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New benzoxazole derivatives as potential VEGFR-2 inhibitors and apoptosis inducers: design, synthesis, anti-proliferative evaluation, flowcytometric analysis, and in silico studies.

Hazem Elkady, Alaa Elwan, Hesham A El-Mahdy, Ahmed S Doghish, Ahmed Ismail, Mohammed S Taghour, Eslam B Elkaeed, Ibrahim H Eissa, Mohammed A Dahab, Hazem A Mahdy, Mohamed M Khalifa,

A new series of benzoxazole derivatives were designed and synthesised to have the main essential pharmacophoric features of VEGFR-2 inhibitors. Cytotoxic activities were evaluated for all derivatives against two human cancer cell lines, MCF-7 and HepG2. Also, the effect of the most cytotoxic derivatives on VEGFR-2 protein concentration was assessed ... Read more >>

J Enzyme Inhib Med Chem (Journal of enzyme inhibition and medicinal chemistry)
[2022, 37(1):397-410]

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Synthesis, biological evaluation, and molecular docking of new series of antitumor and apoptosis inducers designed as VEGFR-2 inhibitors.

Abdallah E Abdallah, Reda R Mabrouk, Maged Mohammed Saleh Al Ward, Sally I Eissa, Eslam B Elkaeed, Ahmed B M Mehany, Mariam A Abo-Saif, Ola A El-Feky, Mohamed S Alesawy, Mohamed Ayman El-Zahabi,

Based on quinazoline, quinoxaline, and nitrobenzene scaffolds and on pharmacophoric features of VEGFR-2 inhibitors, 17 novel compounds were designed and synthesised. VEGFR-2 IC<sub>50</sub> values ranged from 60.00 to 123.85 nM for the new derivatives compared to 54.00 nM for sorafenib. Compounds <b>15<sub>a</sub></b>, <b>15<sub>b</sub></b>, and <b>15<sub>d</sub></b> showed IC<sub>50</sub> from 17.39 to 47.10 µM against ... Read more >>

J Enzyme Inhib Med Chem (Journal of enzyme inhibition and medicinal chemistry)
[2022, 37(1):573-591]

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1,3,4-Oxadiazole-naphthalene hybrids as potential VEGFR-2 inhibitors: design, synthesis, antiproliferative activity, apoptotic effect, and in silico studies.

Mohamed Hagras, Marwa A Saleh, Rogy R Ezz Eldin, Abdelrahman A Abuelkhir, Emad Gamil Khidr, Ahmed A El-Husseiny, Hesham A El-Mahdy, Eslam B Elkaeed, Ibrahim H Eissa,

In the current work, some 1,3,4-oxadiazole-naphthalene hybrids were designed and synthesised as VEGFR-2 inhibitors. The synthesised compounds were evaluated <i>in vitro</i> for their antiproliferative activity against two human cancer cell lines namely, HepG-2 and MCF-7. Compounds that exhibited promising cytotoxicity (<b>5</b>, <b>8</b>, <b>15</b>, <b>16</b>, <b>17</b>, and <b>18</b>) were further evaluated for ... Read more >>

J Enzyme Inhib Med Chem (Journal of enzyme inhibition and medicinal chemistry)
[2022, 37(1):380-396]

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Natural inspired piperine-based ureas and amides as novel antitumor agents towards breast cancer.

Diaaeldin M Elimam, Abdullah A Elgazar, Fardous F El-Senduny, Ramadan A El-Domany, Farid A Badria, Wagdy M Eldehna,

In this work, the natural piperine moiety was utilised to develop two sets of piperine-based amides (5a-i) and ureas (8a-y) as potential anticancer agents. The anticancer action was assessed against triple negative breast cancer (TNBC) MDA-MB-231, ovarian A2780CP and hepatocellular HepG2 cancer cell lines. In particular, 8q stood out as ... Read more >>

J Enzyme Inhib Med Chem (Journal of enzyme inhibition and medicinal chemistry)
[2022, 37(1):39-50]

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Deciphering the molecular mechanism of tetrandrine in inhibiting hepatocellular carcinoma and increasing sorafenib sensitivity by combining network pharmacology and experimental evaluation.

Biao Niu, Sidong Wei, Jianjun Sun, Huibo Zhao, Bing Wang, Guoyong Chen,

<h4>Context</h4>The mechanism of tetrandrine (TET) in hepatocellular carcinoma (HCC) progression and sorafenib (Sora) chemosensitivity deserves investigation.<h4>Objective</h4>Using network pharmacology approaches to elucidate the mechanisms of TET in HCC.<h4>Materials and methods</h4>CCK-8, colony formation, and flow cytometry assays were used to measure cell phenotypes. BALB/c nude mice were divided into Control, Sora (10 mg/kg), ... Read more >>

Pharm Biol (Pharmaceutical biology)
[2022, 60(1):75-86]

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The hsa_circRNA_102049 mediates the sorafenib sensitivity of hepatocellular carcinoma cells by regulating Reelin gene expression.

Shaolei Wang, Dehua Liu, Hong Wei, Yang Hua, Guodong Shi, Jinhan Qiao,

A growing body of research has illuminated that non-coding RNAs (ncRNAs) plays an important role in the development of drug resistance in hepatocellular carcinoma (HCC) cells. The expression profiles of differential expressed genes (DEGs) and ncRNAs related to the sorafenib resistance in HCC cells were analyzed according to the Gene ... Read more >>

Bioengineered (Bioengineered)
[2022, 13(2):2272-2284]

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Long intergenic non-protein coding RNA 1273 confers sorafenib resistance in hepatocellular carcinoma via regulation of methyltransferase 3.

Huifang Kong, Jie Sun, Wei Zhang, Huixin Zhang, Hong Li,

Hepatocellular carcinoma (HCC) is often diagnosed in patients with advanced disease who are ineligible for curative surgical therapies. Sorafenib is a first-line agent approved for the treatment of advanced HCC. However, the frequent resistance of HCC cells to sorafenib greatly reduces its efficacy. Herein, we describe a novel long non-coding ... Read more >>

Bioengineered (Bioengineered)
[2022, 13(2):3108-3121]

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Combining immune checkpoint inhibitor with lenvatinib prolongs survival than lenvatinib alone in sorafenib-experienced hepatocellular carcinoma patients.

Po-Ting Lin, Wei Teng, Wen-Juei Jeng, Chun-Yen Lin, Shi-Ming Lin, I-Shyan Sheen,

<h4>Background</h4>Lenvatinib and immune checkpoint inhibitors (ICIs) were approved as the promising agents for unresectable hepatocellular carcinoma (HCC). Nevertheless, the benefits of combining ICI with lenvatinib in sorafenib-experienced patients remain uncertain. We aimed to investigate whether the combination use of ICI and lenvatinib provides better survival than lenvatinib alone in advanced ... Read more >>

Eur J Gastroenterol Hepatol (European journal of gastroenterology & hepatology)
[2022, 34(2):213-219]

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Epigenetic regulation of ferroptosis via ETS1/miR-23a-3p/ACSL4 axis mediates sorafenib resistance in human hepatocellular carcinoma.

Yuanjun Lu, Yau-Tuen Chan, Hor-Yue Tan, Cheng Zhang, Wei Guo, Yu Xu, Rakesh Sharma, Zhe-Sheng Chen, Yi-Chao Zheng, Ning Wang, Yibin Feng,

<h4>Background</h4>Drug resistance to sorafenib greatly limited the benefits of treatment in patients with hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) participate in the development of drug resistance. The key miRNA regulators related to the clinical outcome of sorafenib treatment and their molecular mechanisms remain to be identified.<h4>Methods</h4>The clinical significance of miRNA-related epigenetic ... Read more >>

J Exp Clin Cancer Res (Journal of experimental & clinical cancer research : CR)
[2022, 41(1):3]

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Recent advances in systemic therapy for hepatocellular carcinoma.

Huajun Zhang, Wuyang Zhang, Longying Jiang, Yongheng Chen,

Hepatocellular carcinoma (HCC) is one of the most common and lethal malignant tumors in the world. Therapeutic options for advanced HCC are limited. Systemic treatment, especially with conventional cytotoxic drugs, is usually ineffective. For more than a decade, sorafenib has been the only systemic drug that has been proven to ... Read more >>

Biomark Res (Biomarker research)
[2022, 10(1):3]

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Ago-RIP Sequencing Identifies New MicroRNA-449a-5p Target Genes Increasing Sorafenib Efficacy in Hepatocellular Carcinoma.

Thea Reinkens, Amelie Stalke, Nicole Huge, Beate Vajen, Marlies Eilers, Vera Schäffer, Oliver Dittrich-Breiholz, Brigitte Schlegelberger, Thomas Illig, Britta Skawran,

<b>BACKGROUND:</b> Patients with hepatocellular carcinoma (HCC) have very limited treatment options. For the last fourteen years, the multi-tyrosine kinase inhibitor sorafenib has been used as standard-of-care therapeutic agent in advanced HCC. Unfortunately, drug resistance develops in many cases. Therefore, we aimed to find a way to mitigate drug resistance and ... Read more >>

J Cancer (Journal of Cancer)
[2022, 13(1):62-75]

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Outcomes of sorafenib treatment of advanced renal cell carcinoma according to International Metastatic Renal Cell Carcinoma Data Consortium risk criteria: analysis of Japanese real-world data from postmarketing all-patient surveillance of sorafenib.

Teruo Inamoto, Haruhito Azuma, Masatoshi Adachi, Yutaka Okayama, Toshiyuki Sunaya, Mototsugu Oya,

<b>Aim:</b> To assess sorafenib survival outcomes in renal cell carcinoma patients using standard International Metastatic Renal Cell Carcinoma Data Consortium (IMDC) risk criteria. <b>Patients & methods:</b> The authors restratified a real-world cohort of 3255 advanced renal cell carcinoma patients, obtained from Japanese sorafenib postmarketing surveillance, to assess survival outcomes using ... Read more >>

Future Oncol (Future oncology (London, England))
[2022, :]

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Cholesterol Sensor SCAP Contributes to Sorafenib Resistance by Regulating Autophagy in Hepatocellular Carcinoma

Danyang Li, Yingcheng Yao, Yuhan Rao, Xinyu Huang, Li Wei, Zhimei You, Guo Zheng, Xiaoli Hou, Yu Su, Zac Varghese, John Moorhead, Yaxi Chen, Xiong Ruan,

<h4>Background: </h4> Hepatocellular carcinoma (HCC) is one of the most malignant tumors and the fourth leading cause of cancer-related death worldwide. Sorafenib is currently acknowledged as a standard therapy for advanced HCC. However, acquired resistance substantially limits the clinical efficacy of sorafenib. Therefore, further investigations of the associated risk factors ... Read more >>

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Single cell RNA-seq analysis identifies a noncoding RNA mediating resistance to sorafenib treatment in HCC.

Kevin Zhou, Romario Nguyen, Liang Qiao, Jacob George,

Mol Cancer (Molecular cancer)
[2022, 21(1):6]

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MiRNA-124-3p.1 sensitizes hepatocellular carcinoma cells to sorafenib by regulating FOXO3a by targeting AKT2 and SIRT1.

Zhe-Bin Dong, Heng-Miao Wu, Yi-Cheng He, Zhong-Ting Huang, Yi-Hui Weng, Hong Li, Chao Liang, Wei-Ming Yu, Wei Chen,

As a multikinase inhibitor, sorafenib is commonly used to treat patients with advanced hepatocellular carcinoma (HCC), however, acquired resistance to sorafenib is a major obstacle to the effectiveness of this treatment. Thus, in this study, we investigated the mechanisms underlying sorafenib resistance as well as approaches devised to increase the ... Read more >>

Cell Death Dis (Cell death & disease)
[2022, 13(1):35]

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Maternal embryonic leucine zipper kinase serves as a potential prognostic marker and leads to sorafenib chemoresistance modified by miR-142-5p in hepatocellular carcinoma.

Hualei Li, Ling Gai, Zhimei Wu, Feng Li,

<h4>Background</h4>Chemotherapy is an important treatment strategy for advanced hepatocellular carcinoma (HCC). Sorafenib is a first-line systemic drug that has been commonly used clinically for patients with advanced HCC. However, the high resistance rate of sorafenib in HCC patients often hinders its long-term efficacy. Therefore, it is vital to reveal the ... Read more >>

Mol Biol Rep (Molecular biology reports)
[2022, :]

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Real-Life Clinical Data of Lenvatinib versus Sorafenib for Unresectable Hepatocellular Carcinoma in Italy.

Valentina Burgio, Massimo Iavarone, Giovanni Giuseppe Di Costanzo, Fabio Marra, Sara Lonardi, Emiliano Tamburini, Fabio Piscaglia, Gianluca Masi, Ciro Celsa, Francesco Giuseppe Foschi, Marianna Silletta, Daniela Caterina Amoruso, Margherita Rimini, Mariangela Bruccoleri, Raffaella Tortora, Claudia Campani, Caterina Soldà, Massimo Giuseppe Viola, Antonella Forgione, Fabio Conti, Francesca Salani, Silvia Catanese, Carmelo Marco Giacchetto, Claudia Fulgenzi, Carmine Coppola, Pietro Lampertico, Antonio Pellino, Gabriele Rancatore, Giuseppe Cabibbo, Francesca Ratti, Federica Pedica, Angelo Della Corte, Massimo Colombo, Francesco De Cobelli, Luca Aldrighetti, Stefano Cascinu, Andrea Casadei-Gardini,

<h4>Background</h4>Lenvatinib has been approved in Italy since October 2019 as a first-line therapy for advanced hepatocellular carcinoma (HCC) and to date data on effectiveness and safety of lenvatinib are not available in our region. To fill this gap, we performed a multicentric analysis of the real-world treatment outcomes with the ... Read more >>

Cancer Manag Res (Cancer management and research)
[2021, 13:9379-9389]

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Efficacy and Safety of Radiotherapy Plus Anti-PD1 Versus Transcatheter Arterial Chemoembolization Plus Sorafenib For Advanced Hepatocellular Carcinoma: a Real-World Study

Jian-Xu Li, Wen-Xiang Deng, Shi-Ting Huang, Xiao-Feng Lin, Mei-Ying Long, Jie Zhang, Ting-Shi Su, Li-Qing Li, Ya-Dan Pang, Chun-Feng Liang, Hong-Mei Zhou, Hai-Yan Lu, Shi-Xiong Liang, Bang-De Xiang,

<h4>Background: </h4> The combination of transcatheter arterial chemoembolization (TACE) plus sorafenib prolonged progression-free survival (PFS) and overall survival (OS) than sorafenib or TACE monotherapy for patients with hepatocellular carcinoma (HCC). This study assessed the efficacy and safety of radiotherapy (RT) plus monoclonal antibody against programmed cell death 1 (anti-PD1) versus ... Read more >>

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First-Line Systemic Treatment Strategies for Unresectable Hepatocellular Carcinoma: A Systematic Review and Network Meta-Analysis of Randomized Clinical Trials.

Wenfeng Liu, Bing Quan, Shenxin Lu, Bei Tang, Miao Li, Rongxin Chen, Zhenggang Ren, Xin Yin,

<h4>Objective</h4>Several new first-line treatments were recently approved for unresectable hepatocellular carcinoma (HCC). In this meta-analysis, we compare the efficacy and safety of first-line systemic treatments to provide information for clinical decision making in unresectable HCC.<h4>Methods</h4>Pubmed, Science Direct, Web of Science, Scopus, Ovid MEDLINE, Embase, Google Scholar, the Cochrane Library, EMbase, ... Read more >>

Front Oncol (Frontiers in oncology)
[2021, 11:771045]

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Beneficial Prognostic Effects of Aspirin in Patients Receiving Sorafenib for Hepatocellular Carcinoma: A Tale of Multiple Confounders.

Luca Ielasi, Francesco Tovoli, Matteo Tonnini, Raffaella Tortora, Giulia Magini, Rodolfo Sacco, Tiziana Pressiani, Franco Trevisani, Vito Sansone, Giovanni Marasco, Fabio Piscaglia, Alessandro Granito,

Case-control observational studies suggested that aspirin might prevent hepatocellular carcinoma (HCC) in high-risk patients, even if randomized clinical trials are lacking. Information regarding aspirin in subjects who already developed HCC, especially in its advanced stage, are scarce. While aspirin might be a low-cost option to improve the prognosis, multiple confounders ... Read more >>

Cancers (Basel) (Cancers)
[2021, 13(24):]

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Dual sEH/COX-2 Inhibition Using PTUPB-A Promising Approach to Antiangiogenesis-Induced Nephrotoxicity.

Wojciech K Jankiewicz, Scott D Barnett, Anna Stavniichuk, Sung Hee Hwang, Bruce D Hammock, Jawad B Belayet, A H Khan, John D Imig,

Kidney injury from antiangiogenic chemotherapy is a significant clinical challenge, and we currently lack the ability to effectively treat it with pharmacological agents. Thus, we set out to investigate whether simultaneous soluble epoxide hydrolase (sEH) and cyclooxygenase-2 (COX-2) inhibition using a dual sEH/COX-2 inhibitor PTUPB could be an effective strategy ... Read more >>

Front Pharmacol (Frontiers in pharmacology)
[2021, 12:744776]

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Genome-wide CRISPR screen identifies regulators of MAPK and MTOR pathways mediating sorafenib resistance in acute myeloid leukemia.

Alisa Damnernsawad, Daniel Bottomly, Stephen E Kurtz, Christopher A Eide, Shannon K McWeeney, Jeffrey W Tyner, Tamilla Nechiporuk,

Drug resistance impedes the long-term effect of targeted therapies in acute myeloid leukemia (AML), necessitating the identification of mechanisms underlying resistance. Approximately 25% of AML patients carry FLT3 mutations and develop post-treatment insensitivity to FLT3 inhibitors, including sorafenib. Using a genome-wide CRISPR screen, we identified LZTR1, NF1, TSC1 or TSC2, ... Read more >>

Haematologica (Haematologica)
[2022, 107(1):77-85]

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Mitochondrial Plasticity Promotes Resistance to Sorafenib and Vulnerability to STAT3 Inhibition in Human Hepatocellular Carcinoma.

Shusil K Pandit, Giada Sandrini, Jessica Merulla, Valentina Nobili, Xin Wang, Alessia Zangari, Andrea Rinaldi, Dheeraj Shinde, Giuseppina M Carbone, Carlo V Catapano,

The multi-kinase inhibitor sorafenib is a primary treatment modality for advanced-stage hepatocellular carcinoma (HCC). However, the therapeutic benefits are short-lived due to innate and acquired resistance. Here, we examined how HCC cells respond to sorafenib and adapt to continuous and prolonged exposure to the drug. Sorafenib-adapted HCC cells show a ... Read more >>

Cancers (Basel) (Cancers)
[2021, 13(23):]

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Potential Synthetic Lethality for Breast Cancer: A Selective Sirtuin 2 Inhibitor Combined with a Multiple Kinase Inhibitor Sorafenib.

Hua-Li Wang, Xue Ma, Xin-Yuan Guan, Chen Song, Guo-Bo Li, Ya-Mei Yu, Ling-Ling Yang,

Sorafenib is a clinically useful multiple kinase inhibitor for the treatment of kidney cancer, liver cancer and acute myelocytic leukemia, while it has shown weak efficacy in suppressing breast cancer. Since sirtuin2 (SIRT2) is an important epigenetic regulator and associated with several cancer types including breast cancer, development and evaluation ... Read more >>

Pharmacol Res (Pharmacological research)
[2021, :106050]

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Case Report: Durable Response to Very Low Dose Tyrosine Kinase Inhibitors in Advanced Hepatocellular Carcinoma.

Tin-Yun Tang, Katherine Daunov, Richard T Lee,

The oral tyrosine kinase inhibitors (TKI) sorafenib, regorafenib, and cabozantinib are approved for advanced hepatocellular carcinoma (aHCC) and improve survival. However, patients on these medications frequently require dose reductions or discontinuation due to multiple side effects leading to poor tolerability. Here we report three different aHCC patients with clinical responses ... Read more >>

Front Oncol (Frontiers in oncology)
[2021, 11:780798]

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