ABSTRACT
Objective: To investigate the potential effect of Lysimachia capillipes capilliposide (LCC) on the chemo sensitivity and the stemness of human ovarian cancer cells. Methods: Cell Counting Kit-8 (CCK8) was used to measure the IC
ABSTRACT
Objective@#To investigate the molecular mechanism of high phosphorylation levels of cofilin-1 (p-CFL-1) associated with paclitaxel resistance in epithelial ovarian cancer (EOC) cells.@*Methods@#Cells displaying varying levels of p-CFL-1 and CFL-1 were created by plasmid transfection and shRNA interference. Cell inhibition rate indicating paclitaxel efficacy was assessed by Cell Counting Kit-8 (CCK-8) assay. Apoptosis was assessed by flow cytometry and protein levels were detected by western blotting. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to measure the expression levels of phosphokinases and phosphatases of CFL-1. Survival analysis evaluated the correlation between the prognosis of EOC patients and the levels of p-CFL-1 and slingshot-1 (SSH-1).@*Results@#High levels of p-CFL-1 were observed in EOC cells that survived treatment with high doses of paclitaxel. SKOV3 cell mutants with upregulated p-CFL-1 showed impaired paclitaxel efficacy, as well as decreased apoptosis rates and pro-survival patterns of apoptosis-specific protein expression. Cytoplasmic accumulation of p-CFL-1 inhibited paclitaxel-induced mitochondrial apoptosis. SSH-1 silencing mediated CFL-1 phosphorylation in paclitaxel-resistant SKOV3 cells. Clinically, the high level of p-CFL-1 and the low level of SSH-1 in EOC tissues were closely related to chemotherapy resistance and poor prognosis in EOC patients.@*Conclusion@#The SSH-1/p-CFL-1 signaling pathway mediates paclitaxel resistance by apoptosis inhibition in EOC and is expected to be a potential prognostic predictor.
Subject(s)
Female , Humans , Antineoplastic Agents, Phytogenic/therapeutic use , Apoptosis , Carcinoma, Ovarian Epithelial/metabolism , Cell Line, Tumor , Cofilin 1/metabolism , Drug Resistance, Neoplasm , Ovarian Neoplasms/metabolism , Paclitaxel/therapeutic use , Phosphoprotein Phosphatases/metabolism , PhosphorylationABSTRACT
Drug metabolism is an orchestrated process in which drugs are metabolized and disposed through a series of specialized enzymes and transporters. Alterations in the expression and/or activity of these enzymes and transporters can affect the bioavailability (pharmacokinetics, or PK) and therapeutic efficacy (pharmacodynamics, or PD) of drugs. Recent studies have suggested that the long non-coding RNAs (lncRNAs) are highly relevant to drug metabolism and drug resistance, including chemo-resistance in cancers, through the regulation of drug metabolism and disposition related genes. This review summarizes the regulation of enzymes, transporters, or regulatory proteins involved in drug metabolism by lncRNAs, with a particular emphasis on drug metabolism and chemo-resistance in cancer patients. The perspective strategies to integrate multi-dimensional pharmacogenomics data for future in-depth analysis of drug metabolism related lncRNAs are also proposed. Understanding the role of lncRNAs in drug metabolism will not only facilitate the identification of novel regulatory mechanisms, but also enable the discovery of lncRNA-based biomarkers and drug targets to personalize and improve the therapeutic outcome of patients, including cancer patients.
ABSTRACT
@#Introduction: Drug-resistance is a major hindrance to successful treatment of AML. Current predictive biomarkers are mainly genetic aberrations and insufficient in foretelling treatment outcome in all acute myeloid leukaemia (AML) due to its heterogeneous and aggressive nature. Proteins are stable and reliable. Secreted proteins in AML may have predictive or prognostic values for early intervention. Proteomic studies on AML are few and further investigations will benefit in selection of best markers. The aim of the study was to identify differentially expressed plasma proteins in AML with different treatment outcome. Methods: Two-dimensional electrophoresis (2-DE) technique was utilised to identify proteins differentially expressed in chemo-sensitive/chemo-resistant AML. Plasma and peripheral blood mononuclear cell (PBMC) lysate proteome analysis were performed on six chemo-resistant, four chemo-sensitive and six healthy controls and seven chemo-resistant, three chemo-sensitive and six healthy controls, respectively. Each experiment was conducted in duplicate or triplicate. Images were captured and protein spots detected by software. Differentially expressed protein spots were excised from gel and proteins were identified using LC/MS/MS. Proteins spots that were also detected in healthy controls were excluded. Results: Comparing mean % volume of each spot demonstrated significantly enhanced expression of apoliprotein-E (APO-E) and haptoglobin (HP) (p<0.05) in plasma and HNRNP H1 (p=0.049) in cell lysate of chemo-sensitive group. Serotransferrin (STF) from plasma and DNA-PK from cell lysate (p=0.01) were associated with chemo-resistance. Conclusion: This preliminary study identified several potential predictive biomarkers associated with chemo-resistance/chemo-sensitivity to treatment in AML. Further studies with a larger number of samples are required to validate the results.
ABSTRACT
] Objective To explore the role and mechanisms of FGF2 in chemo?resistance in breast cancer. Methods The inhibitors for different signal pathway were used to treat two drug?resistant breast cancer cell lines MCF?7/5?Fu and T47D/5?Fu established in our lab. MTS assay was used to determine chemo?sensitivity and Hoechst stain was used to measure apoptosis. Protein activation and FGF2 protein level in cell culture medium were detected by western blot and ELISA respectively. Results Akt inhibitor MK?2206 (20 nM) and mTOR inhibitor AZD8055 (2 nM) significantly reversed the chemo?resistance of MCF?7/5?Fu and T47D/5?Fu cell lines to 5?Fu and paclitaxel, but ERK1/2 inhibitor SCH772984 showed no significant effect. Compared to parent cell lines MCF?7 and T47D, p?Akt and p?S6K (represented as mTORactivity) levels were obviously up?regulated in MCF?7/5?Fu and T47D/5?Fu cell lines, and so do the FGF2 mRNA level and FGF2 protein level from culture medium. Moreover, FGFR inhibitor AZD4547 (4 nM) markedly reversed the chemo?resistance of MCF?7/5?Fu and T47D/5?Fu cell lines to 5?Fu and paclitaxel and down?regulated activation of FGFR?Akt?mTOR signal pathway. In agreement, FGF2 protein (10ng/ml) enhanced the chemo?resistance of MCF?7 and T47D cell lines to 5?Fu and paclitaxel and up?regulated activation of FGFR?Akt?mTOR signal pathway. Conclusion Activation of FGF2?FGFR?Akt?mTOR signal pathway promoted chemo?resistance of breast cancer cells.
ABSTRACT
Gastric cancer is a kind of disease with high incidence and mortality rate,most gastric cancer cases are diagnosed in an advanced,and chemotherapy is the main treatment.Drug resistance is one of the most important causes of therapy failure in gastric cancer patients.It has revealed that the mechanism of tumor resistance mainly involves alterations in cell cycle and proliferation,enhanced DNA repair capacity,defective apoptosis,damaged host immune,altered metabolism of drugs and so on.In recent years,an important molecule-microRNA(miRNA)that regulates the biological behavior of cell has attracted more and more attention.Studies have confirmed that numerous miRNAs can regulate the drug resistance of gastric cancer cells via BCL-2 signaling pathway,PTEN/PI3K/AKT pathway,ABCB1(MDR1/P-gp),autophagy,cell cycle and so on.
ABSTRACT
Objective@#To explore the alteration of plasma metabolomic profiles, screen the new serum markers of multidrug resistant epithelial ovarian cancer (EOC), and investigate the mechanism.@*Methods@#The serum of 132 cases with cisplatin-resistant EOC, cisplatin-sensitive EOC, benign ovarian cyst and healthy donors were collected. Differentially plasma metabolic profiles were identified by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). The significantly different metabolites of each group were screened by using principal component analysis. Then compounds that played a key role in cisplatin resistance were identified by using nuclear magnetic resonance (NMR). The relationships between these compounds and clinical characteristics and prognosis were analyzed.@*Results@#LC-MS/MS identified 25 800 metabolic compounds. According to the descending dimension algorithm by principal component analysis, six compounds which were the biggest contributor to grouping were identified. The identified results of NMR showed that the serum level of C16 Sphinganine was lower while Dodemorph was higher in the EOC than those of the normal control. Compared to the cisplatin sensitive group, cisplatin resistant group exhibited a specific metabolic trait characterized by upregulation of 1-Monopalmitin, Ricinoleic acid methyl ester, Polyoxyethylene (600) mono-ricinoleate/Glycidyl stearate and downregulation of Calycanthidine. The four components were all associated with fatty acid metabolism, and the combinational diagnostic sensitivity of these biomarkers for cisplatin-resistance was 86.50% and the specificity was 81.80%, the area of receiver operating characteristic (ROC) curve was 0.93.@*Conclusions@#The metabolic signatures of normal control, benign ovarian cyst, cisplatin sensitivity and cisplatin resistance can be clearly separated from each other by LC-MS/MS technology.The combinational four biomarkers including Calycanthidine, 1-Monopalmitin, Ricinoleic acid methl ester and Polyoxyethylene (600) mono-ricinoleate/Glycidyl stearate are more sensitive and specific for the diagnosis of cisplatin resistant EOC, and may provide the potentially predict markers of chemotherapeutic response in metabolic level. The fatty acid metabolism may participate in the cisplatin resistant progression of EOC.
ABSTRACT
Chemotherapy is one of the primary treatment for malignant tumors.Platinum drugs as the most commonly used cycle non-specific clinical antitumor drugs show good curative effect in the clinical treatment of solid tumors,however,resistance or cross-resistance of theplatinum analogous has become one of the main obstacles for platinum and its analogous,which limits their clinical applications.miRNAs play an important role in biology,including cell proliferation,differentiation,apoptosis,stress tolerance,and physiological metabolism.There is a close relationship between miRNAs target gene regulation and tumor drug-resistance.This article is mainly about the role of miRNAs in tumor of platinum resistance.
ABSTRACT
Background and purpose:Oxaliplatin (L-OHP) is one of the most commonly used chemotherapy drugs in colorectal cancer and L-OHP-resistance is very common in colorectal cancer therapy. This research was to discuss the reversal effect in L-OHP-resistant human colon cancer cell line LoVo/L-OHP by anemoside B4 (AB4) and tetrandrine (Tet) and to clarify their molecular mechanism. Methods:LoVo/L-OHP cells were treated for 48 h by AB4 and Tet at different concentrations to get non-toxic dose. Drug sensitivity was measured by MTT. After the treatment, the cell cycle and apoptosis of the cells were detected. Expression of P-gp mRNA, zDHHC9 mRNA and SMAD4 mRNA were detected by RT-PCR. Expression of P-gp, zDHHC9 and SMAD4 protein were detected by Western blot. Results:The IC50 of LoVo/L-OHP for L-OHP was (112.5±23.6) μg/mL, and the IC50 decreased to (62.8±21.4) μg/mL (P0.05). The cell apoptosis experiment showed that the apoptotic rate increased after the treatment with AB4 and Tet with non-toxic dose but with no statistical signiifcance (P>0.05). The RT-PCR experiment showed that the expressions of P-gp mRNA and zDHHC9 mRNA were increased and SMAD4 mRNA was decreased in LoVo/L-OHP cells compared with in LoVo cells (P<0.05), while it was found that P-gp mRNA in LoVo/L-OHP cells was decreased after the treatment with AB4 at non-toxic dose (P<0.05). Western blot experiment showed the protein of P-gp in LoVo/L-OHP cells was decreased after treatment with AB4 (P<0.05), which was accordant to the PCR result. The expression of zDHHC9 protein in LoVo/L-OHP cells was decreased in LoVo/L-OHP cells after treatment with Tet (P<0.05). Conclusion:AB4 and Tet have some reversal effect on resistant to L-OHP in LoVo/L-OHP cells. The molec-ular mechanism of the resistance reverse effect was related to down-regulation of P-gp for AB4 and down-regulation of zDHHC9 for Tet.
ABSTRACT
Objective To investigate the contribution of hypoxia-inducible factor inhibitor YC-1 to cisplatin chemo-sensitivity to human ovarian cancer cells A2780s in vitro. Methods Ovarian cancer cells were divided into four groups which were treated with saline, YC-1, cisplatin, and YC-1+cisplatin, separately, mRNA of HIF-1αand VEGF in the A2780s cells were detected by real-time fluorescence quantitative PCR by calculating 2-△△CT;the protein were detected by Western blot, to evaluate the change of hypoxia and angiogenesis capabilities under the ovarian cancer microenvironment. Results Compared with the control group, mRNA and protein of HIF-1αand VEGF expressed less in the group of YC-1, cisplatin and YC-1+cisplatin;while, those in the group of YC-1+cisplatin were lower than the monotherapy (P<0. 05), but no significant difference was detected between the YC-1 and cisplatin groups, and the expression of HIF-1αand VEGF mRNA were positively related(r=0. 830 5)in each group. Conclusion YC-1 exerts the antitumor effect and may contribute to sensitivity to cisplatin in the therapy of ovarian cancer.
ABSTRACT
Intrinsic or acquired chemo-resistance is the main reason for chemotherapy failure, and thus finding ways to reverse chemo-resistance has become an interesting topic for research. Studies have revealed that immunomodulatory molecules are involved in cancer chemo-resistance. Hence, interventions that target immunomodulatory molecules to reverse chemo-resistance have attracted a great deal of concern from domestic and foreign scholars. Immunomodulatory molecules, such as PD-L1, B7-H3, HMGB1, TRAIL, MyD88, and Cytokines (TNF-α, IFN-α, IL-6), have been proven to take part in regulating immune function and tumor drug-resistance characteristics, thereby providing new ideas to the reversal of tumor chemo-resistance. This artide reviews the progression of immuno-modulatory molecules with the change in cancer chemotherapy sensitivity to provide a theoretical basis for the application of new thera-peutic regimen of bio-chemotherapy.
ABSTRACT
Liver cancer is the second most frequent cause of cancer death in men and the sixth leading cause of cancer death in women. Hepatocellular carcinoma (HCC) represents the major subtype in liver cancer and its five-year survival rate remains very poor. Sorafenib, a molecular targeted therapeutic agent, was the first drug approved for the treatment of patients with HCC. However, the clinical response of sorafenib was seriously limited by drug resistance. Autophagy is an evolutionarily conserved mechanism among all eukaryotes. Recently, many studies have indicated that autophagy can be activated as a cellular protective mechanism in many tumour cells. Thus, we hypothesized that autophagy may play an important role in resistance to sorafenib in hepatocellular carcinoma. Although the exact role of autophagy in the sorafenib resistance of HCC is still complex and further studies are needed to be proven, at least it suggests that autophagy may be a new therapeutic target for the sorafenib resistance of HCC.
El cáncer de hígado es la segunda causa de muerte más frecuente por cáncer en los hombres y la sexta causa de muerte por cáncer en las mujeres. El carcinoma hepatocelular (CHC) representa el subtipo principal en el cáncer de hígado, y su tasa de supervivencia de cinco años sigue siendo muy pobre. El sorafenib, un agente terapéutico dirigido selectivamente a moléculas especificas, fue el primer medicamento aprobado para el tratamiento de pacientes con CHC. Sin embargo, la respuesta clínica de sorafenib estaba seriamente limitada por la resistencia al medicamento. La autofagia es un mecanismo evolutivamente conservado entre todos las eucariotas. Recientemente, muchos estudios han indicado que la autofagia puede activarse como mecanismo de protección celular en muchas células tumorales. Por consiguiente, postulamos la hipótesis de que la autofagia puede desempeñar un papel importante en la resistencia del carcinoma hepatocelular al sorafenib. Aunque el papel exacto de la autofagia en la resistencia al sorafenib del CHC es aún complejo y se necesitan estudios adicionales para ser probado, al menos se sugiere que la autofagia puede ser una nueva meta terapéutica frente a la resistencia del sorafenib en el CHC.
Subject(s)
Humans , Autophagy , Sorafenib/therapeutic use , Liver Neoplasms/drug therapy , Drug ResistanceABSTRACT
Hepatocellular carcinoma (HCC) is one of the most common malignant tumours and its five-year survival rate remains low. Autophagy is a catabolic process conserved among all eukaryotes ranging from yeast to mammals. Recently, many studies show that tumour cells can utilize autophagy as a cellular defence mechanism when facing metabolic stress. Thus, we hypothesize that autophagy may play an important role in the resistance of hepatocellular carcinomas to therapy. Although the exact role of autophagy on tumour cells is still complex and further studies are needed to prove the impact of autophagy on HCC, it suggests that autophagy may be a new therapeutic target for the resistance to therapy of HCC.
El carcinoma hepatocelular (CHC) es uno de los tumores malignos más comunes, y su tasa de super-vivencia a los cinco años sigue siendo baja. La autofagia es un proceso catabólico conservado en todos los eucariotas, que abarca desde las levaduras hasta los mamíferos. Recientemente, numerosos estudios han demostrado que las células tumorales pueden utilizar la autofagia como un mecanismo celular de defensa frente al estrés metabólico. De este modo, sostenemos la hipótesis de que la autofagia puede desempeñar un papel importante en la resistencia de los carcinomas hepatocelulares a la terapia. Aunque el papel exacto de la autofagia en las celulares tumorales sigue siendo complejo, y se requieren más estudios a fin de probar el impacto de la autofagia en el CHC, hay indicios de que la autofagia puede ser un nuevo objetivo terapéutico para la resistencia a la terapia del CHC.
Subject(s)
Animals , Humans , Antineoplastic Agents/pharmacology , Autophagy/drug effects , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/physiopathology , Drug Resistance, Neoplasm/drug effects , Drug Resistance, Neoplasm/physiology , Liver Neoplasms/drug therapy , Liver Neoplasms/physiopathologyABSTRACT
OBJECTIVE: The purpose of this study was to determine the mechanism of action of clusterin?known as a chemo-resistance protein?by analyzing its binding with chemotherapeutic agents and elucidating its relation with drug resistance. METHODS: Chemotherapeutic agents were diluted with coating buffer and coated onto 96 well plates. We then had these agents cross-react with purified clusterin and wash the wells to remove residual clusterin. We quantified the amount of clusterin with optical density (OD) measured by binding peroxidase-conjugated secondary antibody associated with mouse monoclonal clusterin antibody. To determine if anticancer drug-clusterin binding is related to chemotherapeutic agent resistance, we compared survival rates in the SKOV-3 cell line, which rarely secretes clusterin. We compared a group of SKOV-3 cells treated with a chemotherapeutic agent and a group treated with both the agent and clusterin, by means of XTT. RESULTS: In binding tests using ELISA OD, ratios of paclitaxel, cisplatin, carboplatin, topotecan, Adriamycin, etoposide, and 5-fluoruracil (5-FU) were 2.34, 2.40, 0.52, 2.44, 1.602, 1.14, and 1.13, respectively. Topotecan, cisplatin, and paclitaxel showed relatively higher binding. In addition, when these drugs were treated with clusterin in SKOV-3 cells, anticancer resistance increased (P<0.05). CONCLUSIONS: The anticancer drug resistance endowed by clusterin is considered to be related to its binding with chemotherapeutic agents.