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Meng X, Dong S, Yangyang L, Wang S, Xu X, Liu T, Zhuang X. Adenosine triphosphate-binding cassette subfamily C members in liver hepatocellular carcinoma: Bioinformatics-driven prognostic value. Medicine (Baltimore) 2022; 101:e28869. [PMID: 35363194 PMCID: PMC9282002 DOI: 10.1097/md.0000000000028869] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 12/16/2021] [Indexed: 01/04/2023] Open
Abstract
Aberrant expression of adenosine triphosphate-binding cassette subfamily C (ABCC), one of the largest superfamilies and transporter gene families of membrane proteins, is associated with various tumors. However, its relationship with liver hepatocellular carcinoma (LIHC) remains unclear.We used the Oncomine, UALCAN, Human Protein Atlas, GeneMANIA, GO, Kyoto Encyclopedia of Genes and Genomes (KEGG), TIMER, and Kaplan-Meier Plotter databases. On May 20, 2021, we searched these databases for the terms ABCC1, ABCC2, ABCC3, ABCC4, ABCC5, ABCC6, ABCC7, ABCC8, ABCC9, ABCC10, ABCC11, ABCC12, ABCC13, and "liver cancer." The exposure group comprised LIHC patients, and the control group comprised normal patients (those with noncancerous liver tissue). All patients shown in the retrieval language search were included. We compared the mRNA expression of these proteins in LIHC and control patients to examine the potential role of ABCC1-13 in LIHC.Relative to the normal liver tissue, mRNA expression of ABCC1/2/3/4/5/6/10 was significantly upregulated (P < .001), and that of ABCC9/11 significantly downregulated (both P < .001), in LIHC. ABCC mRNA expression varied with gender (P < .05), except for ABCC11-13; with tumor grade (P < 0.05), except for ABCC7/12/13; with tumor stage (P < .05), except for ABCC11-13; and with lymph node metastasis status (P < .05), except for ABCC7/8/11/12/13. Based on KEGG enrichment analysis, these genes were associated with the following pathways: ABC transporters, Bile secretion, Antifolate resistance, and Peroxisome (P < .05). Except for ABCC12/13, the ABCCs were significantly associated with B cell, CD8+ T cell, CD4+ T cell, macrophage, neutrophil, and dendritic cell infiltration (P < .05). High mRNA expression of ABCC1/4/5/8 (P < .05) and low expression of ABCC6/7/9/12/13 (P < .05) indicated poor prognosis. Prognostic significance was indicated for ABCC2/13 for both men and women (P < .05); for ABCC1/6/12/13 for tumor grades 1-3 (P < .05); for ABCC5/11/12/13 for all tumor stages (P < .05); for ABCC1/11/12/13 for American Joint Committee on Cancer T stages 1-3 (P < .05); and for ABCC1/5/6/13 for vascular invasion. None showed prognostic significance for microvascular invasion (P < .05).We identified ABCC1/2/3/4/5/6/9/10/11 as potential diagnostic markers, and ABCC1/4/5/6/7/8/9/12/13 as prognostic markers, of LIHC. Our future work will promote the use of ABCCs in the diagnosis and treatment of LIHC.
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Affiliation(s)
- Xiangtong Meng
- Changchun University of Chinese Medicine, 1035 Bo Shuo Road, Changchun City, Jilin Province, China
| | - Shen Dong
- Changchun University of Chinese Medicine, 1035 Bo Shuo Road, Changchun City, Jilin Province, China
| | - Liu Yangyang
- Changchun University of Chinese Medicine, 1035 Bo Shuo Road, Changchun City, Jilin Province, China
- Endocrinology, First Affiliated Hospital to Changchun University of Chinese Medicine, 1478 Gongnong Road, Changchun City, Jilin Province, China
| | - Song Wang
- Changchun University of Chinese Medicine, 1035 Bo Shuo Road, Changchun City, Jilin Province, China
| | - Xiaohao Xu
- Changchun University of Chinese Medicine, 1035 Bo Shuo Road, Changchun City, Jilin Province, China
- Research Center of Traditional Chinese Medicine, First Affiliated Hospital to Changchun University of Chinese Medicine, Changchun City, Jilin Province, China
| | - Tiejun Liu
- Changchun University of Chinese Medicine, 1035 Bo Shuo Road, Changchun City, Jilin Province, China
- Department of Hepatology, First Affiliated Hospital to Changchun University of Chinese Medicine, 1478 Gongnong Road, Changchun City, Jilin Province, China
| | - Xiong Zhuang
- Changchun University of Chinese Medicine, 1035 Bo Shuo Road, Changchun City, Jilin Province, China
- Department of Hepatology, First Affiliated Hospital to Changchun University of Chinese Medicine, 1478 Gongnong Road, Changchun City, Jilin Province, China
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2
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Devan AR, Kumar AR, Nair B, Anto NP, Muraleedharan A, Mathew B, Kim H, Nath LR. Insights into an Immunotherapeutic Approach to Combat Multidrug Resistance in Hepatocellular Carcinoma. Pharmaceuticals (Basel) 2021; 14:656. [PMID: 34358082 PMCID: PMC8308499 DOI: 10.3390/ph14070656] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 07/01/2021] [Accepted: 07/07/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) has emerged as one of the most lethal cancers worldwide because of its high refractoriness and multi-drug resistance to existing chemotherapies, which leads to poor patient survival. Novel pharmacological strategies to tackle HCC are based on oral multi-kinase inhibitors like sorafenib; however, the clinical use of the drug is restricted due to the limited survival rate and significant side effects, suggesting the existence of a primary or/and acquired drug-resistance mechanism. Because of this hurdle, HCC patients are forced through incomplete therapy. Although multiple approaches have been employed in parallel to overcome multidrug resistance (MDR), the results are varying with insignificant outcomes. In the past decade, cancer immunotherapy has emerged as a breakthrough approach and has played a critical role in HCC treatment. The liver is the main immune organ of the lymphatic system. Researchers utilize immunotherapy because immune evasion is considered a major reason for rapid HCC progression. Moreover, the immune response can be augmented and sustained, thus preventing cancer relapse over the post-treatment period. In this review, we provide detailed insights into the immunotherapeutic approaches to combat MDR by focusing on HCC, together with challenges in clinical translation.
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Affiliation(s)
- Aswathy R. Devan
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi 682041, Kerala, India; (A.R.D.); (A.R.K.); (B.N.)
| | - Ayana R. Kumar
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi 682041, Kerala, India; (A.R.D.); (A.R.K.); (B.N.)
| | - Bhagyalakshmi Nair
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi 682041, Kerala, India; (A.R.D.); (A.R.K.); (B.N.)
| | - Nikhil Ponnoor Anto
- The Shraga Segal Department of Microbiology, Immunology, and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O.B. 653, Beer Sheva 84105, Israel; (N.P.A.); (A.M.)
| | - Amitha Muraleedharan
- The Shraga Segal Department of Microbiology, Immunology, and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O.B. 653, Beer Sheva 84105, Israel; (N.P.A.); (A.M.)
| | - Bijo Mathew
- Department of Pharmaceutical Chemistry, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi 682041, Kerala, India;
| | - Hoon Kim
- Department of Pharmacy, and Research Institute of Life Pharmaceutical Sciences, Sunchon National University, Suncheon 57922, Korea
| | - Lekshmi R. Nath
- Department of Pharmacognosy, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi 682041, Kerala, India; (A.R.D.); (A.R.K.); (B.N.)
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3
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Cabral LKD, Tiribelli C, Sukowati CHC. Sorafenib Resistance in Hepatocellular Carcinoma: The Relevance of Genetic Heterogeneity. Cancers (Basel) 2020; 12:1576. [PMID: 32549224 PMCID: PMC7352671 DOI: 10.3390/cancers12061576] [Citation(s) in RCA: 95] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 06/08/2020] [Accepted: 06/10/2020] [Indexed: 02/06/2023] Open
Abstract
Despite advances in biomedicine, the incidence and the mortality of hepatocellular carcinoma (HCC) remain high. The majority of HCC cases are diagnosed in later stages leading to the less than optimal outcome of the treatments. Molecular targeted therapy with sorafenib, a dual-target inhibitor targeting the serine-threonine kinase Raf and the tyrosine kinases VEGFR/PDGFR, is at present the main treatment for advanced-stage HCC, either in a single or combinatory regimen. However, it was observed in a large number of patients that its effectiveness is hampered by drug resistance. HCC is highly heterogeneous, within the tumor and among individuals, and this influences disease progression, classification, prognosis, and naturally cellular susceptibility to drug resistance. This review aims to provide an insight on how HCC heterogeneity influences the different primary mechanisms of chemoresistance against sorafenib including reduced drug intake, enhanced drug efflux, intracellular drug metabolism, alteration of molecular targets, activation/inactivation of signaling pathways, changes in the DNA repair machinery, and negative balance between apoptosis and survival of the cancer cells. The diverse variants, mutations, and polymorphisms in molecules and their association with drug response can be a helpful tool in treatment decision making. Accordingly, the existence of heterogeneous biomarkers in the tumor must be considered to strengthen multi-target strategies in patient-tailored treatment.
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Affiliation(s)
| | | | - Caecilia H. C. Sukowati
- Fondazione Italiana Fegato (Italian Liver Foundation), AREA Science Park, Basovizza, 34149 Trieste, Italy; (L.K.D.C.); (C.T.)
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4
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Ceballos MP, Rigalli JP, Ceré LI, Semeniuk M, Catania VA, Ruiz ML. ABC Transporters: Regulation and Association with Multidrug Resistance in Hepatocellular Carcinoma and Colorectal Carcinoma. Curr Med Chem 2019; 26:1224-1250. [PMID: 29303075 DOI: 10.2174/0929867325666180105103637] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Revised: 10/19/2017] [Accepted: 11/21/2017] [Indexed: 02/07/2023]
Abstract
For most cancers, the treatment of choice is still chemotherapy despite its severe adverse effects, systemic toxicity and limited efficacy due to the development of multidrug resistance (MDR). MDR leads to chemotherapy failure generally associated with a decrease in drug concentration inside cancer cells, frequently due to the overexpression of ABC transporters such as P-glycoprotein (P-gp/MDR1/ABCB1), multidrug resistance-associated proteins (MRPs/ABCCs), and breast cancer resistance protein (BCRP/ABCG2), which limits the efficacy of chemotherapeutic drugs. The aim of this review is to compile information about transcriptional and post-transcriptional regulation of ABC transporters and discuss their role in mediating MDR in cancer cells. This review also focuses on drug resistance by ABC efflux transporters in cancer cells, particularly hepatocellular carcinoma (HCC) and colorectal carcinoma (CRC) cells. Some aspects of the chemotherapy failure and future directions to overcome this problem are also discussed.
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Affiliation(s)
- María Paula Ceballos
- Institute of Experimental Physiology, Faculty of Biochemical and Pharmaceutical Science, Rosario National University, Rosario, Argentina
| | - Juan Pablo Rigalli
- Institute of Experimental Physiology, Faculty of Biochemical and Pharmaceutical Science, Rosario National University, Rosario, Argentina.,Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany
| | - Lucila Inés Ceré
- Institute of Experimental Physiology, Faculty of Biochemical and Pharmaceutical Science, Rosario National University, Rosario, Argentina
| | - Mariana Semeniuk
- Institute of Experimental Physiology, Faculty of Biochemical and Pharmaceutical Science, Rosario National University, Rosario, Argentina
| | - Viviana Alicia Catania
- Institute of Experimental Physiology, Faculty of Biochemical and Pharmaceutical Science, Rosario National University, Rosario, Argentina
| | - María Laura Ruiz
- Institute of Experimental Physiology, Faculty of Biochemical and Pharmaceutical Science, Rosario National University, Rosario, Argentina
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5
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Promotion of growth factor signaling as a critical function of β-catenin during HCC progression. Nat Commun 2019; 10:1909. [PMID: 31015417 PMCID: PMC6478918 DOI: 10.1038/s41467-019-09780-z] [Citation(s) in RCA: 76] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Accepted: 03/29/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. β-catenin is widely thought to be a major oncogene in HCC based on the frequency of mutations associated with aberrant Wnt signaling in HCC patients. Challenging this model, our data reveal that β-catenin nuclear accumulation is restricted to the late stage of the disease. Until then, β-catenin is primarily located at the plasma membrane in complex with multiple cadherin family members where it drives tumor cell survival by enhancing the signaling of growth factor receptors such as EGFR. Therefore, our study reveals the evolving nature of β-catenin in HCC to establish it as a compound tumor promoter during the progression of the disease. Aberrant Wnt/b-catenin signaling is thought to be a major driver of hepatocellular carcinoma. Here, the authors show that β-Catenin is predominantly integrated within the AJ complex during the early stages of this cancer and enhance EGFR signaling to promote tumour survival.
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6
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Shali S, Yu J, Zhang X, Wang X, Jin Y, Su M, Liao X, Yu J, Zhi X, Zhou P. Ecto-5'-nucleotidase (CD73) is a potential target of hepatocellular carcinoma. J Cell Physiol 2018; 234:10248-10259. [PMID: 30417547 DOI: 10.1002/jcp.27694] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Accepted: 10/09/2018] [Indexed: 01/09/2023]
Abstract
High expression of ecto-5'-nucleotidase (CD73) has been reported in a number of epithelium origin malignancies. Here, we hypothesize that CD73 promotes hepatocellular carcinoma (HCC) growth and metastasis and that the effect is mediated by epithelial growth factor receptor (EGFR). HCC cells with different malignancies and Tissue microarrays of the tumor and peritumoral liver tissues from 30 independent patients were used to examine CD73 and EGFR expression. Then, MTT and Ki67 detection, together with cell adhesion, invasion, and migration assays were used to evaluate the effects of CD73 on cell growth and metastasis. The expression of EGFR in HCC cells was also tested after suppressing or overexpressing CD73. Lastly, tumor tissues from nude mice, which had been injected subcutaneously with HCC cells, were transplanted subcutaneously into CD73-/- and wild-type (WT) C57 mice. CD73 expression was higher in HCC cells with greater metastatic potentials and tumor tissues compared with low metastatic cells and peritumor tissues. CD73 and EGFR were coexpressed and positively correlated in tumor and peritumor liver tissues in HCC tissue microarrays. Up-regulationof CD73 by plasmid transfection or by pharmacological agents promoted EGFR expression in HCC cells, whereas suppression of CD73 inhibited these effects. The growth of transplanted tumor tissues was dramatically slower in CD73-/- mice than in WT type mice in the in vivo experiments. CD73 promotes HCC growth and metastasis and upregulated the expression of EGFR in HCC. Thus, CD73 and EGFR are potential targets in the treatment of HCC.
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Affiliation(s)
- Shalaimaiti Shali
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Jiangang Yu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Xin Zhang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Xue Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Youping Jin
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Minsheng Su
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Xiaohong Liao
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Jerry Yu
- Department of Medicine, University of Louisville, Louisville, Kentucky
| | - Xiuling Zhi
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Ping Zhou
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai, China
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7
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Yahya SMM, Fathy SA, El-Khayat ZA, El-Toukhy SE, Hamed AR, Hegazy MGA, Nabih HK. Possible Role of microRNA-122 in Modulating Multidrug Resistance of Hepatocellular Carcinoma. Indian J Clin Biochem 2017; 33:21-30. [PMID: 29371766 DOI: 10.1007/s12291-017-0651-8] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Accepted: 04/11/2017] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) is a hypervascular primary liver cancer characterized by rapid progression, besides, resistance to traditional chemotherapeutic agents. It has been shown that microRNAs play critical roles in regulation of tumor cell sensitivity to drugs through modulating the expression of genes involved in drug transport. The present study investigated whether restoration of miR-122 in HCC cells could alter the cell cycle distribution and the expression of multidrug resistance (MDR)-related genes (ABCB1, ABCC1, ABCG2 and ABCF2). After overexpression of miR-122 in HepG2 cells treated or untreated with doxorubicin doses, total RNAs and protein extracts were isolated for application of QRT-PCR and western blotting techniques. Moreover, cell cycle distribution was monitored by flow cytometry. Our results revealed that, the over expression of miR-122 in HepG2 cells treated or untreated with doxorubicin could modulate the sensitivity of cells to chemotherapeutic drug through downregulation of MDR-related genes, ABCB1 and ABCF2. Interpretation of cell cycle distribution revealed that, the anti-proliferative effect of miR-122 is associated with the accumulation of cells in G0/G1 phase. Moreover, treatment with miR-122 and doxorubicin resulted in high percentage of HCC cells in G0/G1 phase. Taken together, our findings revealed that, overexpression of miR-122 inhibited HCC cell growth by inducing cell cycle arrest and this arrest is associated with down-regulation of MDR-related genes.
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Affiliation(s)
- Shaymaa M M Yahya
- 1Hormones Department, National Research Centre, Dokki, Giza, 12622 Egypt
| | - Shadia A Fathy
- 2Biochemistry Department, Ain Shams University, Cairo, Egypt
| | | | | | - Ahmed R Hamed
- 4Pharmaceutical Research Group, Center of Excellence for Advanced Sciences and Phytochemistry Department National Research Centre, Dokki, Giza, Egypt
| | | | - Heba K Nabih
- 3Medical Biochemistry Department, National Research Centre, Cairo, Egypt
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8
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Wang F, Chen Y, Huang L, Liu T, Huang Y, Zhao J, Wang X, Yang K, Ma S, Huang L, To KKW, Gu Y, Fu L. Cetuximab enhanced the efficacy of chemotherapeutic agent in ABCB1/P-glycoprotein-overexpressing cancer cells. Oncotarget 2016; 6:40850-65. [PMID: 26506420 PMCID: PMC4747373 DOI: 10.18632/oncotarget.5813] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2015] [Accepted: 09/23/2015] [Indexed: 12/15/2022] Open
Abstract
The overexpression of ATP-binding cassette (ABC) transporters is closely associated with the development of multidrug resistance (MDR) in certain types of cancer, which represents a formidable obstacle to the successful cancer chemotherapy. Here, we investigated that cetuximab, an EGFR monoclonal antibody, reversed the chemoresistance mediated by ABCB1, ABCG2 or ABCC1. Our results showed that cetuximab significantly enhanced the cytotoxicity of ABCB1 substrate agent in ABCB1-overexpressing MDR cells but had no effect in their parental drug sensitive cells and ABCC1, ABCG2 overexpressing cells. Furthermore, cetuximab markedly increased intracellular accumulation of doxorubicin (DOX) and rhodamine 123 (Rho 123) in ABCB1-overexpressing MDR cancer cells in a concentration-dependent manner. Cetuximab stimulated the ATPase activity but did not alter the expression level of ABCB1 or block phosphorylation of AKT and ERK. Interestingly, cetuximab decreased the cell membrane fluidity which was known to decrease the function of ABCB1. Our findings advocate further clinical investigation of combination chemotherapy of cetuximab and conventional chemotherapeutic drugs in ABCB1 overexpressing cancer patients.
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Affiliation(s)
- Fang Wang
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China.,Guangdong Esophageal Cancer Institute, Guangzhou, China
| | - Yifan Chen
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China.,Guangdong Esophageal Cancer Institute, Guangzhou, China
| | - Lihua Huang
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Tao Liu
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Yue Huang
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Jianming Zhao
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Xiaokun Wang
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China.,Guangdong Esophageal Cancer Institute, Guangzhou, China
| | - Ke Yang
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Shaolin Ma
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Liyan Huang
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Kenneth Kin Wah To
- School of Pharmacy, The Chinese University of Hong Kong, Hong Kong, China
| | - Yong Gu
- Department of Thoracic Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, China
| | - Liwu Fu
- Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China.,Guangdong Esophageal Cancer Institute, Guangzhou, China
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9
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Singh NS, Bernier M, Wainer IW. Selective GPR55 antagonism reduces chemoresistance in cancer cells. Pharmacol Res 2016; 111:757-766. [PMID: 27423937 PMCID: PMC5026616 DOI: 10.1016/j.phrs.2016.07.013] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2016] [Accepted: 07/11/2016] [Indexed: 01/02/2023]
Abstract
G protein-coupled receptor 55 (GPR55) possesses pro-oncogenic activity and its function can be competitively inhibited with (R,R')-4'-methoxy-1-naphthylfenoterol (MNF) through poorly defined signaling pathways. Here, the anti-tumorigenic effect of MNF was investigated in the human pancreatic cancer cell line, PANC-1, by focusing on the expression of known cancer biomarkers and the expression and function of multidrug resistance (MDR) exporters such as P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP). Incubation of PANC1 cells with MNF (1μM) for 24h significantly decreased EGF receptor, pyruvate kinase M2 (PKM2), and β-catenin protein levels and was accompanied by significant reduction in nuclear accumulation of HIF-1α and the phospho-active forms of PKM2 and β-catenin. Inhibition of GPR55 with either MNF or the GPR55 antagonist CID 16020046 lowered the amount of MDR proteins in total cellular extracts while diminishing the nuclear expression of Pgp and BCRP. There was significant nuclear accumulation of doxorubicin in PANC-1 cells treated with MNF and the pre-incubation with MNF increased the cytotoxicity of doxorubicin and gemcitabine in these cells. Potentiation of doxorubicin cytotoxicity by MNF was also observed in MDA-MB-231 breast cancer cells and U87MG glioblastoma cells, which express high levels of GPR55. The data suggest that inhibition of GPR55 activity produces antitumor effects via attenuation of the MEK/ERK and PI3K-AKT pathways leading to a reduction in the expression and function of MDR proteins.
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MESH Headings
- ATP Binding Cassette Transporter, Subfamily B/metabolism
- Antibiotics, Antineoplastic/metabolism
- Antibiotics, Antineoplastic/pharmacology
- Antimetabolites, Antineoplastic/metabolism
- Antimetabolites, Antineoplastic/pharmacology
- Biomarkers, Tumor/metabolism
- Carrier Proteins/metabolism
- Cell Proliferation/drug effects
- Deoxycytidine/analogs & derivatives
- Deoxycytidine/metabolism
- Deoxycytidine/pharmacology
- Dose-Response Relationship, Drug
- Doxorubicin/metabolism
- Doxorubicin/pharmacology
- Drug Resistance, Neoplasm/drug effects
- Extracellular Signal-Regulated MAP Kinases/metabolism
- Fenoterol/analogs & derivatives
- Fenoterol/pharmacology
- Humans
- Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
- MCF-7 Cells
- Membrane Proteins/metabolism
- Mitogen-Activated Protein Kinase Kinases/metabolism
- Pancreatic Neoplasms/drug therapy
- Pancreatic Neoplasms/metabolism
- Pancreatic Neoplasms/pathology
- Phosphatidylinositol 3-Kinase/metabolism
- Phosphorylation
- Proto-Oncogene Proteins c-akt/metabolism
- Receptors, Cannabinoid
- Receptors, G-Protein-Coupled/antagonists & inhibitors
- Signal Transduction/drug effects
- Thyroid Hormones/metabolism
- beta Catenin/metabolism
- Gemcitabine
- Thyroid Hormone-Binding Proteins
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Affiliation(s)
- Nagendra S Singh
- Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health (NIH), Baltimore, MD 21224, USA.
| | - Michel Bernier
- Translational Gerontology Branch, National Institute on Aging, (NIH), Baltimore, MD 21224, USA.
| | - Irving W Wainer
- Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health (NIH), Baltimore, MD 21224, USA; Mitchell Woods Pharmaceuticals, Shelton, CT 06484, USA.
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10
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Che Y, Ren X, Xu L, Ding X, Zhang X, Sun X. Critical involvement of the α(1,2)-fucosyltransferase in multidrug resistance of human chronic myeloid leukemia. Oncol Rep 2016; 35:3025-33. [PMID: 26986216 DOI: 10.3892/or.2016.4673] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2015] [Accepted: 01/11/2016] [Indexed: 11/05/2022] Open
Abstract
The fucosyltransferases are key enzymes in cell surface antigen synthesis during multidrug resistance (MDR) development. The aim of the present study was to analyze the alteration of α(1,2)-fucosyltransferase involved in MDR development in human chronic myeloid leukemia (CML). FUT1 was overexpressed in three CML/MDR cell lines and peripheral blood mononuclear cells (PBMC) of CML patients. However, no significant changes of FUT2 were observed. The altered levels of FUT1 had a significant impact on the phenotypic variation of MDR of K562 and K562/ADR cells, the activity of EGFR/MAPK pathway and P-glycoprotein (P-gp) expression. Blocking the EGFR/MAPK pathway by its specific inhibitor PD153035 or EGFR small interfering RNA (siRNA) resulted in the reduced MDR of K562/ADR cells. This study indicated that α(1,2)-fucosyltransferase involved in the development of MDR of CML cells probably through FUT1 regulated the activity of EGFR/MAPK signaling pathway and the expression of P-gp.
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MESH Headings
- ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism
- Down-Regulation
- Drug Resistance, Multiple
- Drug Resistance, Neoplasm
- ErbB Receptors/metabolism
- Fucosyltransferases/physiology
- Gene Expression
- Gene Expression Regulation, Enzymologic
- Gene Expression Regulation, Neoplastic
- Humans
- K562 Cells
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/enzymology
- Mitogen-Activated Protein Kinases/metabolism
- Galactoside 2-alpha-L-fucosyltransferase
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Affiliation(s)
- Yuxuan Che
- Department of Medical Oncology, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116027, P.R. China
| | - Xing Ren
- College of Stomatology, Dalian Medical University, Dalian, Liaoning 116027, P.R. China
| | - Liye Xu
- Department of Medical Oncology, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116027, P.R. China
| | - Xiaolei Ding
- Department of Medical Oncology, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116027, P.R. China
| | - Xuan Zhang
- Department of Medical Oncology, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116027, P.R. China
| | - Xiuhua Sun
- Department of Medical Oncology, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116027, P.R. China
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11
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Saeed M, Jacob S, Sandjo LP, Sugimoto Y, Khalid HE, Opatz T, Thines E, Efferth T. Cytotoxicity of the Sesquiterpene Lactones Neoambrosin and Damsin from Ambrosia maritima Against Multidrug-Resistant Cancer Cells. Front Pharmacol 2015; 6:267. [PMID: 26617519 PMCID: PMC4637410 DOI: 10.3389/fphar.2015.00267] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2015] [Accepted: 10/26/2015] [Indexed: 12/26/2022] Open
Abstract
Multidrug resistance is a prevailing phenomenon leading to chemotherapy treatment failure in cancer patients. In the current study two known cytotoxic pseudoguaianolide sesquiterpene lactones; neoambrosin (1) and damsin (2) that circumvent MDR were identified. The two cytotoxic compounds were isolated using column chromatography, characterized using 1D and 2D NMR, MS, and compared with literature values. The isolated compounds were investigated for their cytotoxic potential using resazurin assays and thereafter confirmed with immunoblotting and in silico studies. MDR cells overexpressing ABC transporters (P-glycoprotein, BCRP, ABCB5) did not confer cross-resistance toward (1) and (2), indicating that these compounds are not appropriate substrates for any of the three ABC transporters analyzed. Resistance mechanisms investigated also included; the loss of the functions of the TP53 and the mutated EGFR. The HCT116 p53-/- cells were sensitive to 1 but resistant to 2. It was interesting to note that resistant cells transfected with oncogenic ΔEGFR exhibited hypersensitivity CS toward (1) and (2) (degrees of resistances were 0.18 and 0.15 for (1) and (2), respectively). Immunoblotting and in silico analyses revealed that 1 and 2 silenced c-Src kinase activity. It was hypothesized that inhibition of c-Src kinase activity may explain CS in EGFR-transfected cells. In conclusion, the significant cytotoxicity of 1 and 2 against different drug-resistant tumor cell lines indicate that they may be promising candidates to treat refractory tumors.
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Affiliation(s)
- Mohamed Saeed
- Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University of Mainz Mainz, Germany
| | - Stefan Jacob
- Institut für Biotechnologie und Wirkstoff-Forschung Kaiserslautern, Germany
| | - Louis P Sandjo
- Department of Pharmaceutical Sciences, Centro de Ciências da Saúde, Universidade Federal de Santa Catarina Florianópolis, Brazil ; Institute of Organic Chemistry, Johannes Gutenberg University of Mainz Mainz, Germany
| | - Yoshikazu Sugimoto
- Division of Chemotherapy, Faculty of Pharmacy, Keio University Tokyo, Japan
| | - Hassan E Khalid
- Department of Pharmacognosy, University of Khartoum Khartoum, Sudan
| | - Till Opatz
- Institute of Organic Chemistry, Johannes Gutenberg University of Mainz Mainz, Germany
| | - Eckhard Thines
- Institut für Biotechnologie und Wirkstoff-Forschung Kaiserslautern, Germany ; Institute of Biotechnology and Drug Research, Johannes Gutenberg University of Mainz Mainz, Germany
| | - Thomas Efferth
- Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University of Mainz Mainz, Germany
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12
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Chu C, Noël-Hudson M, Bénard J, Ha-Duong T, Allaoui F, Farinotti R, Bonhomme-Faivre L. Cetuximab directly inhibits P-glycoprotein function in vitro independently of EGFR binding. Eur J Pharm Sci 2015; 76:18-26. [DOI: 10.1016/j.ejps.2015.04.014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2014] [Revised: 04/17/2015] [Accepted: 04/19/2015] [Indexed: 12/17/2022]
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13
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Hoffmann K, Ganten T, Gotthardtp D, Radeleff B, Settmacher U, Kollmar O, Nadalin S, Karapanagiotou-Schenkel I, von Kalle C, Jäger D, Büchler MW, Schemmer P. Impact of neo-adjuvant Sorafenib treatment on liver transplantation in HCC patients - a prospective, randomized, double-blind, phase III trial. BMC Cancer 2015; 15:392. [PMID: 25957784 PMCID: PMC4449604 DOI: 10.1186/s12885-015-1373-z] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2014] [Accepted: 04/27/2015] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Liver Transplantation (LT) is treatment of choice for patients with hepatocellular carcinoma (HCC) within MILAN Criteria. Tumour progression and subsequent dropout from waiting list have significant impact on the survival. Transarterial chemoembolization (TACE) controls tumour growth in the treated HCC nodule, however, the risk of tumour development in the untreated liver is increased by simultaneous release of neo-angiogenic factors. Due to its anti-angiogenic effects, Sorafenib delays the progression of HCC. Aim of this study was to determine whether combination of TACE and Sorafenib improves tumour control in HCC patients on waiting list for LT. METHODS Fifty patients were randomly assigned on a 1:1 ratio in double-blinded fashion at four centers in Germany and treated with TACE plus either Sorafenib (n = 24) or placebo (n = 26). The end of treatment was development of progressive disease according to mRECIST criteria or LT. The primary endpoint of the trial was the Time-to-Progression (TTP). Other efficacy endpoints were Tumour Response, Progression-free Survival (PFS), and Time-to-LT (TTLT). RESULTS The median time of treatment was 125 days with Sorafenib and 171 days with the placebo. Fourteen patients (seven from each group) developed tumour progression during the course of the study period. The Hazard Ratio of TTP was 1.106 (95% CI: 0.387, 3.162). The results of the Objective Response Rate, Disease Control Rate, PFS, and TTLT were comparable in both groups. The incidence of AEs was comparable in the placebo group (n = 23, 92%) and in the Sorafenib group (n = 23, 96%). Twelve patients (50%) on Sorafenib and four patients (16%) on placebo experienced severe treatment-related AEs. CONCLUSION The TTP is similar after neo-adjuvant treatment with TACE and Sorafenib before LT compared to TACE and placebo. The Tumour Response, PFS, and TTLT were comparable. The safety profile of the Sorafenib group was similar to that of the placebo group. TRIAL REGISTRATION ISRCTN24081794.
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Affiliation(s)
- Katrin Hoffmann
- Department of General-, Visceral- and Transplantation-Surgery, Ruprecht-Karls-University, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
| | - Tom Ganten
- Department of Internal Medicine, Ruprecht-Karls-University, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
| | - Daniel Gotthardtp
- Department of Internal Medicine, Ruprecht-Karls-University, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
| | - Boris Radeleff
- Department of Radiology, Ruprecht-Karls-University, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
| | - Utz Settmacher
- Department of General-, Visceral- and Vascular-Surgery, University Hospital, Erlanger Allee 101, 07747, Jena, Germany.
| | - Otto Kollmar
- Department of General and Visceral Surgery, Georg-August-University, Robert-Koch-Str. 40, 37075, Göttingen, Germany.
| | - Silvio Nadalin
- Department of Surgery, University Hospital, Hoppe-Seyler-Straße 3, 72076, Tübingen, Germany.
| | | | - Christof von Kalle
- National Centre of Tumour Diseases, Ruprecht-Karls-University, Im Neuenheimer Feld 460, 69120, Heidelberg, Germany.
| | - Dirk Jäger
- National Centre of Tumour Diseases, Ruprecht-Karls-University, Im Neuenheimer Feld 460, 69120, Heidelberg, Germany.
| | - Markus W Büchler
- Department of General-, Visceral- and Transplantation-Surgery, Ruprecht-Karls-University, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
| | - Peter Schemmer
- Department of General-, Visceral- and Transplantation-Surgery, Ruprecht-Karls-University, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
- Department of General- Visceral- and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 110, D-69120, Heidelberg, Germany.
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14
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Cuestas ML, Oubiña JR, Mathet VL. Hepatocellular carcinoma and multidrug resistance: Past, present and new challenges for therapy improvement. World J Pharmacol 2015; 4:96-116. [DOI: 10.5497/wjp.v4.i1.96] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Revised: 10/02/2014] [Accepted: 12/01/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most frequent form of liver cancer and the third most common cause of cancer-related death in the world. The main risk factor worldwide for this type of malignancy is chronic hepatitis caused by hepatitis B virus and hepatitis C virus infections. Advances in early detection and treatment have improved life expectancy of patients with HCC. However, this disorder remains as a disease with poor prognosis. In fact, epidemiological studies have revealed that there is an 8-mo median survival rate in patients, approximately 20% of whom survive one year while only 5% remain alive after three years. Additionally, HCC is particularly difficult to treat because of its high recurrence rate, and its resistance to conventional chemotherapy is due, among other mechanisms, to several members of the ATP-Binding Cassette protein family involved in drug transport being overexpressed. Fortunately, there is evidence that these patients may benefit from alternative molecular-targeted therapies. This manuscript intends to provide further insight into the etiology and molecular mechanisms related to HCC development and the latest therapeutic approaches to treat this malignancy. The development of effective delivery systems of antitumor drugs able to target the liver parenchyma is also assessed. Finally, the prospects in the development of more efficient drug therapies to overcome multidrug resistance are also examined.
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15
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Su X, Cheng K, Jeon J, Shen B, Venturin GT, Hu X, Rao J, Chin FT, Wu H, Cheng Z. Comparison of two site-specifically (18)F-labeled affibodies for PET imaging of EGFR positive tumors. Mol Pharm 2014; 11:3947-56. [PMID: 24972326 PMCID: PMC4218868 DOI: 10.1021/mp5003043] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
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The
epidermal growth factor receptor (EGFR) serves as an attractive target
for cancer molecular imaging and therapy. Our previous positron emission
tomography (PET) studies showed that the EGFR-targeting affibody molecules 64Cu-DOTA-ZEGFR:1907 and 18F-FBEM-ZEGFR:1907 can discriminate between high and low EGFR-expression
tumors and have the potential for patient selection for EGFR-targeted
therapy. Compared with 64Cu, 18F may improve
imaging of EGFR-expression and is more suitable for clinical application,
but the labeling reaction of 18F-FBEM-ZEGFR:1907 requires a long synthesis time. The aim of the present study is
to develop a new generation of 18F labeled affibody probes
(Al18F-NOTA-ZEGFR:1907 and 18F-CBT-ZEGFR:1907) and to determine whether they are suitable agents
for imaging of EGFR expression. The first approach consisted of conjugating
ZEGFR:1907 with NOTA and radiolabeling with Al18F to produce Al18F-NOTA-ZEGFR:1907. In a second
approach the prosthetic group 18F-labeled-2-cyanobenzothiazole
(18F-CBT) was conjugated to Cys-ZEGFR:1907 to
produce 18F-CBT-ZEGFR:1907. Binding affinity
and specificity of Al18F-NOTA-ZEGFR:1907 and 18F-CBT-ZEGFR:1907 to EGFR were evaluated using
A431 cells. Biodistribution and PET studies were conducted on mice
bearing A431 xenografts after injection of Al18F-NOTA-ZEGFR:1907 or 18F-CBT-ZEGFR:1907 with
or without coinjection of unlabeled affibody proteins. The radiosyntheses
of Al18F-NOTA-ZEGFR:1907 and 18F-CBT-ZEGFR:1907 were completed successfully within 40 and 120 min
with a decay-corrected yield of 15% and 41% using a 2-step, 1-pot
reaction and 2-step, 2-pot reaction, respectively. Both probes bound
to EGFR with low nanomolar affinity in A431 cells. Although 18F-CBT-ZEGFR:1907 showed instability in vivo, biodistribution studies revealed rapid and high tumor accumulation
and quick clearance from normal tissues except the bones. In contrast,
Al18F-NOTA-ZEGFR:1907 demonstrated high in vitro and in vivo stability, high tumor
uptake, and relative low uptake in most of the normal organs except
the liver and kidneys at 3 h after injection. The specificity of both
probes for A431 tumors was confirmed by their lower uptake on coinjection
of unlabeled affibody. PET studies showed that Al18F-NOTA-ZEGFR:1907 and 18F-CBT-ZEGFR:1907 could
clearly identify EGFR positive tumors with good contrast. Two strategies
for 18F-labeling of affibody molecules were successfully
developed as two model platforms using NOTA or CBT coupling to affibody
molecules that contain an N-terminal cysteine. Al18F-NOTA-ZEGFR:1907 and 18F-CBT-ZEGFR:1907 can
be reliably obtained in a relatively short time. Biodistribution and
PET studies demonstrated that Al18F-NOTA-ZEGFR:1907 is a promising PET probe for imaging EGFR expression in living mice.
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Affiliation(s)
- Xinhui Su
- Department of Nuclear Medicine, Zhongshan Hospital Xiamen University , Xiamen 361004, China
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16
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Frasca F, Vella V, Nicolosi ML, Messina RL, Gianì F, Lotta S, Vigneri P, Regalbuto C, Vigneri R. Thyroid cancer cell resistance to gefitinib depends on the constitutive oncogenic activation of the ERK pathway. J Clin Endocrinol Metab 2013; 98:2502-12. [PMID: 23559083 DOI: 10.1210/jc.2012-3623] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
CONTEXT Poorly differentiated thyroid carcinomas are refractory to common anticancer therapies, and novel inhibitors are being tested in these deadly malignancies. The epidermal growth factor receptor (EGFR) tyrosine kinase represents an attractive target for treatment because it is up-regulated in thyroid cancer and plays a role in cancer progression. However, EGFR inhibitors have provided poor results in thyroid carcinomas. OBJECTIVE We evaluated the possible mechanism underlying the resistance of thyroid cancer cells to EGFR inhibitors. DESIGN We tested the effect of the EGFR tyrosine kinase inhibitor gefitinib in a panel of thyroid cancer cell lines. RESULTS We found that in most of the cell lines, although gefitinib inhibited EGFR phosphorylation, it was poorly effective in reducing cell viability. gefitinib, however, was able to inhibit epidermal growth factor-induced cell migration and matrix invasion. In most thyroid cancer cell lines, gefitinib significantly inhibited Akt phosphorylation by inhibiting EGFR activation, but it had limited or no effect on ERK phosphorylation. The poor cell response to gefitinib was associated with genetic alterations, leading to constitutive activation of the ERK pathway, including BRAF(V600E) and HRAS(G12A/Q61R) mutations and RET/PTC1 rearrangement. When BRAF(V600E)-positive thyroid cancer cells were incubated with the specific BRAF inhibitor PLX4032, sensitivity to gefitinib was restored. Similar results were obtained with rat sarcoma and RET/papillary thyroid cancer inhibitors. CONCLUSIONS These results indicate that thyroid cancer resistance to gefitinib is due to the constitutive activation of the mitogenic pathway by either signals downstream of EGFR or other tyrosine kinase receptors. This resistance can be overcome by the combined use of selective inhibitors.
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Affiliation(s)
- Francesco Frasca
- Endocrinology Unit, Department of Clinical and Molecular Bio-Medicine, University of Catania, Garibaldi-Nesima Medical Center, Via Palermo 636, 95122 Catania, Italy.
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17
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Lin S, Hoffmann K, Xiao Z, Jin N, Galli U, Mohr E, Büchler MW, Schemmer P. MEK inhibition induced downregulation of MRP1 and MRP3 expression in experimental hepatocellular carcinoma. Cancer Cell Int 2013; 13:3. [PMID: 23320839 PMCID: PMC3558388 DOI: 10.1186/1475-2867-13-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2012] [Accepted: 01/07/2013] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) exhibits strong intrinsic and acquired drug resistance which is the main obstacle to chemotherapy. Overexpression of ATP binding cassette (ABC) proteins correlates with activation of mitogen activated protein kinase (MAPK) pathway in HCC. Here, we systematically investigated the inhibition of MAPK pathway and its role in regulating HCC cell growth as well as ABC proteins MRP1 and MRP3 expression. METHODS The Raf1 kinase inhibitor (GW5074) and different MEK inhibitors (U0126 and AZD6244) were used to treat HCC cells to identify their effects on HCC cell growth and ABC proteins expression in vitro. Cell viability tests were performed after the treatment of MAPK pathway inhibitors and in combination with gemcitabine or doxorubicin. Western blot was applied to assess the changes of MAPK pathway and protein expression of MRP1 and MRP3. Flow cytometry was used to measure intracellular doxorubicin accumulation after the treatment of MEK inhibitors. RESULTS Both Raf1 inhibitor (GW5074) and MEK inhibitors (U0126 and AZD6244) suppressed HCC cell growth in a dose dependent manner. Pre-treatment of MEK inhibitor U0126 or AZD6244 sensitized HCC cells to gemcitabine or doxorubicin based chemotherapy. Raf1 inhibitor GW5074 had no effect on MRP1 and MRP3 protein expression. Treatment of gemcitabine or doxorubicin activated phosphorylated ERK and induced the upregulation of MRP1 and MRP3. MEK inhibitors U0126 and AZD6244 deactivated phosphorylated ERK, decreased endogenous MRP1 expression, reversed gemcitabine or doxorubicin induced MRP1 and MRP3 upregulation, and increased the intracellular doxorubicin accumulation. CONCLUSION This study provides evidence that MEK inhibitors sensitize HCC cells to chemotherapy by increasing intracellular chemodrug accumulation. MEK inhibirors U0126 and AZD6244 reduced MRP1 as well as MRP3 expression, and may contribute partially to the sensitization. The combination of MEK inhibitor and conventional chemotherapy may offer new therapeutic option for the treatment of resistant HCC.
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Affiliation(s)
- Shibo Lin
- Department of General and Transplant Surgery, Ruprecht-Karls-University, Im Neuenheimer Feld 110, Heidelberg, 69120, Germany
| | - Katrin Hoffmann
- Department of General and Transplant Surgery, Ruprecht-Karls-University, Im Neuenheimer Feld 110, Heidelberg, 69120, Germany
| | - Zhi Xiao
- Department of Breast Surgery, Xiangya Hospital, Zhongnan University, Changsha, 410008, China
| | - Nan Jin
- Department of Hematology, Oncology, and Rheumatology, Ruprecht-Karls-University, Heidelberg, 69120, Germany
| | - Uwe Galli
- Department of General and Transplant Surgery, Ruprecht-Karls-University, Im Neuenheimer Feld 110, Heidelberg, 69120, Germany
| | - Elvira Mohr
- Department of General and Transplant Surgery, Ruprecht-Karls-University, Im Neuenheimer Feld 110, Heidelberg, 69120, Germany
| | - Markus W Büchler
- Department of General and Transplant Surgery, Ruprecht-Karls-University, Im Neuenheimer Feld 110, Heidelberg, 69120, Germany
| | - Peter Schemmer
- Department of General and Transplant Surgery, Ruprecht-Karls-University, Im Neuenheimer Feld 110, Heidelberg, 69120, Germany
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Xu K, Liang X, Shen K, Sun L, Cui D, Zhao Y, Tian J, Ni L, Liu J. MiR-222 modulates multidrug resistance in human colorectal carcinoma by down-regulating ADAM-17. Exp Cell Res 2012; 318:2168-77. [PMID: 22677042 DOI: 10.1016/j.yexcr.2012.04.014] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2012] [Revised: 04/10/2012] [Accepted: 04/13/2012] [Indexed: 12/15/2022]
Abstract
Colorectal carcinoma is a frequent cause of cancer-related death in men and women throughout the world. MicroRNAs are endogenous small noncoding RNAs that negatively regulate gene expression at the posttranscriptional level. We investigated the role of ADAM-17 (a desintegrin and metalloproteases 17) as a novel multidrug resistance (MDR) mechanism in multidrug-resistant colorectal carcinoma (CRC) and the role of miR-222 in the development of MDR in CRC cells. We found that the high expression of ADAM-17, which results in growth factor shedding and growth factor receptor activation could induce drug resistance in CRC. Pharmacological inhibition of ADAM-17, in conjunction with chemotherapy, may have therapeutic potential for the treatment of CRC. ADAM-17 is a predicted target of miR-222, which was downregulated in multidrug-resistant CRC cells. The presence of miR-222 was consistently inversely proportionate to the expression levels of ADAM-17. We found that elevated levels of miR-222 in the mimics-transfected HCT116/L-OHP and HCT-8/VCR cells reduced the ADAM-17 protein level and the luciferase activity of an ADAM-17 3' untranslated region-based reporter and sensitized these cells' apoptosis to some anticancer drugs. Our findings suggest that miR-222 could play a role in the development of MDR by modulation of ADAM-17, the new MDR treatment target in colorectal carcinoma cells.
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Affiliation(s)
- Ke Xu
- State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of pharmacy, East China University of Science and Technology, Shanghai, PR China
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