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المؤلفون: Tiantian Lei, Yi Wang, Xiaofang Xie, Rui He, Suya Du
المصدر: Oncology Reports
مصطلحات موضوعية: 0301 basic medicine, Cancer Research, oncotherapy, Carcinogenesis, Cellular differentiation, GSK 3β inhibitors, Cell, Apoptosis, Review, macromolecular substances, Biology, medicine.disease_cause, Mice, 03 medical and health sciences, Antineoplastic Agents, Immunological, 0302 clinical medicine, GSK-3, Neoplasms, Antineoplastic Combined Chemotherapy Protocols, medicine, Animals, Humans, Lymphocytes, Phosphorylation, Protein Kinase Inhibitors, Glycogen Synthase Kinase 3 beta, Oncogene, Kinase, Cell growth, General Medicine, Cell cycle, Gene Expression Regulation, Neoplastic, Disease Models, Animal, tumorigenesis, glycogen synthase kinase 3β, 030104 developmental biology, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Proteolysis, Disease Progression, Cancer research, Signal Transduction, Transcription Factors
الوصف: Glycogen synthase kinase 3β (GSK 3β), a multifunctional serine and threonine kinase, plays a critical role in a variety of cellular activities, including signaling transduction, protein and glycogen metabolism, cell proliferation, cell differentiation, and apoptosis. Therefore, aberrant regulation of GSK 3β results in a broad range of human diseases, such as tumors, diabetes, inflammation and neurodegenerative diseases. Accumulating evidence has suggested that GSK 3β is correlated with tumorigenesis and progression. However, GSK 3β is controversial due to its bifacial roles of tumor suppression and activation. In addition, overexpression of GSK 3β is involved in tumor growth, whereas it contributes to the cell sensitivity to chemotherapy. However, the underlying regulatory mechanisms of GSK 3β in tumorigenesis remain obscure and require further in-depth investigation. In this review, we comprehensively summarize the roles of GSK 3β in tumorigenesis and oncotherapy, and focus on its potentials as an available target in oncotherapy.
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المؤلفون: Yoshihiro Abiko, Maki Tanaka, Eri Okumura, Osamu Uehara, Masaki Fujishima, Yutaka Kawano, Hideo Takekoshi, Hidekatsu Takeda, Kohichi Takada
المصدر: Oncology Reports
مصطلحات موضوعية: 0301 basic medicine, autophagy, Cancer Research, Chronic bronchitis, Cell Survival, Autophagy-Related Proteins, Antineoplastic Agents, Apoptosis, Eleutherococcus, Pharmacology, Biology, Plant Roots, Acanthopanax senticosus Harms, liver cancer, 03 medical and health sciences, 0302 clinical medicine, Cell Line, Tumor, medicine, Humans, Cell Proliferation, Oncogene, Plant Extracts, Cell growth, Liver Neoplasms, Autophagy, Cancer, Articles, Cell Cycle Checkpoints, General Medicine, Cell cycle, medicine.disease, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, run domain Beclin-1-interacting and cysteine-rich domain-containing, Liver cancer
الوصف: Acanthopanax senticosus (Rupr. et Maxim) Harms (ASH), also known as Siberian ginseng or eleuthero, is a hardy shrub native to China, Korea, Russia and the northern region of Japan. ASH is used for the treatment of several diseases such as heart disease, hypertension, rheumatoid arthritis, allergies, chronic bronchitis, diabetes and cancer. In the present study, the inhibitory effect of the root extract of ASH (ASHE) on HuH‑7 and HepG2 liver cancer cells was examined. ASHE suppressed liver cancer cell proliferation by inducing cell cycle arrest at the G0/G1 phase, as well as apoptosis, as indicated by the increased number of Annexin V and 7‑AAD‑positive cells. Furthermore, the expression of LC3‑II, an autophagy marker, in these cells also increased post treatment with ASHE. LC3‑II induction was further enhanced by co‑treatment with chloroquine. Fluorescence and transmission electron micrographs of ASHE‑treated liver cancer cells showed the presence of an increased number of autophagic vesicles. A decreased protein expression level of run domain Beclin‑1‑interacting and cysteine‑rich domain‑containing, an autophagy inhibitor, with no change in RUBCN mRNA expression was observed, indicating activation of the autophagosome‑lysosome fusion step of autophagy. In conclusion, ASHE exerts cytostatic activity on liver cancer cells via both apoptosis and autophagy, and may serve as a potential therapeutic agent for management of liver cancer and autophagy‑related diseases.
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المؤلفون: Meng Liu, Yingying Yang, Xiyang Zhang, Hengzhi Song, Yuhui Wang, Xiaotian Xu, Xiaoqun Duan, Chengqiong Wei
المصدر: Oncology Reports
مصطلحات موضوعية: 0301 basic medicine, Cancer Research, Small interfering RNA, Epithelial-Mesenchymal Transition, Cell, VSP-17, Antineoplastic Agents, Triple Negative Breast Neoplasms, epithelial-mesenchymal transformation, AMP-Activated Protein Kinases, adenosine 5′-monophosphate-activated protein kinase, 03 medical and health sciences, 0302 clinical medicine, Downregulation and upregulation, Antigens, CD, Cell Movement, Cell Line, Tumor, medicine, Humans, Vimentin, metastasis, Neoplasm Invasiveness, peroxisome proliferator-activated receptor γ, Chemistry, AMPK, Cell migration, Articles, General Medicine, Transfection, Cell cycle, Cadherins, PPAR gamma, 030104 developmental biology, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, triple-negative breast cancer, Cancer research, Signal transduction, Signal Transduction
الوصف: VSP-17, a novel peroxisome proliferator-activated receptor γ (PPARγ) agonist, has been previously demonstrated to suppress the metastasis of triple-negative breast cancer (TNBC) by upregulating the expression levels of E-cadherin, which is a key marker of epithelial-mesenchymal transition (EMT). However, the mechanism of action of VSP-17, in particular whether it may be associated with the EMT process, remains unknown. The present study investigated the ability of VSP-17 to inhibit the invasiveness and migratory ability of TNBC cell lines (MDA-MB-231 and MDA-MB-453) performed in in vitro experiments. including cell migration assay, cell invasion assay, cell transfection, RT-qPCR, western blot (WB) analysis and immunofluorescence. The present study aimed to ascertain whether and how the PPARγ/AMP-activated protein kinase (AMPK) signaling pathway serves a role in the inhibitory effects of VSP-17 on cell migration and invasion. The results revealed that both treatment with compound C (an AMPK inhibitor) and transfection with small interfering RNA (si)AMPK notably diminished the inhibitory effect of VSP-17 treatment on the migration and invasion of MDA-MB-231 and MDA-MB-453 cells, indicating that VSP-17 may, at least partly, exert its effects via AMPK. Furthermore, both compound C and siAMPK markedly diminished the VSP-17-induced downregulation of vimentin expression levels and upregulation of E-cadherin expression levels, further indicating that the VSP-17-induced inhibition of the EMT process may be dependent on AMPK. The combination of GW9662 (a PPARγ antagonist) or siPPARγ diminished the inhibitory effect of VSP-17 treatment on the migration and invasion of the TNBC cells, indicating that PPARγ may serve an important role in the VSP-17-induced inhibition of the migration and invasion of TNBC cells. In addition, both GW9662 and siPPARγ significantly reversed the VSP-17-induced downregulation of vimentin expression levels and upregulation of E-cadherin expression levels, implying that the VSP-17-induced inhibition of the EMT process may be dependent on PPARγ. VSP-17 treatment also upregulated the expression levels of p-AMPK, which could be reversed by either GW9662 or siPPARγ, indicating that the VSP-17-induced activation of the AMPK signaling pathway was PPARγ-dependent. In conclusion, the findings of the present study indicated that VSP-17 treatment may inhibit the migration and invasion of TNBC cells by suppressing the EMT process via the PPARγ/AMPK signaling pathway.
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المؤلفون: Hai‑Anh Ha, Jo‑Hua Chiang, Fuu‑Jen Tsai, Da‑Tian Bau, Yu‑Ning Juan, Yu‑Hsiang Lo, Mann‑Jen Hour, Jai‑Sing Yang
المصدر: Oncology Reports
مصطلحات موضوعية: 0301 basic medicine, Cancer Research, Cell Survival, colorectal cancer, Apoptosis, 03 medical and health sciences, 0302 clinical medicine, Antineoplastic Combined Chemotherapy Protocols, Autophagy, Humans, Viability assay, Fragmentation (cell biology), Protein kinase B, PI3K/AKT/mTOR pathway, fluorouracil-resistant HT-29 cells, Cell growth, Chemistry, TOR Serine-Threonine Kinases, Articles, MJ-33, General Medicine, Cell cycle, 030104 developmental biology, Oncology, Drug Resistance, Neoplasm, Glycerophosphates, 030220 oncology & carcinogenesis, Cancer research, Fluorouracil, Drug Screening Assays, Antitumor, Colorectal Neoplasms, HT29 Cells, Proto-Oncogene Proteins c-akt, Signal Transduction
الوصف: Novel quinazolinone compounds have been studied in the field of drug discovery for a long time. Among their broad range of pharmacological effects, certain compounds effectively inhibit cancer cell proliferation. MJ-33 is a quinazolinone derivative with proposed anticancer activities that was synthesized in our laboratory. The present study aimed to evaluate the anticancer activity of MJ-33 in fluorouracil (5FU)-resistant colorectal cancer cells (HT-29/5FUR) and to investigate the underlying molecular mechanisms. The cell viability assay results indicated that HT-29/5FUR cell viability was inhibited by MJ-33 treatment in a concentration-dependent manner compared with the control group. The cellular morphological alterations observed following MJ-33 treatment indicated the occurrence of apoptosis and autophagy, as well as inhibition of cell proliferation in a time-dependent manner compared with the control group. The acridine orange, LysoTracker Red and LC3-green fluorescent protein staining results indicated that MJ-33 treatment significantly induced autophagy compared with the control group. The DAPI/TUNEL dual staining results demonstrated increased nuclear fragmentation and condensation following MJ-33 treatment compared with the control group. The Annexin V apoptosis assay and image cytometry analysis results demonstrated a significant increase in apoptotic cells following MJ-33 treatment compared with the control group. The western blotting results demonstrated markedly decreased Bcl-2, phosphorylated (p)-BAD, pro-caspase-9 and pro-caspase-3 expression levels, and notably increased cytochrome c and apoptotic peptidase activating factor 1 expression levels following MJ-33 treatment compared with the control group. Moreover, the expression levels of autophagy-related proteins, including autophagy related (ATG)-5, ATG-7, ATG-12, ATG-16, p62 and LC3-II, were increased following MJ-33 treatment compared with the control group. Furthermore, MJ-33-treated HT-29/5FUR cells displayed decreased expression levels of p-AKT and p-mTOR compared with control cells. The results suggested that MJ-33-induced apoptosis was mediated by AKT signaling, and subsequently modulated via the mitochondria-dependent signaling pathway. Therefore, the results suggested that suppression of AKT/mTOR activity triggered autophagy in the HT-29/5FUR cell line. In summary, the results indicated that MJ-33 inhibited HT-29/5FUR cell viability, and induced apoptosis and autophagy via the AKT/mTOR signaling pathway. The present study may provide novel insight into the anticancer effects and mechanisms underlying MJ-33 in 5FU-resistant colorectal cancer cells.
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المؤلفون: Chuying Huang, Qiang Liu, Xibiao Yang, Weiwei Bian, Lin Wan, Yuan Gao, Yun Du, Honglian Liu
المصدر: Oncology Reports
مصطلحات موضوعية: 0301 basic medicine, Cancer Research, Lung Neoplasms, NSCLC, Zoledronic Acid, Mice, 0302 clinical medicine, Carcinoma, Non-Small-Cell Lung, Antineoplastic Combined Chemotherapy Protocols, heterocyclic compounds, Phosphorylation, JAK/STAT3, skin and connective tissue diseases, Drug Synergism, Gefitinib, Articles, General Medicine, Cell cycle, Oncology, 030220 oncology & carcinogenesis, Female, Tyrosine kinase, Signal Transduction, medicine.drug, STAT3 Transcription Factor, Epithelial-Mesenchymal Transition, Cell Survival, 03 medical and health sciences, Cell Line, Tumor, medicine, Animals, Humans, Epithelial–mesenchymal transition, Lung cancer, neoplasms, non-small cell lung cancer, gefitinib resistance, Cell Proliferation, Janus Kinases, Oncogene, business.industry, Cancer, medicine.disease, Xenograft Model Antitumor Assays, respiratory tract diseases, 030104 developmental biology, Drug Resistance, Neoplasm, Cancer cell, Cancer research, business
الوصف: Studies have shown that suppression of both the JAK/STAT3 pathway and epithelial-mesenchymal transition (EMT) may overturn the resistance of non-small cell lung cancer (NSCLC) cells to gefitinib. Zoledronic acid (ZA) injection is used to treat and prevent multiple forms of osteoporosis, hypercalcemia and bone metastasis-related complications of malignancy. Clinical research has shown that ZA may exert antitumour effects and delay the progression of NSCLC. In the present study, we investigated whether ZA combined with gefitinib could re-sensitise NSCLC cells to gefitinib in vitro and in vivo through inhibition of the JAK/STAT3 signalling pathway and EMT reversal. The results revealed that ZA potently increased the sensitivity of gefitinib-resistant lung cancer cells to gefitinib. ZA decreased activation of JAK/STAT3 signalling and reversed EMT in the H1975 and HCC827GR cell lines. Furthermore, addition of IL-6 to ZA-pretreated gefitinib-resistant cell lines abrogated the effect of ZA and restored the cellular resistance to tyrosine kinase inhibitors. Finally, ZA-based combinatorial therapy effectively inhibited the growth of xenografts derived from gefitinib-resistant cancer cells, which was correlated with the inhibition of the JAK/STAT3 signalling pathway and EMT reversal. In conclusion, ZA re-sensitised gefitinib-resistant lung cancer cells through inhibition of the JAK/STAT3 signalling pathway and EMT reversal. The combination of ZA and gefitinib may be a promising therapeutic strategy to reverse gefitinib resistance and prolong the survival of patients with NSCLC.
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المؤلفون: Qing Ning, Li Zhang, Rongling Zhong, Xiaowen Zhou, Lei Wu, Zhi Xia, Bojia Liu
المصدر: Oncology Reports
مصطلحات موضوعية: Male, STAT3 Transcription Factor, 0301 basic medicine, erlotinib, Cancer Research, Lung Neoplasms, medicine.drug_class, EGFR, Apoptosis, Caspase 3, Tyrosine-kinase inhibitor, STAT3, Erlotinib Hydrochloride, Mice, 03 medical and health sciences, 0302 clinical medicine, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Antineoplastic Combined Chemotherapy Protocols, medicine, Animals, Humans, heterocyclic compounds, Epidermal growth factor receptor, neoplasms, Oncogene, biology, Chemistry, Articles, General Medicine, NSCLC cells, Cell cycle, respiratory tract diseases, Huanglian Jiedu decoction, ErbB Receptors, 030104 developmental biology, Proto-Oncogene Proteins c-bcl-2, Oncology, 030220 oncology & carcinogenesis, Mutation, biology.protein, Cancer research, Erlotinib, Drugs, Chinese Herbal, Signal Transduction, medicine.drug
الوصف: Erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is widely used in the treatment of non‑small cell lung cancer (NSCLC). However, erlotinib resistance leads to high mortality in patients with NSCLC, while the activation of STAT3 is closely related to erlotinib resistance. Studies have shown that the main components of Huanglian Jiedu Decoction (HJD) have antitumor effects. Therefore, the anticancer effect of HJD combined with erlotinib on NSCLC cells was investigated. The NSCLC HCC827, HCC827ER, and H1975 cell lines as well as xenograft nude mice were selected as models to study the effects of HJD. The proapoptotic effects of HJD were examined by CCK‑8 and apoptosis assays. ELISA, immunostaining, and western blot analysis were also performed. HJD considerably enhanced the anticancer effect of erlotinib in both EGFR‑TKI‑resistant and ‑sensitive NSCLC cells. HJD promoted erlotinib‑induced apoptosis and caspase 3 activity. The co‑treatment also inhibited the expression of Bcl‑XL, Bcl‑2, and p‑STAT3. In addition, siSTAT3 had similar functions with HJD. In particular, the apoptotic rates of erlotinib‑stimulated HCC827, HCC827ER, and H1975 cells were enhanced by transfecting siSTAT3. Furthermore, overexpression of STAT3 significantly inhibited HJD‑mediated erlotinib sensitization. The combined use of HJD with erlotinib significantly reduced tumor growth in erlotinib‑resistant HCC827ER and H1975 xenografts, induced caspase 3, and inhibited Ki67, STAT3, and Bcl‑2 expression. HJD significantly alleviated erlotinib resistance by regulating the STAT3/Bcl‑2 signaling pathway, which is a promising method to overcome the EGFR‑TKI resistance of NSCLC.
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المؤلفون: Yonghong Wang, Zhenglan Huang, Wenli Feng, Hui Zhang, Hao Yang, Xin Wang
المصدر: Oncology Reports
مصطلحات موضوعية: 0301 basic medicine, Cancer Research, Wnt/β-catenin signaling pathway, Antineoplastic Agents, Apoptosis, Biology, TCF7, 03 medical and health sciences, 0302 clinical medicine, chronic myeloid leukemia, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, hemic and lymphatic diseases, medicine, T Cell Transcription Factor 1, Gene silencing, Humans, RNA-Seq, Wnt Signaling Pathway, neoplasms, beta Catenin, Cell Proliferation, Gene knockdown, Oncogene, Gene Expression Regulation, Leukemic, Wnt signaling pathway, Myeloid leukemia, Imatinib, ATP-binding cassette transporters, General Medicine, Articles, Multidrug Resistance-Associated Protein 2, 030104 developmental biology, Oncology, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Catenin, Cancer research, Imatinib Mesylate, imatinib resistance, K562 Cells, medicine.drug, K562 cells
الوصف: Clinical resistance to ABL tyrosine kinase inhibitor (TKI) imatinib remains a critical issue in the treatment of chronic myeloid leukemia (CML). Transcription factor 7 (TCF7) is one of the main Wnt/β‑catenin signaling mediators. Previous studies have shown that TCF7 is vital for tumor initiation, and targeting TCF7 can reduce drug resistance in many types of cancer. However, the role of TCF7 in CML imatinib‑resistant cells is unclear. In the present study, we analyzed the transcriptomic data from CML clinical samples in the Gene Expression Omnibus (GEO) and performed experimental verification in the CML imatinib‑resistant cell line K562/G01. We found that the expression of TCF7 was independent of BCR‑ABL1 activity. Silencing of TCF7 downregulated the expression levels of CTNNB1, CCND1, and ABCC2, and therefore inhibited proliferation, weakened colony formation, and increased the drug sensitivity of imatinib‑resistant cells. After analyzing the transcriptomic data of four groups (Scramble, TCF7_KD, Scramble+imatinib, and TCF7_KD+imatinib) using bioinformatics, we noted that Wnt/β‑catenin and ATP‑binding cassette (ABC) transporter signaling pathways were upregulated in imatinib‑resistant cells under conventional dose of imatinib, and TCF7 knockdown could neutralize this effect. Next, using ChIP‑qPCR, we demonstrated that TCF7 was recruited to the promoter region of ABCC2 and activated gene transcription. In summary, our results highlight that the upregulation of Wnt/β‑catenin and ABC transporter signaling pathways induced by imatinib treatment of resistant cells confers imatinib resistance, and reveal that targeting TCF7 to regulate the Wnt/β‑catenin/TCF7/ABC transporter signaling axis may represent an effective strategy for overcoming imatinib resistance.
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المؤلفون: Dehua Zhao, Jisheng Wang, Jing Chen, Xiaoqing Long
المصدر: Oncology Reports
مصطلحات موضوعية: 0301 basic medicine, Oncology, renal impairment, Cancer Research, medicine.medical_specialty, Lung Neoplasms, hepatic impairment, Renal function, Antineoplastic Agents, Review, Kidney, Nephrotoxicity, 03 medical and health sciences, 0302 clinical medicine, Pharmacokinetics, Carcinoma, Non-Small-Cell Lung, Internal medicine, tyrosine kinase inhibitors, medicine, dose adjustment, Humans, Drug Dosage Calculations, Renal Insufficiency, Lung cancer, Protein Kinase Inhibitors, non-small cell lung cancer, Dose-Response Relationship, Drug, business.industry, Cancer, General Medicine, medicine.disease, Molecular medicine, respiratory tract diseases, Hepatobiliary Elimination, Renal Elimination, 030104 developmental biology, Biological Variation, Population, Liver, 030220 oncology & carcinogenesis, Toxicity, business, Tyrosine kinase, Liver Failure
الوصف: In recent years, a number of tyrosine kinase inhibitors (TKIs) have been approved for the treatment of non‑small cell lung cancer. These novel treatments exhibit improved efficacy and toxicity when compared to conventional chemotherapy agents. TKIs are administered orally, which has the advantages of improved flexibility and convenience for the patients. However, challenges have arisen in the use of these novel agents. Prescribing drugs for patients with hepatic or renal function impairment poses a challenge for clinicians due to the large pharmacokinetic variability in each individual patient. Moreover, several TKIs have been shown to cause laboratory test abnormalities normally associated with hepatic or renal injury. The aim of the present review was to discuss the effects of hepatic and renal function impairment on the pharmacokinetic variability of 17 TKIs and their potential hepatotoxicity and nephrotoxicity, and to recommend dose adjustment for patients with hepatic or renal impairment.
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المؤلفون: Nikolaos Ioannou, Said Abdullah Khelwatty, Helmout Modjtahedi, Satvinder Mudan, Angus G. Dalgleish, Tanzeel Khan, Alan M. Seddon
المصدر: Oncology Reports
مصطلحات موضوعية: 0301 basic medicine, Cancer Research, Afatinib, pancreatic cancer, STAT3, Inhibitory Concentration 50, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, combinational therapy, Growth factor receptor, Cell Movement, Cell Line, Tumor, tyrosine kinase inhibitors, Antineoplastic Combined Chemotherapy Protocols, medicine, cancer, Humans, Receptors, Growth Factor, Dinaciclib, Protein Kinase Inhibitors, Cell Proliferation, Clinical Trials as Topic, Ceritinib, business.industry, Cell Cycle, Drug Synergism, Articles, General Medicine, targeted therapy, HER family, Cyclin-Dependent Kinases, Gemcitabine, Pancreatic Neoplasms, Dasatinib, 030104 developmental biology, Oncology, chemistry, Research Design, 030220 oncology & carcinogenesis, Cancer research, Erlotinib, Drug Screening Assays, Antitumor, business, Drug Antagonism, Tyrosine kinase, biological, SRC, medicine.drug
الوصف: Pancreatic cancer is one of the most aggressive, heterogeneous and fatal type of human cancers for which more effective therapeutic agents are urgently needed. Here, we investigated the sensitivity of a panel of seven human pancreatic cancer cell lines (HPCCLs) to treatment with various tyrosine kinase inhibitors (TKIs), cyclin‑dependent kinase (CDK) inhibitors, an inhibitor of STAT3 stattic, and a cytotoxic agent gemcitabine both as single agents and in combination. The membranous expression of various receptors and the effect of selected agents on cell cycle distribution, cell signaling pathways and migration was determined using flow cytometry, western blot analysis and scratch wound healing assays, respectively. While the expression of both HER‑3 and HER‑4 was low or negative, the expression of EGFR and HER2 was high or intermediate in all HPCCLs. Of all the agents examined, the CDK1/2/5/9 inhibitor, dinacicilib, was the most potent agent which inhibited the proliferation of all seven HPCCLs with IC50 values of ≤10 nM, followed by SRC targeting TKI dasatinib (IC50 of ≤258 nM), gemcitabine (IC50 of ≤330 nM), stattic (IC50 of ≤2 µM) and the irreversible pan‑HER TKI afatinib (IC50 of ≤2.95 µM). Treatment with afatinib and dasatinib inhibited the ligand‑induced phosphorylation of EGFR and SRC respectively. Statistically significant associations were found between HER2 expression and response to treatment with the ALK/IGF‑IR/InsR inhibitor ceritinib and fibroblast growth factor receptor (FGFR)1/2/3 inhibitor AZD4547, HER3 and IGF‑IR expression and their response to treatment with TKIs targeting HER family members (erlotinib and afatinib), and c‑MET and ALK7 expression and their response to treatment with stattic. Interestingly, treatment with a combination of afatinib with dasatinib and gemcitabine with dasatinib resulted in synergistic tumor growth inhibition in all HPCCLs examined. In contrast, the combination of afatinib with dinaciclib was found to be antagonistic. Finally, the treatment with afatinib, dasatinib and dinaciclib strongly inhibited the migration of all HPCCLs examined. In conclusion, the CDK1/2/5/9 inhibitor dinaciclib, irreversible pan‑HER TKI afatinib and SRC targeting TKI dasatinib were most effective at inhibiting the proliferation and migration of HPCCLs and the combination of afatinib with dasatinib and gemcitabine with dasatinib led to synergistic tumor growth inhibition in all HPCCLs examined. Our results support further investigation on the therapeutic potential of these combinations in future clinical trials in pancreatic cancer.
وصف الملف: application/pdf
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المؤلفون: Junko Takei, Takuro Nakamura, Masato Sano, Tomokazu Ohishi, Hideki Hosono, Hiroyuki Harada, Yusuke Sayama, Mika K. Kaneko, Teizo Asano, Manabu Kawada, Miyuki Yanaka, Yukinari Kato
المصدر: Oncology Reports
مصطلحات موضوعية: 0301 basic medicine, Cancer Research, medicine.drug_class, Cell, Apoptosis, CHO Cells, Monoclonal antibody, Flow cytometry, Mice, 03 medical and health sciences, chemistry.chemical_compound, Antineoplastic Agents, Immunological, Cricetulus, 0302 clinical medicine, Cell Line, Tumor, medicine, Animals, Humans, antitumor activity, Cell adhesion, Antibody-dependent cell-mediated cytotoxicity, medicine.diagnostic_test, Squamous Cell Carcinoma of Head and Neck, Chemistry, Antibody-Dependent Cell Cytotoxicity, Antibodies, Monoclonal, Epithelial cell adhesion molecule, Articles, General Medicine, oral cancer, Cell cycle, Epithelial Cell Adhesion Molecule, Xenograft Model Antitumor Assays, stomatognathic diseases, 030104 developmental biology, medicine.anatomical_structure, Oncology, monoclonal antibody, Cell culture, EpCAM, 030220 oncology & carcinogenesis, Cancer research, Female, Mouth Neoplasms, ADCC, CDC
الوصف: The epithelial cell adhesion molecule (EpCAM) is a calcium‑independent, homophilic, intercellular adhesion factor classified as a transmembrane glycoprotein. In addition to cell adhesion, EpCAM also contributes to cell signaling, differentiation, proliferation, and migration. EpCAM is an essential factor in the carcinogenesis of numerous human cancers. In the present study, we developed and validated an anti‑EpCAM monoclonal antibody (mAb), EpMab‑16 (IgG2a, kappa), by immunizing mice with EpCAM‑overexpressing CHO‑K1 cells. EpMab‑16 specifically reacted with endogenous EpCAM in oral squamous cell carcinoma (OSCC) cell lines in flow cytometry and Western blot analyses. It exhibited a plasma membrane‑like stain pattern in OSCC tissues upon immunohistochemical analysis. The KD for EpMab‑16 in SAS and HSC‑2 OSCC cells were assessed via flow cytometry at 1.1x10‑8 and 1.9x10‑8 M, respectively, suggesting moderate binding affinity of EpMab‑16 for EpCAM. We then assessed whether the EpMab‑16 induced antibody‑dependent cellular cytotoxicity (ADCC) and complement‑dependent cytotoxicity (CDC) against OSCC cell lines, and antitumor capacity in a murine xenograft model. In vitro experiments revealed strong ADCC and CDC inducement against OSCC cells treated with EpMab‑16. In vivo experiments on OSCC xenografts revealed that EpMab‑16 treatment significantly reduced tumor growth compared with the control mouse IgG. These data indicated that EpMab‑16 could be a promising treatment option for EpCAM‑expressing OSCCs.
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