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1.
Article in Chinese | WPRIM | ID: wpr-936281

ABSTRACT

OBJECTIVE@#To construct a polylactic acid-glycolic acid-polyethylene glycol (PLGA-PEG) nanocarrier (N-Pac-CD133) coupled with a CD133 nucleic acid aptamer carrying paclitaxel for eliminating lung cancer stem cells (CSCs).@*METHODS@#Paclitaxel-loaded N-Pac-CD133 was prepared using the emulsion/solvent evaporation method and characterized. CD133+ lung CSCs were separated by magnetic bead separation and identified for their biological behaviors and gene expression profile. The efficiency of paclitaxel-loaded N-Pac-CD133 for targeted killing of lung cancer cells was assessed in vitro. SCID mice were inoculated with A549 cells and received injections of normal saline, empty nanocarrier linked with CD133 aptamer (N-CD133), paclitaxel, paclitaxel-loaded nanocarrier (N-Pac) or paclitaxel-loaded N-Pac-CD133 (n=8, 5 mg/kg paclitaxel) on days 10, 15 and 20, and the tumor weight and body weight of the mice were measured on day 40.@*RESULTS@#Paclitaxel-loaded N-Pac-CD133 showed a particle size of about 100 nm with a high encapsulation efficiency (>80%) and drug loading rate (>8%), and was capable of sustained drug release within 48 h. The CD133+ cell population in lung cancer cells showed the characteristic features of lung CSCs, including faster growth rate (30 days, P=0.001) and high expressions of tumor stem cell markers OV6(P < 0.001), CD133 (P=0.001), OCT3/4 (P=0.002), EpCAM (P=0.04), NANOG (P=0.005) and CD44 (P=0.02). Compared with N-Pac and free paclitaxel, paclitaxel-loaded N-Pac-CD133 showed significantly enhanced targeting ability and cytotoxicity against lung CSCs in vitro (P < 0.001) and significantly reduced the formation of tumor spheres (P < 0.001). In the tumor-bearing mice, paclitaxel-loaded N-Pac-CD133 showed the strongest effects in reducing the tumor mass among all the treatments (P < 0.001).@*CONCLUSION@#CD133 aptamer can promote targeted delivery of paclitaxel to allow targeted killing of CD133+ lung CSCs. N-Pac-CD133 loaded with paclitaxel may provide an effective treatment for lung cancer by targeting the lung cancer stem cells.


Subject(s)
Animals , Cell Line, Tumor , Drug Carriers , Lung , Mice , Mice, SCID , Nanoparticles , Neoplasms , Neoplastic Stem Cells , Paclitaxel/pharmacology , Polyethylene Glycols/pharmacology
2.
Article in Chinese | WPRIM | ID: wpr-927899

ABSTRACT

Objective: To investigate the effect of Xuanfu Daizhe decoction on the stemness of esophageal cancer cells. Methods: The BALB/c nude mice were randomly divided into the control group and experimental group, 5 mice in each group, which were continuously administered with normal saline and Xuanfu Daizhe decoction (9.89 g/kg) by gastrogavage, respectively. Human esophageal carcinoma cells ECA-109 (5×106) were subcutaneously injected into the mice on the 8th day. Tumor volume was measured twice a week. The mice were sacrificed 4 weeks after injection, and the tumor tissue and mouse serum were collected. The expressions of the major stemness-regulating transcription factors, i.e., NANOG, OCT4 and SOX2, were detected by RT-qPCR, Western Blot and immunohistochemistry. ECA-109 cells were treated with 10% fetal bovine serum and serum from the above two groups of mice for 48 hours respectively, and three replicate wells were set in each group, and the expressions of NANOG, OCT4, SOX2 and the levels of AKT and p-AKT were detected by RT-qPCR and Western Blot, respectively. ALDH activity in tumor cells was detected by flow cytometry; the number of spheroids of tumor cells was detected by the spheroidization experiment. Results: Compared with the control group, the growth and size of esophageal cancer tumors were significantly inhibited by Xuanfu Daizhe Decoction; the expressions of NANOG, OCT4, SOX2, the ALDH activity, the number of spheroids, and the levels of AKT and phosphorylated AKT (p-AKT) in esophageal cancer cells were significantly reduced by Xuanfu Daizhe Decoction both in vivo and in vitro. Conclusion: Xuanfu Daizhe Decoction inhibits the stemness of esophageal cancer cells, it may be a potentially effective drug for the treatment of esophageal cancer and provides a theoretical basis for the exploration of new effective drugs for the treatment of esophageal cancer.


Subject(s)
Animals , Esophageal Neoplasms/pathology , Mice , Mice, Nude , Proto-Oncogene Proteins c-akt , Transcription Factors
3.
Braz. J. Pharm. Sci. (Online) ; 58: e18754, 2022. tab, graf
Article in English | LILACS-Express | LILACS | ID: biblio-1374529

ABSTRACT

Abstract Hypoxia-inducible factors (HIFs) and cancer stem cells (CSCs) are two challenging causes of radiotherapy and chemotherapy resistance, leading to most cases of failure and recurrence in breast cancer therapy. This study was conducted to investigated the inhibitory effect of combination therapy with doxorubicin (an anthracycline) and FM19G11 (an HIF inhibitor) on MCF-7 cells and their CSC-like cells (CSC-LCs). MCF-7 CSC-LCs with a CD44+/CD24- phenotype were sorted and characterized by flow cytometry. A combination of doxorubicin and FM19G11 caused more cytotoxic effects on MCF-7 and CSC-LCs compared to doxorubicin monotherapy. The largest synergistic effect was observed in CSC-LCs under hypoxic conditions; however, MCF-7 cells showed no synergism in normoxic conditions. The administration of doxorubicin and FM19G11 induced late apoptotic and necrotic cell death in MCF-7 and CSC-LCs. Additionally, G2 phase arrest was observed in both cells. Our results demonstrated that co-administration of FM19G11 and doxorubicin had a synergistic effect in hypoxia and improved drug resistance in breast cancer stem cells.

4.
Acta Pharmaceutica Sinica B ; (6): 609-620, 2021.
Article in English | WPRIM | ID: wpr-881159

ABSTRACT

The Hedgehog (HH) signaling pathway plays important roles in gastrointestinal carcinogenesis and the gastrointestinal tumor microenvironment (TME). Aberrant HH signaling activation may accelerate the growth of gastrointestinal tumors and lead to tumor immune tolerance and drug resistance. The interaction between HH signaling and the TME is intimately involved in these processes, for example, tumor growth, tumor immune tolerance, inflammation, and drug resistance. Evidence indicates that inflammatory factors in the TME, such as interleukin 6 (IL-6) and interferon-

5.
Acta Pharmaceutica Sinica B ; (6): 55-70, 2021.
Article in English | WPRIM | ID: wpr-881124

ABSTRACT

Cancer stem cells (CSCs) are a subpopulation of cancer cells with functions similar to those of normal stem cells. Although few in number, they are capable of self-renewal, unlimited proliferation, and multi-directional differentiation potential. In addition, CSCs have the ability to escape immune surveillance. Thus, they play an important role in the occurrence and development of tumors, and they are closely related to tumor invasion, metastasis, drug resistance, and recurrence after treatment. Therefore, specific targeting of CSCs may improve the efficiency of cancer therapy. A series of corresponding promising therapeutic strategies based on CSC targeting, such as the targeting of CSC niche, CSC signaling pathways, and CSC mitochondria, are currently under development. Given the rapid progression in this field and nanotechnology, drug delivery systems (DDSs) for CSC targeting are increasingly being developed. In this review, we summarize the advances in CSC-targeted DDSs. Furthermore, we highlight the latest developmental trends through the main line of CSC occurrence and development process; some considerations about the rationale, advantages, and limitations of different DDSs for CSC-targeted therapies were discussed.

6.
Frontiers of Medicine ; (4): 178-207, 2021.
Article in English | WPRIM | ID: wpr-880961

ABSTRACT

Breast cancer is one of the most common malignancies that seriously threaten women's health. In the process of the malignant transformation of breast cancer, metabolic reprogramming and immune evasion represent the two main fascinating characteristics of cancer and facilitate cancer cell proliferation. Breast cancer cells generate energy through increased glucose metabolism. Lipid metabolism contributes to biological signal pathways and forms cell membranes except energy generation. Amino acids act as basic protein units and metabolic regulators in supporting cell growth. For tumor-associated immunity, poor immunogenicity and heightened immunosuppression cause breast cancer cells to evade the host's immune system. For the past few years, the complex mechanisms of metabolic reprogramming and immune evasion are deeply investigated, and the genes involved in these processes are used as clinical therapeutic targets for breast cancer. Here, we review the recent findings related to abnormal metabolism and immune characteristics, regulatory mechanisms, their links, and relevant therapeutic strategies.


Subject(s)
Breast Neoplasms , Cell Proliferation , Cell Transformation, Neoplastic , Energy Metabolism , Female , Humans , Lipid Metabolism , Signal Transduction
7.
Protein & Cell ; (12): 440-454, 2021.
Article in English | WPRIM | ID: wpr-880929

ABSTRACT

Dedifferentiation of cell identity to a progenitor-like or stem cell-like state with increased cellular plasticity is frequently observed in cancer formation. During this process, a subpopulation of cells in tumours acquires a stem cell-like state partially resembling to naturally occurring pluripotent stem cells that are temporarily present during early embryogenesis. Such characteristics allow these cancer stem cells (CSCs) to give rise to the whole tumour with its entire cellular heterogeneity and thereby support metastases formation while being resistant to current cancer therapeutics. Cancer development and progression are demarcated by transcriptional dysregulation. In this article, we explore the epigenetic mechanisms shaping gene expression during tumorigenesis and cancer stem cell formation, with an emphasis on 3D chromatin architecture. Comparing the pluripotent stem cell state and epigenetic reprogramming to dedifferentiation in cellular transformation provides intriguing insight to chromatin dynamics. We suggest that the 3D chromatin architecture could be used as a target for re-sensitizing cancer stem cells to therapeutics.

8.
Article in Chinese | WPRIM | ID: wpr-906441

ABSTRACT

Objective:To elucidate the potential molecular markers and drug-compound-target mechanism of Epimedii Folium intervention on breast cancer stem cells(BCSCs) through chip analysis combined with network pharmacology and experimental validation. Method:Relevant drug information was retrieved in Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) to obtain the active components and potential targets of Epimedii Folium. "Breast Cancer Stem Cells" were searched in Gene Expression Omnibus(GEO)database,and GSE98239 chip data were obtained through analysis and screening. Then GEO2R online analysis tool was used to obtain the differential genes to draw differential gene heat map and volcano map. The differential gene network map of Epimedii Folium intervention for breast cancer stem cells was constructed by Cytoscape 3.8.0,and Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis of drug and disease genes were performed. Human breast cancer MDA-MB-231 cells were divided into 20%,40%,60% Epimedii Folium drug-containing serum group and control group. Cell counting kit-8(CCK-8),and Western blot were used to detect the effect of Epimedii Folium drug-containing serum intervention on cell activity and target protein expression in breast cancer cells. Result:Twenty-three active components including flavones,sterols,alkaloids and sesquiterpenoids were obtained from Epimedii Folium. It was found that Epimedii Folium interacted with B-cell lymphoma-2-like protein 1(BCL2L1),matrix metallopeptidase 2(MMP2),prostaglandin-endoperoxide synthase 2(PTGS2),vascular endothelial growth factor A(VEGFA),transforming growth factor beta receptor 1(TGFBR1) and other pivotal genes in breast cancer stem cells,participated in the induction of new angiogenesis and cell migration,enabled the continuous self-renewal of BCSCs,decreased apoptosis and cell migration,thus promoting the recurrence and metastasis of breast cancer. KEGG results showed that Epimedii Folium intervened in multiple differential expressed genes(DEGs)of transforming growth factor-<italic>β</italic>(TGF-<italic>β</italic>),vascular endothelial growth factor(VEGF),phosphoinositide 3kinase/protein kenase B(PI3K/Akt),mitogen-activated protein kinese(MAPK)and mammalian target of rapamycin(mTOR)subpathways in cancer signaling pathways to exert its efficacy in intervening breast cancer stem cells. Experiments showed that the survival rate of breast cancer cells was significantly reduced and the expression levels of TGFBR1 and Smad2 in breast cancer cells significantly decreased after the intervention of Epimedii Folium drug-containing serum(<italic>P</italic><0.01). Conclusion:Several components in different concentrations of drug-containing serum of Epimedii Folium can synergistically act on target differentially expressed genes of breast cancer stem cells,and inhibit the proliferation of breast cancer cells by down-regulating the expression levels of TGFBR1,a key molecule in the TGF-<italic>β</italic> pathway,and Smad2,a downstream signal.

9.
Article in Chinese | WPRIM | ID: wpr-906083

ABSTRACT

Objective:To explore the effect of Shugan Yishen prescription(SGYS) on the tamoxifen (TAM) -resistant cell line LCC9 by the intervention of exosome-mediated crosstalk in the breast cancer microenvironment. Method:Four groups of serum were set up, specifically, a blank group, a TAM (2 mg·kg<sup>-1</sup>·d<sup>-1</sup>) group,an SGYS(113.2 g·kg<sup>-1</sup>·d<sup>-1</sup>) group,and a combination group. The exosomes of LCC9 cells were extracted by ultracentrifugation and identified by transmission electron microscopy (TEM),nanoparticle tracking analysis (NTA), and Western blot. Then the collected LCC9 exosomes (LCC9-EXO) were co-cultured with bone marrow mesenchymal stem cells(BMMSCs),and 10% of the above four groups of serum were added to the co-culture system. After 48 hours of co-culture,the exosomes of BMMSCs (BMMSCs-EXO) were extracted and incubated with LCC9 cells. Fluorescence microscope was used to observe the uptake of exosomes by cells. Cell counting kit-8 (CCK-8) assay,flow cytometry, and Transwell assay were used to detect the effects of drug-containing serum in the four groups on the proliferation,apoptosis, and migration of LCC9 cells. Western blot was used to detect the protein expression of CD24,CD44,human epidermal growth factor 2(HER2), and estrogen receptor <italic>α</italic> (ER<italic>α</italic>) in each group. Result:Fluorescence microscope observed that LCC9-EXO could be taken up by BMMSCs,and BMMSCs-EXO could be taken up by LCC9 cells. CCK-8 assay revealed that compared with the TAM group,the SGYS group and the combination group showed reduced cell proliferation ability at each period (<italic>P</italic><0.05),especially the combination group,but no statistically significant difference between the SGYS group and the combination group was observed (<italic>P</italic><0.05). Flow cytometry revealed that compared with the TAM group,the SGYS group and the combination group showed increased levels of apoptosis (<italic>P</italic><0.05). Transwell assay revealed that compared with the TAM group,the SGYS group and the combination group showed decreased cell migration ability (<italic>P</italic><0.05). Western blot revealed that compared with the TAM group,the SGYS group and the combination group showed up-regulated expression of ERα and CD24(<italic>P</italic><0.05),and down-regulated expression of HER2 and CD44 (<italic>P</italic><0.05). The effect of the combination group on protein expression was superior to that of the SGYS group (<italic>P</italic><0.05). Conclusion:SGYS reverses the TAM resistance of LCC9 cells by interfering with the crosstalk between BMMSCs-EXO and LCC9-EXO.

10.
Acta Pharmaceutica Sinica B ; (6): 1400-1411, 2021.
Article in English | WPRIM | ID: wpr-888811

ABSTRACT

A major mitochondrial enzyme for protecting cells from acetaldehyde toxicity is aldehyde dehydrogenase 2 (ALDH2). The correlation between ALDH2 dysfunction and tumorigenesis/growth/metastasis has been widely reported. Either low or high ALDH2 expression contributes to tumor progression and varies among different tumor types. Furthermore, the ALDH2∗2 polymorphism (rs671) is the most common single nucleotide polymorphism (SNP) in Asia. Epidemiological studies associate ALDH2∗2 with tumorigenesis and progression. This study summarizes the essential functions and potential ALDH2 mechanisms in the occurrence, progression, and treatment of tumors in various types of cancer. Our study indicates that ALDH2 is a potential therapeutic target for cancer therapy.

11.
Chinese Journal of Lung Cancer ; (12): 538-547, 2021.
Article in Chinese | WPRIM | ID: wpr-888594

ABSTRACT

BACKGROUND@#Lung cancer is the malignant tumor with the highest incidence and mortality in China, among which non-small cell lung cancer (NSCLC) accounts for about 80%. Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) targeted therapy has been playing an important role in treatment of NSCLC. However, unavoidable therapeutic resistance significantly limits the clinical efficacy of EGFR-TKI. As a key member of the forkhead box protein family, FOXC1 is aberrantly expressed in NSCLC and involved in NSCLC progression. The aim of this work is to investigate the effect and potential mechanism of FOXC1 on gefitinib resistance in NSCLC.@*METHODS@#Western blot was performed to assess the expression of FOXC1 protein in HCC827/GR cells. Immunohistochemistry (IHC) assays were performed in human NSCLC tissues with gefitinib resistance. HCC827/GR cells were transfected with shRNA specifically targeting FOXC1 mRNA and stable cell lines were established. The effects of FOXC1 on cell viability and apoptosis were analyzed using a new methyl thiazolyl tetrazolium assay (MTS assay) and flow cytometry. Self-renewal ability was determined by mammosphere-formation analysis. Quantitative real-time PCR (qRT-PCR) and Western blot were employed to detect the expression of SOX2, Nanog, OCT4 and CD133. Flow cytometry analysis were further used to detect the level of CD133. IHC assays were used to detect the levels of SOX2 and CD133 in NSCLC tissues with genfitiinb resistance. Correlations of the expressions of FOXC1, CD133 and SOX2 with each other in lung adenocarcinoma samples were analyzed based on The Cancer Genome Atlas (TCGA) database.@*RESULTS@#The expression of FOXC1 is significantly increased in HCC827/GR cells compared with HCC827 cells (P<0.05). IHC results showed FOXC1 was highly expressed in NSCLC tissues with gefitinib resisitance. Knockdown of FOXC1 significantly increased the sensitivity of HCC827/GR cells to gefitinib. The cell viability was decreased and the apoptosis was promoted (P<0.05). Moreover, FOXC1 knockdown apparently inhibited the expression of SOX2 and CD133, and decreased the mammosphere-formation capacity in HCC827/GR cells. In NSCLC tissues with gefitinib resistance, the expressions of SOX2 and CD133 were significantly higher compared with gefitinib-sensitive tissues (P<0.01). Meanwhile, the expressions of FOXC1, CD133 and SOX2 with each other were positively correlated (P<0.05).@*CONCLUSIONS@#FOXC1 could increase gefitinib resitance in NSCLC, by which mechanism is related to the regulation of cancer stem cell properties.

12.
Chinese Journal of Biotechnology ; (12): 2719-2736, 2021.
Article in Chinese | WPRIM | ID: wpr-887836

ABSTRACT

Primary liver cancer (PLC) is an aggressive tumor and prone to metastasize and recur. According to pathological features, PLC are mainly categorized into hepatocellular carcinoma, intrahepatic cholangiocarcinoma, mixed hepatocellular cholangiocarcinoma, and fibrolamelic hepatocellular carcinoma, etc. At present, surgical resection, radiotherapy and chemotherapy are still the main treatments for PLC, but the specificities are poor and the clinical effects are limited with a 5-year overall survival rate of 18%. Liver cancer stem cells (LCSCs) are a specific cell subset existing in liver cancer tissues. They harbor the capabilities of self-renewal and strong tumorigenicity, driving tumor initiation, metastasis, drug resistance and recurrence of PLC. Therefore, the identification of molecular markers and the illustration of mechanisms for stemness maintenance of LCSCs can not only reveal the molecular mechanisms of PLC tumorigenesis, but also lay a theoretical foundation for the molecular classification, prognosis evaluation and targeted therapy of PLC. The latest research showed that the combination of 5-fluorouracil and CD13 inhibitors could inhibit the proliferation of CD13+ LCSCs, thereby reducing overall tumor burden. Taken together, LCSCs could be the promising therapeutic targets of PLC in the future. This review summarizes the latest progress in molecular markers, mechanisms for stemness maintenance and targeted therapies of LCSCs.


Subject(s)
Carcinoma, Hepatocellular/genetics , Humans , Liver Neoplasms/genetics , Neoplastic Stem Cells , Prognosis
13.
J Biosci ; 2020 Sep; : 1-9
Article | IMSEAR | ID: sea-214234

ABSTRACT

Cancer stem cells (CSCs) from colorectal cancer (CRC), characterized by CD133 expression, have beenassociated with 5-fluorouracile (5-FU) chemoresistance. DNA repair mechanisms, such as O6-alkylguanineDNA alkyltransferase (MGMT) and mismatch repair (MMR) systems, have also been correlated to 5-FUresistance in CRC. The aim of this study was to evaluate the modulation of CD133 and MGMT in MMRproficient and MMR-deficient CRC cells under 5-FU treatment and the effect of this drug in CSCs. CD133 andMGMT methylation status were determined in MMR-proficient (SW480 and HT29) and MMR-deficient (RKOand HCT116) cell lines by methylation-specific PCRs. SW480 and RKO were selected to determine modulation of CD133, MGMT and MMR expression after 5-FU treatment by qPCR. In addition, CD133, MGMTand MMR were analyze in SW480 and RKO CSCs. No association between promoter methylation and MGMTand CD133 expression was found. 5-FU treatment increased CD133 expression independently to MMR statusin SW480 and RKO and was able to increase hMLH1 expression in RKO, a MMR-deficient cell line. RKO/CSCs overexpressed CD133 and MMR (hMSH2 and hMSH6) while SW480/CSCs showed a significantincrease in CD133, MMR (hMLH1, hMSH2 and hMSH6) and MGMT, moreover 5-FU resistance thanparental cell lines. Thus, although CSCs 5-FU chemoresistance appears to be independently to MMR status,hMLH1 might play a key role in CSC response to 5-FU. New drugs exploding these differences could benefitthe prognostic of patients with CRC.

14.
J Cancer Res Ther ; 2020 Jan; 15(6): 1547-1552
Article | IMSEAR | ID: sea-213569

ABSTRACT

Objective: Lung cancer is the leading cause of cancer-related death worldwide with a relatively low 5-year relative survival rate of 16%. Novel and efficient therapeutic approach for lung cancer is desperately needed. Materials and Methods: Targeting cancer stem cells (CSCs) provides a promising strategy to eradicate malignancies. The Notch signaling pathway plays an important role in the control of cell fates and developmental processes including CSCs. The function of Notch1 in the regulation of CSCs and whether targeting Notch1 could be a potential therapy for lung cancer were explored in this study. Lung CSCs (LCSCs) were isolated from A549 cells and identified as CD44+/CD24– cells by magnetic-assisted cell sorting, then the putative LCSCs were treated with Notch1 inhibitor and Notch1 small interfering RNAs (siRNAs); the growth and proliferation of LCSCs were investigated to test the effect of Notch1 blocking on the growth and viability of LCSCs. Results: CD44+/CD24– cells isolated from A549 cells possessed stem cell-like properties with high expression of Notch1. Blocking Notch1 by inhibitor DAPT or siRNA both inhibited the growth capacity of LCSCs. Conclusion: Our discovery demonstrated a depression of growth in CD44+/CD24– and A549 cells caused by blockade of Notch signaling pathway. Further studies are needed to demonstrate the detailed effects of Notch1 blocking on the LCSCs. Nevertheless, targeting the Notch pathway has exhibited great potential to be an improved lung cancer treatment

15.
Article in Chinese | WPRIM | ID: wpr-861560

ABSTRACT

Cancer stem cells (CSCs) are a group of tumor cells with the potential for self-replication, multicellular differentiation, and therapeutic resistance—factors which contribute to tumor recurrence, distant metastasis, and the failure of tumor treatment. Mitochondrial homeostasis plays a key role in stemness maintenance and differentiation regulation of CSCs. Mitophagy or selective autophagy of mitochondria, is an important regulatory mechanism for the maintenance of mitochondrial homeostasis. However, the role of mitophagy in CSCs is controversial. Considering that mitophagy regulates mitochondrial quality control, it was originally thought to positively regulate tumor suppression and maintain intracellular homeostasis. However, in recent years, mitophagy has been reported to be involved in reducing oxidative stress damage of tumor cells and promoting tumor progression. Further research on the mechanism of mitophagy regulation can reveal new therapeutic targets for tumor treatment. In this review, we have focused on the role of mitophagy in stemness maintenance, metabolic transformation, and therapeutic resistance of CSCs.

16.
Article in Chinese | WPRIM | ID: wpr-873018

ABSTRACT

Objective:To observe the effect of Zengmian Yiliu (ZMYL) formula and its effective components (PAWU) on the growth inhibition of ovarian cancer stem cell transplanted tumor in nude mice and the Notch signal receptor (Notch) / Notch signal ligand 1 (Jagged1) signal pathway in tumor tissue. Method:Ovarian cancer stem cells were cultured in serum-free suspension to establish the transplanted tumor model of ovarian cancer stem cells in nude mice, and then divided into model group, ZMYL group (36 g·kg-1), PAWU group (5.8 g·kg-1), cisplatin (DDP) group (2.5 g·kg-1), and PAWU (5.8 g·kg-1) + DDP group (2.5 mg·kg-1).After successful modeling, the drugs were given by gavage for 21 days.To observe the effect of Zengmian Yiliu decoction and its effective components on tumor weight in nude mice, the morphological changes of tumor cells were observed under light microscope, immunohistochemistry and real-time fluorescence quantitative polymerase chain reaction(Real-time PCR)were used to detect the expressions of Notch 1, Jagged1, Hairy and enhancer of split 1 (Hes1) protein and mRNA in tumor tissues. Result:The tumor inhibition rates of ZMYL, PAWU, DDP and combination groups were 35.91%, 32.94%, 57.65% and 69.05%, respectively.Compared with the model group, the tumor weight of ZMYL group, PAWU group, DDP group and combination groups decreased significantly (P<0.05).Compared with PAWU group, the tumor weight of combination groups decreased significantly (P<0.05).Immunohistochemistry showed that compared with the model group, the positive expressions of Notch1, Jagged1 in ZMYL group, PAWU group, DDP group and combination groups were down-regulated (P<0.05),and the positive expressions of Hes1 in ZMYL group, DDP group and combination groups were down-regulated (P<0.05).Compared with combination groups, the positive expressions of Notch1, Jagged1 and Hes1 in ZMYL group, PAWU group, DDP group were up-regulated (P<0.05). Real time PCR showed that compared with the model group, the expressions of Notch1 mRNA in ZMYL group, PAWU group, DDP group and combination groups decreased significantly (P<0.05).Compared with model group, the expressions of Jagged1 and Hes1 mRNA in ZMYL group, PAWU group and combination groups decreased significantly (P<0.05).Compared with DDP group, the expressions of Notch1, Jagged1 and Hes1 mRNA in combination groups decreased significantly (P<0.05). Conclusion:The growth of ovarian cancer stem cells transplanted in nude mice can be inhibited by Zengmian Yiliu formula and its effective components.The effective components have a significant synergistic effect in the combination with cisplatin.Its mechanism is correlated to the inhibition of Notch/Jagged1 signaling pathway activation.

17.
Article in Chinese | WPRIM | ID: wpr-843249

ABSTRACT

RNA N6-methyladenosine (m6A) modification is one of the most pervasive epigenetic modifications that correlate with gene expression, regulated by a variety of methylases, demethylases and reader proteins. m6A has been found crucial during cancer progression, aberrant changes of which contribute to tumorigenesis and metastasis. It's also been reported to be influential on chemotherapy and radiotherapy resistance of malignant tumors by inducing cancer stem cells (CSC) generation and enhancing post-therapy damage resistance, thus causing the progression or recurrence. In this review, we review the regulation of RNA m6A modification and focus on recent advances in functions of dysregulated m6A modification in the pathogenesis of cancer progression and recurrence. In addition, we also discuss the possible participation of CSC in this process combining current perspectives on the chemotherapy and radiotherapy resistance mechanism of CSC.

18.
Journal of Integrative Medicine ; (12): 196-202, 2020.
Article in English | WPRIM | ID: wpr-829109

ABSTRACT

Hepatocellular carcinoma (HCC) is a prevalent and highly malignant cancer throughout the world. Effective treatment of this disease is impeded by the high rate of metastasis, recurrence, and chemoresistance. Recent studies have revealed the close relationship between the malignant phenotype of HCC and cancer stem cells (CSCs). Therefore, CSC-targeted therapy is considered a promising strategy to eradicate HCC. Traditional Chinese medicine (TCM) can be effective in preventing recurrence and metastasis of some advanced HCC. A growing amount of literature has discovered that extracts or compounds derived from TCM exert an anti-CSC effect. This review introduces some formulas and chemical compounds derived from TCMs that have been reported to inhibit CSCs of HCC; these TCM-related drugs may help to provide an alternative approach to help manage cancers, especially for HCC which has a great potential of metastasis, recurrence, and chemoresistance.

19.
Article in Chinese | WPRIM | ID: wpr-857050

ABSTRACT

Aim To investigate the effect of long non-coding RNA (LncRNA) HIT on the resistance of ima-tinib (IM) in SUP-B15 cell line of acute lymphoblastic leukemia (ALL) and the related mechanisms. Methods SUP-B15 cells were treated with concentration gradient IM and saline as IMR and control groups. The lentivirus transfected LncRNA HIT shRNAl # and 2# vector in IMR group cells to knock down the HIT expression as IMR shHITl # and 2# group cells. CCK-8 assay was used to detect IM half-inhibitory concentration ( ICjo ). Fluorescence quantitative PCR (qPCR) was applied to detect the expression levels of LncRNA HIT, QKI, 0ct4 and Sox2 mRNA. Western blot was employed to detect the expression levels of QKI, 0ct4 and Sox2 protein. Results Compared with those in control cells, there was significantly higher IM ICjq, higher expression of LncRNA HIT, 0ct4 and Sox2, and lower expression of QKI in groups of IMR, IMR shHITl# and 2# cells. Compared with those in IMR cells, there was significantly lower IM IC∗, lower expression of LncRNA HIT, 0ct4 and Sox2, and higher expression of QKI in groups of IMR shHITl# and 2# cells. The difference was statistically significant (P < 0. 05). Conclusions LncRNA HIT can increase the expression of Sox2 and 0ct4 via inhibiting the expression of QKI protein, and mediating the formation of IM resistance in ALL cells.

20.
Article in Chinese | WPRIM | ID: wpr-849717

ABSTRACT

Hepatocellular carcinoma (HCC), as a global malignant tumor with high morbidity and mortality, has seriously endangered human health. In the treatment of HCC, chemotherapy resistance is the knotty problem. Long non-coding RNA (lncRNA), as a new multifunctional molecule with complex mechanisms, plays a role in the biological processes of HCC, such as development, progression, invasion and migration, and participates in the complex mechanism of drug resistance through abnormal regulation of gene expression. In this paper, to seek for the new method for solving the chemotherapeutic resistance of HCC based on the research of lncRNA, the effect and mechanism of lncRNA on chemotherapeutic resistance of HCC were summarized.

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