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1.
Pharm Res ; 37(4): 72, 2020 Mar 25.
Artículo en Inglés | MEDLINE | ID: mdl-32215748

RESUMEN

PURPOSE: Combination of PCI and chemotherapy represents a promising strategy for combating drug resistance of cancer. However, poor solubility of photosensitizers and unselectively released drugs at unwanted sites significantly impaired the treatment efficacy. Therefore, in the present study, we aimed to develop a nano-platform which could efficiently co-entrapping photosensitizers and chemotherapeutics for active targeting therapy of drug resistant cancers. METHODS: Two pro-drugs were respectively developed by covalently linking the Ce6 with each other via the GSH-sensitive linkage and the PTX with mPEG-PLA-COOH through the ROS sensitive-linker. The dual-responsive nanoparticles (PNP-Ce6) was developed by emulsion/solvent evaporation method and further modified with tLyp-1 peptides. Physicochemical properties of nanoparticles were determined by the TEM and DLC. Cellular uptake assay was investigated with the Ce6 acting as the fluorescent probe and cell growth was studied by the MTT experiment. In vivo tumor targeting and anti-tumor assay was investigated on the colorectal cancer-bearing mice. RESULTS: The developed tPNP-Ce6 were stable enough under the normal physiological conditions. However, free Ce6 and PTX were completely released when exposed the tPNP-Ce6 to the redox environment. Excellent tumor-targeting drug delivery was achieved by the tPNP-Ce6, which in turn resulted in satisfactory anit-tumor effect. Of great importance, super inhibition effect on tumor progress was achieved by the combination therapy when compared with the group only received with chemotherapy.. CONCLUSION: The results obtained in the present study indicated that the developed tPNP-Ce6 may have great potential in enhancing the therapeutic efficacy of drug-resistant colorectal cancer. Graphical Abstract Left: Targeting delivery of drug to tumor site by the tumor recognizable and dual-responsive nanoparticles and penetrating into tumor inner via the mediation of irradiation. Right: Nanoparticle distribution within tumor tissues with green represents the blood vessels stained with CD31, blue signal represents the cell nuclei stained with DAPI and red shows fluorescence of Ce6 as the indicator of the nanoparticles.


Asunto(s)
Neoplasias Colorrectales/tratamiento farmacológico , Resistencia a Antineoplásicos , Nanopartículas , Fotoquimioterapia , Animales , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos , Células Endoteliales de la Vena Umbilical Humana , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Fármacos Fotosensibilizantes/administración & dosificación , Profármacos , Ensayos Antitumor por Modelo de Xenoinjerto
2.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 42(1): 24-29, 2020 Feb 28.
Artículo en Chino | MEDLINE | ID: mdl-32131936

RESUMEN

Objective To explore the methods of screening and biological characteristics of lung cancer stem cells. Methods We selected the ABCG2 +and ABCG2 -cells from SPC-A-1/adriamycin(ADM)cell line induced by ADM and analyzed the tumorigenicity of ABCG2 +and ABCG2 -cells in vivo by flow cytometry and transplantation in nude mice. Results The average fluorescence intensity of SPC-A-1 cells was(1.001±0.014)×10 2,which was significantly lower than that of SPC-A-1/ADM cells [(10.257±0.023) ×10 2 ](t=17.320,P=0.001);the difference was also statistically significant between the ABCG2/BCRP-FITC treatment group and the SPC-A-1 control group(t=5.269,P=0.021) and the SPC-A-1 control group(t=6.869, P=0.012) and between the SPC-A-1/ADM cell control group and the SPC-A-1/ADM cell homotype control group(t=8.112,P=0.015).The positive rate of SPC-A-1/ADM cells treated with ABCG2/BCRP-FITC was 9.8%,39.84 times higher than that of SPC-A-1 cells;it showed significant difference between the ABCG2/BCRP-FITC group and the SPC-A-1/ADM group(t=9.120,P=0.005) and the SPC-A-1/ADM group(t=8.257,P= 0.006).The positive rate of group B cells was 684 times that of group A cells,and the difference was statistically significant(t=11.235,P=0.001),and the fluorescence intensity of group B cells was strong.The average tumorigenic volume of the mice inoculated with SPC-A-1 cells,group A cells,and group B cells was(6.96±1.82),(6.70±2.55),and(9.17±2.41) mm 3,respectively.Among them,group B was the highest,but there was no significant difference among these three groups(F=2.362,P=0.086).The tumorigenic rate of group B cells was 75.00%,which was significantly higher than that of SPC-A-1 cells and group A cells(F=19.780,P=0.002). Conclusion ABCG2 cells from human lung adenocarcinoma SPC-A-1/ADM cell line can be isolated by ABCG2 antibody combined with immunomagnetic beads sorting method,and the tumor formation rate in nude mice can be observed to explore the identification and biological characterization of lung cancer stem cells.


Asunto(s)
Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Resistencia a Antineoplásicos , Neoplasias Pulmonares/genética , Proteínas de Neoplasias/genética , Células Madre Neoplásicas/citología , Animales , Línea Celular Tumoral , Humanos , Ratones , Ratones Desnudos
3.
Anticancer Res ; 40(3): 1419-1426, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32132038

RESUMEN

BACKGROUND/AIM: Anti-cancer drug resistance restricts the efficacy of chemotherapy in malignant tumors. Casein kinase 2α (CK2α) is highly expressed in 5-fluorouracil (5FU)-resistant colorectal cancer (CRC) cells. We hypothesized that inhibition of CK2α might reduce CRC resistance to 5FU. MATERIALS AND METHODS: To investigate the role of CK2α in 5FU-resistant CRC cells, we assessed cell viability, apoptosis, cyclin-dependent kinase 4 (CDK4) activity, cell-cycle progression, invasion, and sphere formation in 5FU-resistant CRC cells. RESULTS: CK2α levels were significantly increased in 5FU-resistant CRC cells compared to those in wild-type CRC cells. During exposure to 5FU, viability, CDK4 activity, cell-cycle progression, invasion, and sphere formation were enhanced, while apoptosis was decreased in 5FU-resistant CRC cells. These effects were mediated by the inhibiting effects of CK2α on endoplasmic reticulum (ER) stress. Combination of CK2α knockdown with 5FU treatment promoted apoptosis of 5FU-resistant CRC cells by inducing ER stress. CONCLUSION: 5FU treatment in combination with a CK2α inhibitor may exert a synergistic effect against drug-resistant cancer cells.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Quinasa de la Caseína II/antagonistas & inhibidores , Neoplasias Colorrectales/tratamiento farmacológico , Fluorouracilo/farmacología , Quinasa de la Caseína II/metabolismo , Línea Celular Tumoral , Neoplasias Colorrectales/enzimología , Quinasa 4 Dependiente de la Ciclina/metabolismo , Resistencia a Antineoplásicos , Sinergismo Farmacológico , Estrés del Retículo Endoplásmico/efectos de los fármacos , Fluorouracilo/administración & dosificación , Humanos , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/farmacología
4.
Anticancer Res ; 40(3): 1451-1458, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32132042

RESUMEN

BACKGROUND/AIM: Resistance to chemotherapeutic agents is the main cause of reduced survival in non-small cell lung cancer (NSCLC) patients. The Hedgehog (HH) pathway has been shown to be crucial in cell development and survival. Activated in several types of cancer it might be a potent bypass mechanism mediating chemotherapy resistance. MATERIALS AND METHODS: HCC827 NSCLC cells were treated with sub-lethal doses of pemetrexed to produce pemetrexed resistance. RT-qPCR was performed to measure gene expression of HH pathway proteins. A cell growth assay was used to measure the impact of the HH-inhibitor Gant61 in naïve and chemoresistant cell lines. RESULTS: Pemetrexed resistant cells showed significantly increased expression of HH signaling genes (GLI1, GLI2, GLI3, PTCH1, SHH). Supporting these results, pemetrexed resistant cells treated with the HH inhibitor Gant61 showed reduced proliferation compared to naïve cells. CONCLUSION: HH pathway may play an important role in mediating pemetrexed resistance in NSCLC cells. Blocking the HH pathway may be a potential option to overcome this resistance.


Asunto(s)
Proteínas Hedgehog/metabolismo , Pemetrexed/farmacología , Antineoplásicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Procesos de Crecimiento Celular/efectos de los fármacos , Línea Celular Tumoral , Resistencia a Antineoplásicos , Expresión Génica/efectos de los fármacos , Proteínas Hedgehog/antagonistas & inhibidores , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Piridinas/farmacología , Pirimidinas/farmacología , Transducción de Señal
5.
Med Sci Monit ; 26: e918216, 2020 Mar 04.
Artículo en Inglés | MEDLINE | ID: mdl-32129321

RESUMEN

BACKGROUND Chemoresistance is a primary hindrance for current cancer treatments. The influence of abnormal mitochondria in chemotherapy resistance is not well known. To explore the correlation between mitochondria and acquired chemoresistance, this work studied alterations in mitochondrial dynamics, biogenesis, and functions for paclitaxel-resistant cancer cell line A549/Taxol and its parental line A549. MATERIAL AND METHODS Mitochondrial morphology was observed by transmission electron microscopy and confocal microscopy. We measured the mitochondrial mass and mitochondrial membrane potential using fluorescent dyes. The glucose metabolic profile and ATP (adenosine triphosphate) content were determined by bioluminescent cell assays. Seahorse bio-energy analyzer XF24 was used to detect the mitochondrial respiratory function. The expressions of mitochondrial dynamics and biogenesis related genes were quantified using real-time polymerase chain reaction. RESULTS We observed fusion morphology of the mitochondrial network in A549/Taxol cells, with upregulation of fusion genes (Mfn1 and Mfn2) and downregulation of fission gene Fis1. In A549/Taxol cells, mitochondrial mass showed a significant decrease, while the mitochondrial biogenesis pathway was strongly activated. Despite the decreased mitochondrial membrane potential, the capability for mitochondrial respiration was not impaired in A549/Taxol cells. CONCLUSIONS Our study revealed a series changes of mitochondrial characteristics in paclitaxel-resistant cells. Mfn1 and Mfn2 and PGC-1alpha increased, while Fis1 expression and mitochondrial oxidative phosphorylation decreased in A549/Taxol cell lines. These changes to mitochondrial fusion, fission, and biological function contributed to the occurrence of paclitaxel resistance in tumor cells which induced paclitaxel resistance.


Asunto(s)
Resistencia a Antineoplásicos , Dinámicas Mitocondriales , Biogénesis de Organelos , Paclitaxel/farmacología , Células A549 , GTP Fosfohidrolasas/metabolismo , Humanos , Potencial de la Membrana Mitocondrial , Microscopía Confocal , Microscopía Electrónica de Transmisión , Mitocondrias/ultraestructura , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Proteínas Mitocondriales/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo
6.
J Cancer Res Clin Oncol ; 146(4): 843-858, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32056006

RESUMEN

PURPOSE: Increased ATP-binding-cassette (ABC) transporter activity is a major cause of chemotherapy resistance in cancer. The ABC transporter family member ABCB1 is often overexpressed in colorectal cancer (CRC). Phosphatidylinositol-4,5-bisphosphat (PI(4,5)P2)-dependent pathways are involved in the regulation of ABCB1 function. The protein Myristoylated Alanine-Rich C-Kinase Substrate (MARCKS) is a pivotal regulator of PI(4,5)P2 and inactivated in many CRC cancers via genetic deletion or hyperphosphorylation. Therefore, MARCKS may critically impact ABCB1. METHODS: CRC samples as well as CRC cell lines were tested for a connection between MARCKS and ABCB1 via immunofluorescence and Western-blot analysis. ABCB1 function was studied via calcein influx assay under treatment with known ABCB1 inhibitors (verapamil, tariquidar) as well as the kinase inhibitor bosutinib. ABCB1 internalization and MARCKS translocation was analyzed via confocal microscopy exploiting the endocytosis inhibitors chlorpromazine and dynasore. Abundance of PI(4,5)P2 was monitored by intramolecular fluorescence resonance energy transfer (FRET). Reproductive cell survival was studied via colorimetric WST-1 and clonogenic assays in combination with exposure to the chemotherapeutics doxorubicin and 5-fuorouracil (5-FU). RESULTS: We found increased ABCB1 expression in MARCKS negative CRC patient tumor samples and established CRC cell lines. Mechanistically, the reconstitution of MARCKS function via recombinant expression or the pharmacological inhibition of MARCKS phosphorylation led to a substantial decrease in ABCB1 activity. In CRC cells, bosutinib treatment resulted in a MARCKS translocation from the cytosol to the plasma membrane, while simultaneously, ABCB1 was relocated to intracellular compartments. Inhibition of MARCKS phosphorylation via bosutinib rendered cells more sensitive to the chemotherapeutics doxorubicin and 5-FU. CONCLUSIONS: Cells devoid of MARCKS function showed incomplete ABCB1 internalization, leading to higher ABCB1 activity enhancing chemoresistance. Vice versa our data suggest the prevention of MARCKS inhibition by reversing hyperphosphorylation or genomic restoration after deletion as two promising approaches to overcome tumor cell resistance towards chemotherapeutic ABCB1 substrates.


Asunto(s)
Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Sustrato de la Proteína Quinasa C Rico en Alanina Miristoilada/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Compuestos de Anilina , Línea Celular Tumoral , Resistencia a Antineoplásicos , Fluoresceínas/metabolismo , Transferencia Resonante de Energía de Fluorescencia , Células HT29 , Humanos , Microscopía Confocal , Sustrato de la Proteína Quinasa C Rico en Alanina Miristoilada/deficiencia , Nitrilos , Fosforilación , Quinolinas
7.
J Korean Med Sci ; 35(5): e31, 2020 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-32030920

RESUMEN

BACKGROUND: Mechanism and predictive biomarkers for tyrosine kinase inhibitor (TKI) resistance of advanced clear cell renal cell carcinoma (ccRCC) have not been fully evaluated. METHODS: We performed gene expression profiling on samples from an acquired TKI resistance cohort that consisted of 10 cases of TKI-treated ccRCC patients with matched tumor tissues harvested at pre-treatment and TKI-resistant post-treatment periods. In addition, a public microarray dataset from patient-derived xenograft model for TKI-treated ccRCC (GSE76068) was retrieved. Commonly altered pathways between the datasets were investigated by Ingenuity Pathway Analysis using commonly regulated differently expressed genes (DEGs). The significance of candidate DEG on intrinsic TKI resistance was assessed through immunohistochemistry in a separate cohort of 101 TKI-treated ccRCC cases. RESULTS: TNFRSF1A gene expression and tumor necrosis factor (TNF)-α pathway were upregulated in ccRCCs with acquired TKI resistance in both microarray datasets. Also, high expression (> 10% of labeled tumor cells) of TNF receptor 1 (TNFR1), the protein product of TNFRSF1A gene, was correlated with sarcomatoid dedifferentiation and was an independent predictive factor of clinically unfavorable response and shorter survivals in separated TKI-treated ccRCC cohort. CONCLUSION: TNF-α signaling may play a role in TKI resistance, and TNFR1 expression may serve as a predictive biomarker for clinically unfavorable TKI responses in ccRCC.


Asunto(s)
Biomarcadores de Tumor , Carcinoma de Células Renales , Resistencia a Antineoplásicos , Neoplasias Renales , Inhibidores de Proteínas Quinasas , Receptores Tipo I de Factores de Necrosis Tumoral , Transducción de Señal , Factor de Necrosis Tumoral alfa , Adulto , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Renales/diagnóstico , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/terapia , Femenino , Humanos , Inmunohistoquímica , Neoplasias Renales/diagnóstico , Neoplasias Renales/metabolismo , Neoplasias Renales/terapia , Masculino , Persona de Mediana Edad , Pronóstico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptores Tipo I de Factores de Necrosis Tumoral/metabolismo , Análisis de Supervivencia , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/metabolismo
8.
Crit Rev Oncol Hematol ; 147: 102886, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32014673

RESUMEN

In several tumors the PI3K/AKT/mTOR pathway is frequently disrupted, an event that results in uncontrolled cell proliferation and tumor growth. Through the years, several compounds have been developed to inhibit the pathway at different steps: the mammalian target of rapamycin (mTOR) seemed to be the most qualified target. However, this kinase has such a key role in cell survival that mechanisms of resistance are rapidly developed. Nevertheless, clinical results obtained with mTOR inhibitors in breast cancer, renal cell carcinoma, neuroendocrine tumors and mantle cell lymphoma push oncologists to actively further develop these drugs, maybe by better selecting the population to which they are offered, through the research of predictive factors of responsiveness. In this review, we aim to describe mechanisms of resistance to mTOR inhibitors, from preclinical and clinical perspectives.


Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Linfoma de Células del Manto , Fosfatidilinositol 3-Quinasa/metabolismo , Fosfatidilinositol 3-Quinasas/fisiología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Adulto , Proliferación Celular , Resistencia a Antineoplásicos , Humanos , Inhibidores de Proteínas Quinasas
9.
Medicine (Baltimore) ; 99(3): e18892, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-32011517

RESUMEN

RATIONALE: Small cell carcinoma of the esophagus (SCCE) is an uncommon but lethal disease characterized by dismal prognosis. Only 10% of advanced SCCE patients survive longer than 1 year. Resection is a choice for limited-stage cases, whereas the optimal treatment regimen for primary SCCE is yet to be elucidated. To the best of our knowledge, the efficacy of S-1 plus apatinib for irinotecan-refractory SCCE has not been reported before. PATIENT CONCERNS: A 61-year old, previously healthy male was admitted for dysphagia and fatigue. Endoscopic biopsy revealed a tumor in the middle third of the esophagus. Further exams including abdomen computed tomography excluded distant metastasis. DIAGNOSES: Primary SCCE (pT1bN1M0, IIB) was established after salvage operation. INTERVENTIONS: The tumor was enlarged after 1 cycle of first-line chemotherapy using irinotecan plus cisplatin, which indicated drug resistance. Second-line oral apatinib (425 mg daily) plus S-1 (60 mg, twice daily for 4 weeks with a 2-week drug-free interval) for a month showed efficacy, as shown by decreased serum neuron-specific enolase and stable of the esophageal lesion. Thereafter, salvage minimally invasive Ivor-Lewis esophagectomy and 2-field lymph node dissection was performed, followed by oral apatinib plus S-1 at the prior dosage for 6 months. In addition, maintenance therapy using low-dose apatinib (250 mg daily) plus S-1 (40 mg, twice daily for 4 weeks with a 2-week interval) were administered for another 6 months. Then the patient was followed up irregularly at the outpatient clinic. OUTCOMES: The adverse events including hand-foot syndrome, hypertension, vomiting, leukopenia, impaired hepatic function, and fatigue were mainly tolerable. Forty months after the operation, he was readmitted for back pain and disseminated bone metastases appeared in magnetic resonance images. His progression-free survival could not be obtained precisely, and his overall survival was longer than 40 months up to September 2019. LESSONS: S-1 plus apatinib followed by a timely esophagectomy with curative intent might be an alternative option for chemotherapy-refractory SCCE in selected patients. Better evidence is warranted.


Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Carcinoma de Células Pequeñas/tratamiento farmacológico , Neoplasias Esofágicas/tratamiento farmacológico , Ácido Oxónico/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridinas/uso terapéutico , Tegafur/uso terapéutico , Carcinoma de Células Pequeñas/cirugía , Combinación de Medicamentos , Resistencia a Antineoplásicos , Quimioterapia Combinada , Neoplasias Esofágicas/cirugía , Esofagectomía , Humanos , Irinotecán/uso terapéutico , Masculino , Persona de Mediana Edad , Terapia Recuperativa
11.
Adv Exp Med Biol ; 1202: 13-33, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32034707

RESUMEN

Purines and pyrimidines are fundamental signaling molecules in controlling the survival and proliferation of astrocytes, as well as in mediating cell-to-cell communication between glial cells and neurons in the healthy brain. The malignant transformation of astrocytes towards progressively more aggressive brain tumours (from astrocytoma to anaplastic glioblastoma) leads to modifications in both the survival and cell death pathways which overall confer a growth advantage to malignant cells and resistance to many cytotoxic stimuli. It has been demonstrated, however, that, in astrocytomas, several purinergic (in particular adenosinergic) pathways controlling cell survival and death are still effective and, in some cases, even enhanced, providing invaluable targets for purine-based chemotherapy, that still represents an appropriate pharmacological approach to brain tumours. In this chapter, the current knowledge on both receptor-mediated and receptor-independent adenosine pathways in astrocytomas will be reviewed, with a particular emphasis on the most promising targets which could be translated from in vitro studies to in vivo pharmacology. Additionally, we have included new original data from our laboratory demonstrating a key involvement of MAP kinases in the cytostastic and cytotoxic effects exerted by an adenosine analogue, 2-CdA, which with the name of Cladribine is already clinically utilized in haematological malignancies. Here we show that 2-CdA can activate multiple intracellular pathways leading to cell cycle block and cell death by apoptosis of a human astrocytoma cell line that bears several pro-survival genetic mutations. Although in vivo data are still lacking, our results suggest that adenosine analogues could therefore be exploited to overcome resistance to chemotherapy of brain tumours.


Asunto(s)
Adenosina/metabolismo , Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Transducción de Señal , Adenosina/análogos & derivados , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Resistencia a Antineoplásicos/efectos de los fármacos , Glioma/tratamiento farmacológico , Glioma/patología , Humanos , Transducción de Señal/efectos de los fármacos
12.
J Photochem Photobiol B ; 204: 111811, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32028187

RESUMEN

The development of multidrug resistance is often associated with the over-expression of P-glycoprotein (P-gp). This protein prevents drug accumulation and extrudes them out of the cell before they reach the intended target. The aim of this study was to develop an in vitro MCF-7 cell line with increased expression of P-gp and test the phototoxicity of a novel photoactivated zinc phthalocyanine tetrasulfonic acid (ZnPcS4) on these cells. The over-expressed P-gp MCF-7 cells (MCF-7/DOX) were developed from wildtype (WT) MCF-7 cells by a stepwise continuous exposure of the WT cells to different concentrations of Doxorubicin (DOX) (0.1 - 1 µM) over a period of 4 months. The P-gp expression was measured using flow cytometry, immunofluorescence and enzyme immunoassay. To verify whether zinc phthalocyanine-mediated photodynamic therapy (ZnPcS4 - PDT) is effective in MCF-7/DOX, we studied the subcellular localization, phototoxicity and nuclear damage. The flow cytometry result showed two distinct peaks of P-gp positive and negative expression in MCF-7/DOX cell population, which correlates with the ELISA-based assay (p˂0.001). The ME16C (Normal breast cells) was used as control. The localization studies showed that ZnPcS4 have greater affinity for lysosome than mitochondria. Phototoxicity results indicated that photoactivated zinc phthalocyanine decreased the cell proliferation and viability as the drug and laser light dosages increased to 16 µM and 20 J/cm2 respectively. PDT-induced cytotoxicity using lactose dehydrogenase (LDH) enzyme leakage as measure did not increase likewise. The ZnPcS4-induced PDT was less effective for MCF-7/DOX cells which could be attributed to decreased retention of ZnPcS4 in major cellular organelles due to the presence of increased drug efflux P-gp. The current findings suggest that, increased P-gp expression, a characteristic of multidrug resistance together with other related intrinsic mechanisms might contribute to render MCF-7/DOX cells less sensitive to ZnPcS4-induced phototoxicity.


Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Proliferación Celular/efectos de los fármacos , Indoles/farmacología , Láseres de Semiconductores , Compuestos Organometálicos/farmacología , Adenosina Trifosfato/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular/efectos de la radiación , Doxorrubicina/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de la radiación , Femenino , Humanos , Indoles/química , Células MCF-7 , Compuestos Organometálicos/química , Fotoquimioterapia , Rodamina 123/química , Rodamina 123/metabolismo
13.
Artículo en Chino | MEDLINE | ID: mdl-32074750

RESUMEN

Objective: To analyze the differentially expressed genes related to the chemosensitivity with the TPF regimen for hypopharyngeal squamous cell carcinoma and to measure potential functional targeting genes expressions. Methods: Twenty-nine patients with primary hypopharyngeal cancer who underwent induction chemotherapy with TPF from January 2013 to December 2017 in Beijing Tongren Hospital were enrolled for microarray analysis, including 28 males and 1 female, aged from 43 to 73 years old. Among them, 16 patients were sensitive to chemotherapy while 13 patients were non-sensitive. Illumina Human HT-12 Bead Chip was applied to analyze the gene expressions and online bioinformatics analysis was used to analyze the differentially expressed genes. Reverse transcription and quantitative real-time PCR (RT-qPCR) was used to measure the mRNA expression of potential functional genes of TPF induction chemotherapy in 43 samples, 29 from original patients and 14 from additional patients. Graphpad prism 7.0 software was used for statistical analysis. Results: A total of 1 381 significantly differentially expressed genes were screened out. By GO analysis, up-regulated genes included sequestering in extracellular matrix, chemokine receptor binding and potassium channel regulator activity; down-regulated genes included regulation of angiogenesis, calcium ion binding and natural killer cell activation involved in immune response. With KEGG database analysis, down-regulated pathways included ECM-receptor interaction and peroxisome and up-regulated pathways included Glutathione metabolism and PPAR signaling pathway. The expressions of CD44 and IL-6R were significantly different and appeared biologically significant. CD44 was significantly upregulated in insensitive tissues (0.54±0.06) compared with sensitive tissues (0.33±0.04)(P<0.01). IL-6R was significantly downregulated in insensitive tissues (0.44±0.03) compared with sensitive tissues. (0.68±0.03) (P<0.01). Conclusion: CD44 and IL-6R may be potentially functional genes of TPF induction chemotherapy in hypopharyngeal squamous cell carcinoma.


Asunto(s)
Carcinoma de Células Escamosas/tratamiento farmacológico , Neoplasias Hipofaríngeas/tratamiento farmacológico , Quimioterapia de Inducción , Adulto , Anciano , Carcinoma de Células Escamosas/genética , Resistencia a Antineoplásicos , Femenino , Regulación Neoplásica de la Expresión Génica , Genes Relacionados con las Neoplasias , Humanos , Receptores de Hialuranos/genética , Neoplasias Hipofaríngeas/genética , Masculino , Persona de Mediana Edad , Receptores de Interleucina-6/genética
14.
Chemistry ; 26(11): 2470-2477, 2020 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-31912555

RESUMEN

Multidrug resistance (MDR) is regarded as a main obstacle for effective chemotherapy, and P-glycoprotein (P-gp)-mediated drug efflux has been demonstrated to be the key factor responsible for MDR. In this study, a novel pH-responsive hybrid drug delivery system was developed by conjugating d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), a kind of P-gp inhibitor, on the surface of laponite nanodisks to overcome MDR. The prepared LM-TPGS display excellent colloidal stability, a high encapsulation efficiency of doxorubicin (DOX), and a pH-responsive drug release profile. In vitro experiments verified that LM-TPGS/DOX could exhibit significantly enhanced therapeutic efficacy in treating DOX-resistant breast cancer cells (MCF-7/ADR) through inhibiting the activity of P-gp-mediated drug efflux and effectively accumulating DOX within cancer cells. In vivo results revealed that LM-TPGS/DOX outstandingly suppressed MCF-7/ADR tumors with low side effects. Therefore, the high drug payload, enhanced inhibition efficacy to drug-resistant cells, and low side effects make the LM-TPGS/DOX a promising nanoplatform to reverse MDR for effective chemotherapy.


Asunto(s)
Antibióticos Antineoplásicos/química , Doxorrubicina/química , Nanocápsulas/química , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Antibióticos Antineoplásicos/farmacología , Doxorrubicina/farmacología , Composición de Medicamentos/métodos , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Humanos , Polietilenglicoles/química , Polietilenglicoles/metabolismo , Vitamina E/química , Vitamina E/metabolismo
15.
Cancer Sci ; 111(3): 932-939, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31961053

RESUMEN

The treatment for anaplastic lymphoma kinase (ALK)-positive lung cancer has been rapidly evolving since the introduction of several ALK tyrosine kinase inhibitors (ALK-TKI) in clinical practice. However, the acquired resistance to these drugs has become an important issue. In this study, we collected a total of 112 serial biopsy samples from 32 patients with ALK-positive lung cancer during multiple ALK-TKI treatments to reveal the resistance mechanisms to ALK-TKI. Among 32 patients, 24 patients received more than two ALK-TKI. Secondary mutations were observed in 8 of 12 specimens after crizotinib failure (G1202R, G1269A, I1171T, L1196M, C1156Y and F1245V). After alectinib failure, G1202R and I1171N mutations were detected in 7 of 15 specimens. G1202R, F1174V and G1202R, and P-gp overexpression were observed in 3 of 7 samples after ceritinib treatment. L1196M + G1202R, a compound mutation, was detected in 1 specimen after lorlatinib treatment. ALK-TKI treatment duration was longer in the on-target treatment group than that in the off-target group (13.0 vs 1.2 months). In conclusion, resistance to ALK-TKI based on secondary mutation in this study was similar to that in previous reports, except for crizotinib resistance. Understanding the appropriate treatment matching resistance mechanisms contributes to the efficacy of multiple ALK-TKI treatment strategies.


Asunto(s)
Quinasa de Linfoma Anaplásico/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Resistencia a Antineoplásicos/genética , Neoplasias Pulmonares/genética , Grupo de Ascendencia Continental Asiática , Carbazoles/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Crizotinib/uso terapéutico , Humanos , Lactamas Macrocíclicas/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Mutación/genética , Piperidinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Proteínas Recombinantes/genética , Sulfonas/uso terapéutico
16.
Biochim Biophys Acta Rev Cancer ; 1873(1): 188341, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31931113

RESUMEN

Understanding the molecular mechanisms driving resistance to anti-cancer drugs is both a crucial step to define markers of response to therapy and a clinical need in many cancer settings. YAP and TAZ transcriptional cofactors behave as oncogenes in different cancer types. Deregulation of YAP/TAZ expression or alterations in components of the multiple signaling pathways converging on these factors are important mechanisms of resistance to chemotherapy, target therapy and hormone therapy. Moreover, response to immunotherapy may also be affected by YAP/TAZ activities in both tumor and microenvironment cells. For these reasons, various compounds inhibiting YAP/TAZ function by different direct and indirect mechanisms have been proposed as a mean to counter-act drug resistance in cancer. A particularly promising approach may be to simultaneously target both YAP/TAZ expression and their transcriptional activity through BET inhibitors.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Antineoplásicos/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Transactivadores/metabolismo , Factores de Transcripción/metabolismo , Microambiente Tumoral/efectos de los fármacos , Proteínas Adaptadoras Transductoras de Señales/genética , Resistencia a Antineoplásicos/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Redes y Vías Metabólicas/efectos de los fármacos , Redes y Vías Metabólicas/genética , Neoplasias/genética , Neoplasias/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Transactivadores/genética , Factores de Transcripción/genética , Microambiente Tumoral/genética
17.
Life Sci ; 243: 117255, 2020 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-31923418

RESUMEN

BACKGROUND: The occurrence in drug resistance of chronic myeloid leukemia (CML) was accompanied by autophagy activation. Abnormal circular RNAs (circRNAs) participated in this progression. This study attempted to investigate the potential role of circ_0009910 in imatinib resistance of CML cells. METHODS: The expression of circ_0009910 and miR-34a-5p was measured by quantitative real-time polymerase chain reaction (qRT-PCR). The characterization of circ_0009910 was investigated using oligo (dT)18 primers, Actinomycin D and RNase R. Cell viability (IC50 value) and apoptosis were assessed by Cell Counting Kit-8 (CCK8) assay and flow cytometry assay, respectively. The relative protein expression was quantified by western blot. The relationship among miR-34a-5p, circ_0009910 and ULK1 was predicted by online bioinformatics tool, and verified by dual-luciferase reporter assay and RNA immunoprecipitation (RIP). RESULTS: The expression of circ_0009910 was up-regulated in the serum of imatinib-resistance CML patients and K562/R cells, and associated with unfavorable clinicopathologic features. Circ_0009910 in K562 and K562/R cells was mainly localized in the cytoplasm. Circ_0009910 knockdown inhibited cell proliferation and autophagy, but induced apoptosis in K562/R cells. Circ_0009910 targeted miR-34a-5p to regulate ULK1. MiR-34a-5p depression rescued the effects of circ_0009910 knockdown on apoptosis and autophagy in K562/R cells. CONCLUSION: Circ_0009910 accelerated imatinib-resistance in CML cells by modulating ULK1-induced autophagy via targeting miR-34a-5p, providing a potential target in imatinib resistance of CML.


Asunto(s)
Antineoplásicos/uso terapéutico , Homólogo de la Proteína 1 Relacionada con la Autofagia/fisiología , Autofagia/fisiología , Mesilato de Imatinib/uso terapéutico , Péptidos y Proteínas de Señalización Intracelular/fisiología , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , MicroARNs/genética , Resistencia a Antineoplásicos , Humanos , Células K562 , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/patología
18.
Life Sci ; 243: 117256, 2020 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-31923419

RESUMEN

AIMS: Chemotherapy and molecularly targeted therapy are main strategies for treatment of cancers. However, long-term treatment makes cancer cells acquire resistance to anti-cancer drugs, which severely limits the effects of cancer treatment. NcRNAs, especially miRNAs and lncRNAs, have been reported to play key roles in drug resistance and could restore drug responses in resistant cells. MAIN METHODS: We presented a network-based framework to systematically identify drug resistance associated miRNAs and lncRNAs. First, we constructed a comprehensive heterogeneous miRNA-lncRNA regulatory network through integrating curated miRNA regulations to lncRNA, and significantly co-expressed miRNA-miRNA, lncRNA-lncRNA and miRNA-lncRNA interactions for each cancer type. Second, random walk with restart (RWR) was utilized to identify novel drug resistance associated ncRNAs. KEY FINDINGS: We predicted 470 associations of 34 miRNAs and 79 lncRNAs for 27 drugs in 10 cancer types. In addition, leave-one-out cross validation (LOOCV) demonstrated the effectiveness of the proposed approach. Next, we also demonstrated that the integrated heterogeneous cancer-specific network achieved better performance than the general curated miRNA-lncRNA regulatory network. What's more, we found that the drug resistance associated ncRNAs validated by high-throughput technology was also a reliable source for prediction. SIGNIFICANCE: We proposed a new framework to identify novel and reliable drug resistance associated ncRNAs, which provides new perspectives for drug resistance mechanism and new guidance for clinical cancer treatment.


Asunto(s)
Resistencia a Antineoplásicos/genética , MicroARNs/genética , ARN Largo no Codificante/genética , Algoritmos , Redes Reguladoras de Genes , Humanos , Neoplasias/clasificación , Neoplasias/genética
19.
J Cancer Res Clin Oncol ; 146(2): 343-356, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31932908

RESUMEN

PURPOSE: We set out to determine whether clinically tested epigenetic drugs against class I histone deacetylases (HDACs) affect hallmarks of the metastatic process. METHODS: We treated permanent and primary renal, lung, and breast cancer cells with the class I histone deacetylase inhibitors (HDACi) entinostat (MS-275) and valproic acid (VPA), the replicative stress inducer hydroxyurea (HU), the DNA-damaging agent cis-platinum (L-OHP), and the cytokine transforming growth factor-ß (TGFß). We used proteomics, quantitative PCR, immunoblot, single cell DNA damage assays, and flow cytometry to analyze cell fate after drug exposure. RESULTS: We show that HDACi interfere with DNA repair protein expression and trigger DNA damage and apoptosis alone and in combination with established chemotherapeutics. Furthermore, HDACi disrupt the balance of cell adhesion protein expression and abrogate TGFß-induced cellular plasticity of transformed cells. CONCLUSION: HDACi suppress the epithelial-mesenchymal transition (EMT) and compromise the DNA integrity of cancer cells. These data encourage further testing of HDACi against tumor cells.


Asunto(s)
Reparación del ADN/fisiología , Proteínas de Unión al ADN/metabolismo , Inhibidores de Histona Desacetilasas/farmacología , Neoplasias/tratamiento farmacológico , Animales , Benzamidas/farmacología , Plasticidad de la Célula/efectos de los fármacos , Cisplatino/farmacología , Enzimas Reparadoras del ADN/metabolismo , Resistencia a Antineoplásicos , Humanos , Hidroxiurea/farmacología , Masculino , Ratones , Ratones Endogámicos BALB C , Metástasis de la Neoplasia , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patología , Piridinas/farmacología , Factor de Crecimiento Transformador beta/farmacología , Ácido Valproico/farmacología
20.
Life Sci ; 244: 117280, 2020 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-31926239

RESUMEN

AIMS: Recently, chemoresistance has been recognized as an obstacle in the treatment of gastric cancer (GC). The aim of this study was to investigate the biological functions and underlying mechanisms of propofol in GC chemoresistance. MAIN METHODS: CCK-8 assay, flow cytometry and immunofluorescent staining were performed to assess the IC50 concentration, cell apoptosis and autophagy activity of cisplatin in both GC chemosensitive cells (SGC7901) and chemoresistant cells (SGC7901/CDDP). The expression pattern of MALAT1 in GC cells was detected by qRT-PCR. The shRNAs and overexpressing plasmids were employed for the loss or gain-of-function. Dual-luciferase reporter assay was subjected to verify the binding relationship between MALAT1 and miR-30e. Besides, ATG5 mRNA and protein levels were determined using qRT-PCR and western blot analysis. Furthermore, GC xenograft mice model was established to validate the in vitro findings. KEY FINDINGS: Chemoresistant GC cells presented higher IC50 of cisplatin, increased autophagy activity and stronger expression of MALAT1. The application of propofol promoted cell apoptosis and reduced the activity of autophagy through downregulating MALAT1. Silencing of MALAT1 inhibited chemo-induced autophagy, whereas MALAT1 overexpression promoted autophagy in GC cells. Mechanistic researches demonstrated that MALAT1 could bind with miR-30e to regulate ATG5 expression, thus causing the suppression of autophagy. In vivo GC xenograft model treated with both propofol and cisplatin also showed significantly decreased tumor size and weight, which was enhanced by knockdown of MALAT1. SIGNIFICANCE: Altogether, our study revealed a novel mechanism of propofol of lncRNA MALAT1/miR-30e/ATG5 mediated autophagy-related chemoresistance in GC, casting new lights on the understanding of propofol.


Asunto(s)
MicroARNs/genética , Propofol/metabolismo , ARN Largo no Codificante/metabolismo , Animales , Apoptosis/efectos de los fármacos , Autofagia/genética , Proteína 5 Relacionada con la Autofagia/genética , Proteína 5 Relacionada con la Autofagia/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , China , Cisplatino/metabolismo , Cisplatino/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Ratones , Ratones Desnudos , MicroARNs/metabolismo , Propofol/farmacología , ARN Largo no Codificante/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
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