) signaling is known to regulate stem cell pluripotency and differentiation to trigger cell proliferation, organ development, and tissue regeneration during embryonic development. Unbalanced IGF/IGF-1R signaling can promote cancer cell proliferation and activate cancer reprogramming in tumor tissues, especially in the liver. Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death, with a high incidence and mortality rate in Asia. Most patients with advanced HCC develop tyrosine kinase inhibitor (TKI)-refractoriness after receiving TKI treatment. Dysregulation of IGF/IGF-1R signaling in HCC may activate expression of cancer stemness that leads to TKI refractoriness and tumor recurrence. In this review, we summarize the evidence for dysregulated IGF/IGF-1R signaling especially in hepatitis B virus (HBV)-associated HCC. The regulation of cancer stemness expression and drug resistance will be highlighted. Current clinical treatments and potential therapies targeting IGF/IGF-1R signaling for the treatment of HCC will be discussed.


Asunto(s)
Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Receptor IGF Tipo 1/metabolismo , Transducción de Señal , Somatomedinas/metabolismo , Carcinoma Hepatocelular/complicaciones , Carcinoma Hepatocelular/tratamiento farmacológico , Citocinas/metabolismo , Resistencia a Antineoplásicos/efectos de los fármacos , Hepatitis B/complicaciones , Hepatitis B/metabolismo , Hepatitis B/virología , Virus de la Hepatitis B/fisiología , Humanos , Neoplasias Hepáticas/complicaciones , Neoplasias Hepáticas/tratamiento farmacológico , Terapia Molecular Dirigida/métodos , Recurrencia Local de Neoplasia , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptor IGF Tipo 1/antagonistas & inhibidores , Replicación Viral
17.
Int J Mol Sci ; 22(4)2021 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-33671869

RESUMEN

Cancer-associated fibroblasts (CAFs) are one of the most abundant and critical components of the tumor stroma. CAFs can impact many important steps of cancerogenesis and may also influence treatment resistance. Some of these effects need the direct contact of CAFs and cancer cells, while some involve paracrine signals. In this study, we investigated the ability of head and neck squamous cell carcinomas (HNSCC) patient-derived CAFs to promote or inhibit the colony-forming ability of HNSCC cells. The effect of cisplatin on this promoting or inhibiting influence was also studied. The subsequent analysis focused on changes in the expression of genes associated with cancer progression. We found that cisplatin response in model HNSCC cancer cells was modified by coculture with CAFs, was CAF-specific, and different patient-derived CAFs had a different "sensitizing ratio". Increased expression of VEGFA, PGE2S, COX2, EGFR, and NANOG in cancer cells was characteristic for the increase of resistance. On the other hand, CCL2 expression was associated with sensitizing effect. Significantly higher amounts of cisplatin were found in CAFs derived from patients who subsequently experienced a recurrence. In conclusion, our results showed that CAFs could promote and/or inhibit colony-forming capability and cisplatin resistance in HNSCC cells via paracrine effects and subsequent changes in gene expression of cancer-associated genes in cancer cells.


Asunto(s)
Antineoplásicos/farmacología , Fibroblastos Asociados al Cáncer/efectos de los fármacos , Fibroblastos Asociados al Cáncer/metabolismo , Cisplatino/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias de Cabeza y Cuello/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Anciano , Anciano de 80 o más Años , Línea Celular Tumoral , Técnicas de Cocultivo , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Neoplasias de Cabeza y Cuello/patología , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/patología , Comunicación Paracrina/efectos de los fármacos , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Ensayo de Tumor de Célula Madre
18.
Eur J Med Chem ; 216: 113285, 2021 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-33662676

RESUMEN

The development of resistance poses a serious problem in the therapy of cancer due to the necessity of a multiple-drug and unlimited treatment of affected patients. In chronic myeloid leukemia (CML), the introduction of imatinib has revolutionized the therapy. The persistence of an untreatable cancer stem cell pool and other resistance-causing factors, however, also impede the cure of this malignancy. New therapeutic approaches are therefore essential to overcome current treatment drawbacks. In this regard, an intervention in the STAT5 signaling pathway can significantly improve drug response, as this central signaling node induces the formation of highly resistant CML cells. In the present study, we continued the design of efficient chemosensitizers derived from the partial PPARγ agonist telmisartan. The developed 2-carbonitriles or 2-carboxymethyl esters showed improved potency in sensitizing K562-resistant cells to imatinib treatment, even at concentrations, which are considered patient-relevant. At 5 µM, for instance, 2d sensitized the cells in such a manner that the resistance was fully overcome and the recovered efficacy of imatinib resulted in >76% cell death. Importantly, all compounds were non-cytotoxic per se. A transactivation experiment showed that only the carbonitriles are partial agonists of PPARγ, which does not seem to be involved in the mode of action. Yet, immunoassays revealed a suppression of the STAT5 phosphorylation status by co-application of the most active derivatives with imatinib. This mechanism consequently resulted in reduced cell proliferation and induction of cell death in resistant CML cells.


Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Nitrilos/química , Animales , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Células COS , Línea Celular Tumoral , Chlorocebus aethiops , Diseño de Fármacos , Regulación de la Expresión Génica , Humanos , Mesilato de Imatinib/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Nitrilos/farmacología , PPAR gamma/genética , PPAR gamma/metabolismo , Fosforilación/efectos de los fármacos , Factor de Transcripción STAT5/antagonistas & inhibidores , Factor de Transcripción STAT5/genética , Factor de Transcripción STAT5/metabolismo , Telmisartán/química , Telmisartán/farmacología , Activación Transcripcional/efectos de los fármacos , Proteínas Supresoras de Tumor/antagonistas & inhibidores , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismo
19.
Eur J Med Chem ; 216: 113317, 2021 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-33706147

RESUMEN

The P-glycoprotein (Pgp) is a major transporter involved in multidrug resistance (MDR) of cancer cells leading to chemotherapy failure. In our previous study, we demonstrated that the amide derivatives of pyxinol are promising modulators against Pgp-mediated MDR in cancer. In the present study, we designed and synthesized novel pyxinol derivatives linked to amino acid residues. We evaluated MDR (paclitaxel (Ptx) resistance) reversal potency of forty pyxinol derivatives in KBV cells and analyzed their structure-activity relationships. Half of our derivatives sensitized KBV cells to Ptx at non-toxic concentrations, among which the pyxinol compound bearing a methionine residue (3c) exhibited the best activity in MDR reversal. Compound 3c was found to possess high selectivity toward Pgp and sensitize the KBV cells to Pgp substrates by blocking the efflux function of Pgp. This manifestation may be attributed to its high binding affinity with Pgp, as suggested by docking studies. Overall, the biological profile and ease of synthesizing these pyxinol derivatives render them promising lead compounds for further development for Pgp-mediated MDR.


Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Aminoácidos/química , Antineoplásicos/química , Resistencia a Antineoplásicos , Sapogeninas/química , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Sitios de Unión , Dominio Catalítico , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Humanos , Simulación de Dinámica Molecular , Paclitaxel/farmacología , Relación Estructura-Actividad
20.
Eur J Med Chem ; 216: 113336, 2021 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-33725657

RESUMEN

P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) is a phenomenon in which cells become resistant to structurally and mechanistically unrelated drugs resulting in low intracellular drug concentrations. It is one of the noteworthy problems in malignant tumor clinical therapeutics. So P-gp protein is one of the ideal targets to solve MDR. Based on the lead compound 5m obtained from our previous work, a series of furan derivatives featuring alkyl-substituted phenols and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline were designed and synthesized as reversal agents against P-gp in this paper. Compound 16 containing isopropoxy possessed good potency against P-gp mediated MDR in MCF-7/ADR (IC50 (doxorubicin) = 0.73 µM, RF = 69.6 with 5 µM 16 treated). Western blot results and Rh123 accumulation assays showed that 16 effectively inhibited P-gp efflux function but not its expression. The preliminary structure-activity relationship and docking studies demonstrated that compound 16 would be a potential P-gp inhibitor. Most worthy of mention is that compound 16 has achieved satisfactory results in combination with a variety of anti-tumor drugs, such as doxorubicin, paclitaxel, and vincristine. This study forwards a hopeful P-gp inhibitor for withstanding malignant tumor cell with multidrug resistance setting the basis for further studies.


Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Antineoplásicos/farmacología , Diseño de Fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Furanos/química , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Antineoplásicos/síntesis química , Antineoplásicos/metabolismo , Sitios de Unión , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Doxorrubicina/farmacología , Furanos/metabolismo , Furanos/farmacología , Humanos , Simulación del Acoplamiento Molecular , Paclitaxel/farmacología , Relación Estructura-Actividad , Tetrahidroisoquinolinas/química , Tetrahidroisoquinolinas/metabolismo , Tetrahidroisoquinolinas/farmacología
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