scholarly journals Lovastatin Enhances Cytotoxicity of Temozolomide via Impairing Autophagic Flux in Glioblastoma Cells

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Zhiyuan Zhu ◽  
Pingde Zhang ◽  
Ning Li ◽  
Karrie Mei Yee Kiang ◽  
Stephen Yin Cheng ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Drug Resistance ◽  
Tumor Recurrence ◽  
Autophagic Flux ◽  
Mtor Signaling Pathway ◽  
Anticancer Effect ◽  
Western Blot Assay ◽  
Promising Strategy ◽  
Cellular Apoptosis ◽  
Chemotherapy Efficacy

Drug resistance to temozolomide (TMZ) contributes to the majority of tumor recurrence and treatment failure in patients with glioblastoma multiforme (GBM). Autophagy has been reported to play a role in chemoresistance in various types of cancer, including GBM. The anticancer effect of statins is arousing great research interests and has been demonstrated to modulate autophagic function. In this study, we investigated the combinational effects of lovastatin and TMZ on treating U87 and U251 GBM cell lines. Cytotoxicity was measured by MTT and colony formation assays; apoptosis was measured by flow cytometry; the cellular autophagic function was detected by the EGFP-mRFP-LC3 reporter and western blot assay. The results showed that lovastatin might enhance the cytotoxicity of TMZ, increase the TMZ-induced cellular apoptosis, and impair the autophagic flux in GBM cells. Lovastatin triggered autophagy initiation possibly by inhibiting the Akt/mTOR signaling pathway. Moreover, lovastatin might impair the autophagosome-lysosome fusion machinery by suppressing LAMP2 and dynein. These results suggested that lovastatin could enhance the chemotherapy efficacy of TMZ in treating GBM cells. The mechanism may be associated with impaired autophagic flux and thereby the enhancement of cellular apoptosis. Combining TMZ with lovastatin could be a promising strategy for GBM treatment.

scholarly journals HMGB1 Promotes Resistance to Doxorubicin in Human Hepatocellular Carcinoma Cells by Inducing Autophagy via the AMPK/mTOR Signaling Pathway

2021 ◽  
Vol 11 ◽  
Author(s):  
Junhua Li ◽  
Wei Zhou ◽  
Qiang Mao ◽  
Dandan Gao ◽  
Lin Xiong ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Drug Resistance ◽  
Signaling Pathway ◽  
High Mobility ◽  
Adenosine Monophosphate ◽  
Mtor Signaling ◽  
Autophagic Flux ◽  
Mtor Signaling Pathway ◽  
Acquired Drug Resistance ◽  
Hmgb1 Expression

Chemoresistance remains as a major hindrance in the treatment of hepatocellular carcinoma (HCC). High mobility group box protein 1 (HMGB1) enhances autophagic flux and protects tumor cells from apoptosis, which results in acquired drug resistance. However, the exact mechanisms underlying HMGB1-modulated autophagy in HCC chemoresistance remain to be defined. In the present study, we found that administration of doxorubicin (DOX) significantly promoted HMGB1 expression and induced HMGB1 cytoplasmic translocation in human HCC cell lines BEL7402 and SMMC7721, which enhanced autophagy that contributes to protecting HCC cells from apoptosis and increasing drug resistance. Moreover, we observed HMGB1 translocation and elevation of autophagy in DOX-resistant BEL7402 and SMMC7721 cells. Additionally, inhibition of HMGB1 and autophagy increased the sensitivities of BEL-7402 and SMMC-7721 cells to DOX and re-sensitized their DOX-resistant cells. Subsequently, we confirmed with HMGB1 regulated autophagy by activating the 5ʹ adenosine monophosphate-activated protein kinase (AMPK)/mTOR pathway. In summary, our results indicate that HMGB1 promotes acquired DOX resistance in DOX-treated BEL7402 and SMMC7721 cells by enhancing autophagy through the AMPK/mTOR signaling pathway. These findings provide the proof-of-concept that HMGB1 inhibitors might be an important targeted treatment strategy for HCC.

scholarly journals Suppression of steroid 5α-reductase type I promotes cellular apoptosis and autophagy via PI3K/Akt/mTOR pathway in multiple myeloma

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Renjie Dou ◽  
Jinjun Qian ◽  
Wei Wu ◽  
Yanxin Zhang ◽  
Yuxia Yuan ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Type I ◽  
Disease Course ◽  
Mtor Signaling Pathway ◽  
Hairpin Rna ◽  
Aberrant Expression ◽  
Transcriptomic Sequencing ◽  
Family Protein ◽  
Cellular Apoptosis ◽  
Autophagic Process

AbstractSteroid 5α-reductase type I (SRD5A1) is a validated oncogene in many sex hormone-related cancers, but its role in multiple myeloma (MM) remains unknown. Based on gene expression profiling (GEP) of sequential MM samples during the disease course, we found that the aberrant expression of SRD5A1 was correlated with progression and poor prognosis in MM patients. In this study, the oncogenic roles of SRD5A1 were validated in human MM cell lines (ARP1 and H929) and the xenograft MM model as well as the 5TMM mouse model. MTT and flow cytometry were used to assess MM cell proliferation, cell cycle, and apoptosis post inducible knockdown SRD5A1 by lentivirus-mediated short-hairpin RNA (shRNA). Transcriptomic sequencing, immunofluorescence, and western blot were used to investigate the effects of SRD5A1 suppression on cell apoptosis and autophagy. Mechanistically, SRD5A1 downregulation simultaneously regulated both the Bcl-2 family protein-mediated apoptosis and the autophagic process via PI3K/Akt/mTOR signaling pathway in MM cells. Meanwhile, the autophagy inhibitor (3-methyladenine) and SRD5A1 inhibitor (Dutasteride) were utilized to evaluate their anti-myeloma effect. Thus, our results demonstrated that SRD5A1 downregulation simultaneously regulated both the apoptosis and the autophagic process in MM cells. The dual autophagy–apoptosis regulatory SRD5A1 may serve as a biomarker and potential target for MM progression and prognosis.

Effect of ADM on Proliferation and Apoptosis of Human Gastric Cancer Cell SGC-7901

2012 ◽  
Vol 535-537 ◽  
pp. 2434-2437
Author(s):  
Shu Li Shao ◽  
Wei Wei Chen ◽  
Wei Wei Zhang ◽  
Wei Zhao ◽  
Feng Ying Li
Keyword(s):  
Flow Cytometry ◽  
Human Gastric Cancer ◽  
Agarose Gel ◽  
Dna Ladder ◽  
Cell Cycles ◽  
Proliferation And Apoptosis ◽  
Ic50 Values ◽  
Cellular Apoptosis ◽  
Blue Stain ◽  
Morphologic Changes

To observe the effect of ADM on cells apoptosis of SGC-7901 cells. The SGC-7901 cells were treated by ADM. And the inhibitory ratio of cells was measured by trypan blue stain assay, the IC50 value was calculated. Cells apoptosis were detected by DNA agarose gel electrophoresis.The cell cycles were analyzed by flow cytometry system after treatment with ADM. Morphologic changes were observed using phase-contrast microscopy . The SGC-7901 cells proliferation were remarkably inhibited by ADM. The IC50 values were 5.7 μg / mL. The typical DNA ladder on agarose gel electrophoresis for analysis of cellular apoptosis were significantly appeared. ADM could restrain the SGC-7901 cells proliferation, and to cause the morphologic changes of apoptosis. Apoptosis peaks appeared with flow cytometry analysis.

scholarly journals (Pro)renin receptor regulates autophagy and apoptosis in podocytes exposed to high glucose

2015 ◽  
Vol 309 (3) ◽  
pp. E302-E310 ◽  
Author(s):  
Caixia Li ◽  
Helmy M. Siragy
Keyword(s):  
Signaling Pathway ◽  
High Glucose ◽  
Caspase 3 ◽  
Mtor Signaling ◽  
Autophagic Flux ◽  
Bafilomycin A1 ◽  
Mtor Signaling Pathway ◽  
Autophagosome Formation ◽  
Podocyte Injury ◽  
Protein Levels

High glucose reduces autophagy and enhances apoptosis of podocytes. Previously, we reported that high glucose induced podocyte injury through upregulation of the (pro)renin receptor (PRR). We hypothesized that increasing PRR reduces autophagy and increases apoptosis of mouse podocytes exposed to high glucose via activation of the PI3K/Akt/mTOR signaling pathway. Mouse podocytes were cultured in normal (5 mmol/l) or high (25 mmol/l) d-glucose for 48 h. High glucose significantly increased mRNA and protein levels of PRR, phosphorylation of PI3K/Akt/mTOR, and p62. In contrast, high glucose decreased activation of UNC-51-like kinase-1 (ULK1) by phosphorylating Ser757 and protein levels of microtubule-associated protein-1 light chain 3B (LC3B)-II and Lamp-2. Bafilomycin A1 increased LC3BII and p62 accumulation in high-glucose-treated cells. High glucose reduced the autophagic flux. Confocal microscopy studies showed significant reduction in the protein level of LC3B in response to high glucose. Cyto-ID autophagy staining showed a significant decrease in autophagosome formation with high glucose. In the absence of PRR, activation of Akt with sc-79 or mTOR with MHY-1485 increased p62 accumulation. Caspase-3/7 activity and apoptosis monitored by TUNEL assay were significantly increased in podocytes treated with high glucose. PRR siRNA significantly reversed the effects of high glucose. Based on these data, we conclude that high glucose decreases autophagy and increases apoptosis in mouse podocytes through the PRR/PI3K/Akt/mTOR signaling pathway.

scholarly journals Nuclear-Targeted TAT-PZLL-D3 Co-Delivery DOX and p53 for Chemotherapy Resistance of SCLC

2021 ◽  
Author(s):  
Dan Wang ◽  
Tianshou Cao ◽  
Wanyu Li ◽  
Li Li ◽  
Qunfa Huang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Tumor Recurrence ◽  
High Efficiency ◽  
Chemotherapy Resistance ◽  
A549 Cells ◽  
Delivery Vector ◽  
Transactivator Of Transcription ◽  
Almost All

Abstract Small cell lung cancer (SCLC) accounts for 13% ~ 15% of lung cancer. It is a subtype with high malignancy and poor prognosis. Almost all patients with SCLC will inevitably have drug resistance and tumor recurrence, which has become an urgent problem in the treatment of SCLC. Nuclear-targeted drug delivery system, which enables intra-nuclear release of anticancer drugs, is expected to address this challenge. In this study, based on transactivator of transcription (TAT)’s active transport property to the nucleus, we developed a high-efficiency nucleus-targeted co-delivery vector that delivers genes and drugs directly into the nucleus of A549 cells. The system is based on a poly-(N-ε-carbobenzyloxy-L-lysine) (PZLL) and dendritic polyamidoamine (PAMAM) block copolymer (PZLL-D3) with TAT modified on the surface of carrier. In vitro studies showed that DOX and p53 could can be effectively transported to the nucleus and kill the cancer cells. Thus, such deliver system would bypass the drug resistance and tumor recurrence problem.

Celastrol Inhibits the Proliferation and Decreases Drug Resistance of Cisplatin-Resistant Gastric Cancer SGC7901/DDP Cells

2021 ◽  
Vol 21 ◽  
Author(s):  
Dongmei Zhan ◽  
Tengyang Ni ◽  
Haibo Wang ◽  
Mengying Lv ◽  
Masataka Sunagawa ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Drug Resistance ◽  
Signaling Pathway ◽  
Resistance Index ◽  
Mtor Signaling ◽  
Control Group ◽  
Human Gastric Cancer ◽  
Cancer Resistance ◽  
Mtor Signaling Pathway ◽  
Expression Levels

Background: This study aimed to determine the effect and mechanism of Celastrol inhibiting the proliferation and decreases drug resistance of cisplatin-resistant gastric cancer cells. Objective: To explore the effect and mechanism of Celastrol on proliferation and drug resistance of human gastric cancer cisplatin-resistant cells SGC7901/DDP. Methods: The thiazole blue (MTT) method was used to detect the sensitivity of human gastric cancer cisplatin-resistant cells SGC7901/DPP to cisplatin and Celastrol to determine the Drug resistance index (DRI). According to the half inhibitory concentration (IC50) value, the action concentration of the following experimental drugs was set to reduce the cytotoxicity; Annexin V-FITC/PI double staining method was used to detect the apoptosis of SGC7901/DDP cells induced by Celastrol; Western Blot was used to examine the expression levels of P-glycoprotein (P-gp), Multidrug Resistance Associated Protein 1 (MRP1), Breast Cancer Resistance Associated Protein (Breast Cancer Resistance)-relative protein (BCRP), and mechanistic Target of Rapamycin (mTOR) pathway related proteins; Real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) was used to detect the mRNA expression levels of P-gp, MRP1, and BCRP. Results: (1) Compared with the control group (We set the untreated group as the control group), the proliferation of the SGC7901/DPP cells was significantly inhibited after treating with 0.1-6.4μmol/L Celastrol in a time- and concentration-dependent manner (P<0.05). The Drug resistance index DRI of the SGC7901/DPP cells to DDP was 5.64. (2) Compared with the control group, Celastrol could significantly inhibit the proliferation and induce the apoptosis of the SGC7901/DPP cells (P<0.05). (3) The mRNA and protein expression levels of P-gp, MRP1, and BCRP in the SGC7901/DPP cells were significantly higher than those in the SGC7901 cells. However, after treating with Celastrol, the expression levels of P-gp, MRP1, and BCRP in the SGC7901/DPP cells were significantly reduced (P<0.05). (4) Compared with the control group, the Celastrol treatment also reduced the expression of the mTOR signaling pathway related proteins, suggesting that the mTOR signaling pathway may be involved in the process of Celastrol inhibiting the proliferation of the SGC7901/DDP cells and reducing their drug resistance. (5) Significantly, the combination of Celastrol and DDP reduced the expression of P-gp, MRP1, and BCRP in the SGC7901/DPP cells. Conclusion: Celastrol can inhibit the proliferation of the SGC7901/DDP cells, induce their apoptosis, and reduce the expression of drug resistance genes, probably by inhibiting the expression of the proteins related to the mTOR signaling pathway.

Overexpression of TEL-MN1 Fusion Enhances Resistance of HL-60 Cells to Idarubicin

Chemotherapy ◽  
2018 ◽  
Vol 63 (6) ◽  
pp. 308-314 ◽  
Author(s):  
Shenglan Gong ◽  
Mengqiao Guo ◽  
Gusheng Tang ◽  
Jianmin Yang ◽  
Huiying Qiu
Keyword(s):  
Flow Cytometry ◽  
Drug Resistance ◽  
Cell Viability ◽  
Cell Apoptosis ◽  
Chromosome Abnormality ◽  
Chemotherapy Resistance ◽  
Retroviral Vector ◽  
Promote Cell Proliferation ◽  
Enhanced Resistance

Background: The translocation t(12; 22) (p13;q12) is a recurrent but infrequent chromosome abnormality in human myeloid malignancies. To date, the role of TEL-MN1 fusion in leukemogenic process and drug resistance is still largely unknown. Methods: In the present study, the TEL-MN1 fusion was transfected into HL-60 cells to upregulate TEL-MN1 expression via a retroviral vector. MTT assay was employed to examine cell viability and flow cytometry was performed to evaluate cell apoptosis. Idarubicin was used to treat HL-60 cells for estimating the effect of TEL-MN1 fusion on the chemotherapy resistance. Results: The results showed that overexpression of TEL-MN1 in HL-60 cells could promote cell proliferation, suggesting that TEL-MN1 may be involved in the leukemogenesis process. HL-60 cells treated with idarubicin showed a weakened cell viability, whereas TEL-MN1 overexpression attenuated the idarubicin-induced inhibition of cell viability and acceleration of cell apoptosis of HL-60 cells. Conclusion: Taken together, our results indicated that TEL-MN1 fusion is an oncogene involved in the leukemogenesis process and TEL-MN1 overexpression enhanced resistance of HL-60 cells to idarubicin, which may provide a useful tool for studying the mechanism of leukemogenesis and drug resistance.

Growth Inhibition of Nasopharyngeal Carcinoma Cells Mediated by p53 Gene-Containing Nanolipid Composites

2020 ◽  
Vol 20 (10) ◽  
pp. 6026-6032
Author(s):  
Yongshan Cheng ◽  
Shanying Wu ◽  
Xinting Tie ◽  
Xiaodong Huang ◽  
Lihua Cui
Keyword(s):  
Cell Cycle ◽  
Flow Cytometry ◽  
Nasopharyngeal Carcinoma ◽  
Growth Inhibition ◽  
Transfection Efficiency ◽  
P53 Gene ◽  
Theoretical Support ◽  
Novel Drugs ◽  
Cellular Apoptosis

To study the growth inhibition and cell cycle changes in nasopharyngeal carcinoma (CNE1) cells after transfection with p53 gene. A mixture of nano-liposomes and plasmid containing p53 was used for transfecting CNE1 cells. Cellular apoptosis was examined after transfection using the CCK-8 reagent method with flow cytometry. The results showed that a ratio of nanoliposome/p-ORF-GFP of 3.5:1 showed the highest transfection efficiency in CNE1 cells. The cells transfected with a mixture of composites in this proportion showed significant apoptosis of up to 50–70%. In addition, we observed that cell cycle changes-measured using flow cytometry-as well as cellular apoptosis were accelerated after administration of composites. The CCK-8 kit was used to determine the viability of nano-liposome-encapsulated p53 transfected cells. In vitro experiments showed that the combination significantly inhibited the growth of CNE1 cells with an inhibition rate of approximately 63.8%. Therefore, the nanocomposites have a significant effect on inhibiting the growth of CNE1 cells. Through the investigation of apoptosis and cell cycle changes in CNE1 cells we found that the nanoliposome-encapsulated p53 gene can inhibit growth in these cells, and might therefore serve as a novel treatment strategy for adjuvant treatment of nasopharyngeal carcinoma and ca also reduce incompatibility issues with radiotherapy and chemotherapy. This method can also provide technical and theoretical support for the development of novel drugs.

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