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Jingya Sun, Xin Wang, Boyun Tang, Hongchun Liu, Minmin Zhang, Yueqin Wang, Fangfang Ping, Jian Ding, Aijun Shen, Meiyu Geng
Over the past decade, therapies targeting the VEGF/VEGFR and mTOR pathways have served as the standard of care for the clinical management of renal cell carcinoma (RCC) patients. Albeit promising, these targeted drugs have attained only modest clinical benefits with limited prolonged progression-free survival. Therefore, alternative reasonable and applicable therapeutic approaches should be introduced to improve the clinical outcome of RCC patients. Methods: FDA approved kinase inhibitors were screened to evaluate their abilities to suppress the proliferation of RCC cells...
2018: Theranostics
Yusuke Oku, Naoyuki Nishiya, Takaaki Tazawa, Takaya Kobayashi, Nanami Umezawa, Yasuyo Sugawara, Yoshimasa Uehara
The main reasons for failure of cancer chemotherapy are intrinsic and acquired drug resistance. The Hippo pathway effector Yes-associated protein (YAP) is associated with resistance to both cytotoxic and molecular targeted drugs. Several lines of evidence indicate that YAP activates transcriptional programmes to promote cell cycle progression and DNA damage responses. Therefore, we hypothesised that YAP is involved in the sensitivity of cancer cells to small-molecule agents targeting cell cycle-related proteins...
June 2018: FEBS Open Bio
Ryota Kanemaru, Fumiyuki Takahashi, Motoyasu Kato, Yoichiro Mitsuishi, Ken Tajima, Hiroaki Ihara, Moulid Hidayat, Aditya Wirawan, Yoshika Koinuma, Daisuke Hayakawa, Shigehiro Yagishita, Ryo Ko, Tadashi Sato, Norihiro Harada, Yuzo Kodama, Fariz Nurwidya, Shinichi Sasaki, Shin-Ichiro Niwa, Kazuhisa Takahashi
PURPOSE: Transforming growth factor β (TGFβ)-mediated epithelial-mesenchymal transition (EMT) of alveolar epithelial cells contributes to pulmonary fibrosis. Dasatinib (DAS), a potent and broad-spectrum tyrosine kinase inhibitor, has been widely studied as an anti-cancer agent. However, the therapeutic application of DAS for pulmonary fibrosis has not been clarified. Our purpose here is to investigate the effect of DAS on TGFβ1-induced EMT in human alveolar and bronchial epithelial cells in vitro and to evaluate the efficacy of DAS on lung fibrosis in vivo...
June 20, 2018: Lung
Federico Rossari, Filippo Minutolo, Enrico Orciuolo
Bcr-Abl inhibitors paved the way of targeted therapy epoch. Imatinib was the first tyrosine kinase inhibitor to be discovered with high specificity for Bcr-Abl protein resulting from t(9, 22)-derived Philadelphia chromosome. Although the specific targeting of that oncoprotein, several Bcr-Abl-dependent and Bcr-Abl-independent mechanisms of resistance to imatinib arose after becoming first-line therapy in chronic myelogenous leukemia (CML) treatment.Consequently, new specific drugs, namely dasatinib, nilotinib, bosutinib, and ponatinib, were rationally designed and approved for clinic to override resistances...
June 20, 2018: Journal of Hematology & Oncology
Shengping Wen, Yu Su, Rong Wu, Shiwei Zhou, Qianhao Min, Gao-Chao Fan, Li-Ping Jiang, Rong-Bin Song, Jun-Jie Zhu
The accurate therapeutic evaluation for chronic myeloid leukemia (CML) drug is of great importance to minimize side effects and enhance efficacy. Herein, a facile and precise surface-enhanced scattering (SERS) approach based on coupled plasmonic field has been introduced to evaluate the therapeutic outcomes of antileukemia drug through ultrasensitive assay of caspase-3 activity in apoptotic cells. Caspase-3 as an apoptosis indicator could specifically cleave the N-terminus of biotinylated DEVD-peptide (biotin-Gly-Asp-Gly-Asp-Glu-Val-Asp-Gly-Cys) immobilized on the Au nanoparticle-decorated TiO2 nanotube arrays (TiO2 /Au NTAs) substrate...
June 2, 2018: Biosensors & Bioelectronics
Takaaki Sugihara, Nathan W Werneburg, Matthew C Hernandez, Lin Yang, Ayano Kabashima, Petra Hirsova, Lavanya Yohanathan, Carlos Sosa, Mark Joseph Truty, George Vasmatzis, Gregory J Gores, Rory L Smoot
The hippo pathway effector, Yes-associated protein (YAP) is a transcriptional co-activator implicated in cholangiocarcinoma (CCA) pathogenesis. YAP is known to be regulated by a serine/threonine kinase relay module (MST1/2 - LATS1/2) culminating in phosphorylation of YAP at Serine 127 (S127) and cytoplasmic sequestration. However, YAP also undergoes tyrosine phosphorylation, and the role of tyrosine phosphorylation in YAP regulation remains unclear. Herein, YAP regulation by tyrosine phosphorylation was examined in human and mouse CCA cells, as well as patient-derived xenograft (PDX) models...
June 14, 2018: Molecular Cancer Research: MCR
Guanhua Rao, In-Kyu Kim, Fabio Conforti, Jing Liu, Yu-Wen Zhang, Giuseppe Giaccone
PURPOSE: Oncogenic KRAS mutations occur frequently in solid tumours, but no clinically applicable targeted strategy is yet available for treating human cancers with mutant KRAS. Here we aimed to identify a strategy for the treatment of KRAS-driven cancers. EXPERIMENTAL DESIGN: Cell viability and colony forming assays were used to assess the in vitro effect of dasatinib and trametinib as single agents or in combination. Western blot was used to analyse the phosphorylated protein and total protein levels...
June 11, 2018: European Journal of Cancer
Hadir M Maher, Nourah Z Alzoman, Shereen M Shehata, Norah O Abanmy
Dasatinib (DAS) is a tyrosine kinase inhibitor (TKI) used in the treatment of chronic myeloid leukemia and in the management of ulcerative colitis (UC). Since some nutraceuticals (e.g. curcumin, olive oil, and cocoa extract) could alter the function of ABC transporters and /or CYP450 enzymes, DAS bioavailability could potentially be affected following their co-administration. This work aims at studying the possibility of PK interaction between DAS and the selected nutraceuticals in UC rats using UPLC- MS/MS...
2018: PloS One
Makoto Nishimori, Tomoyuki Honjo, Kenji Kaihotsu, Naohiko Sone, Sachiko Yoshikawa, Junichi Imanishi, Kazuhiko Nakayama, Noriaki Emoto, Masanori Iwahashi
Pulmonary arterial hypertension (PAH) is a rare complication of dasatinib that was approved as a first-line therapy for chronic myelocytic leukemia (CML). A 24-year-old man presenting dyspnea at rest and leg edema was admitted to our hospital. He had been diagnosed with CML and prescribed dasatinib for 4 years. Chest X-ray showed significant bilateral pleural effusion and heart enlargement. Echocardiography revealed interventricular septal compression and elevated peak tricuspid regurgitation pressure gradient of 66...
2018: Case Reports in Cardiology
Jinyao Wang, Yizhe Wang, Chunlei Zheng, Kezuo Hou, Tieqiong Zhang, Xiujuan Qu, Yunpeng Liu, Jian Kang, Xuejun Hu, Xiaofang Che
Tyrosine kinase Inhibitors (TKIs) of epidermal growth factor receptor (EGFR) has considerably benefited for non-small cell lung carcinomas (NSCLC) harbor mutations in EGFR. However, the factors attenuating EGFR-TKI efficiency are obstacles to inhibit the proliferation of EGFR-mutant NSCLC cells successfully. Clarifying the insensitivity mechanisms of EGFR-TKI would help to develop new treatment strategy. In this study, the sensitivity of EGFR-mutant NSCLC cell lines, PC9 and HCC827, to icotinib was detected...
June 8, 2018: Cell Biology International
Csilla Fazakas, Chandran Nagaraj, Diana Zabini, Attila G Végh, Leigh M Marsh, Imola Wilhelm, István A Krizbai, Horst Olschewski, Andrea Olschewski, Zoltán Bálint
The multi-kinase inhibitor dasatinib is used for treatment of imatinib-resistant chronic myeloid leukemia, but is prone to induce microvascular dysfunction. In lung this can manifest as capillary leakage with pleural effusion, pulmonary edema or even pulmonary arterial hypertension. To understand how dasatinib causes endothelial dysfunction we examined the effects of clinically relevant concentrations of dasatinib on both human pulmonary arterial macro- and microvascular endothelial cells (ECs). The effects of dasatinib was compared to imatinib and nilotinib, two other clinically used BCR/Abl kinase inhibitors that do not inhibit Src...
2018: Frontiers in Physiology
Tomonori Nakazato, Noriyoshi Iriyama, Michihide Tokuhira, Maho Ishikawa, Eriko Sato, Tomoiku Takaku, Kei-Ji Sugimoto, Hiroyuki Fujita, Isao Fujioka, Yuta Kimura, Yoshinobu Aisa, Eisaku Iwanaga, Norio Asou, Masahiro Kizaki, Yoshihiro Hatta, Norio Komatsu, Tatsuya Kawaguchi
We performed a retrospective study to evaluate the incidence of second malignancies (SMs) in chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors (TKIs). We analyzed data from 339 patients with CML who were extracted from the CML Cooperative Study Group database. The standardized incidence ratio (SIR) was calculated to assess the risk of SMs using data from the Cancer Registries in Japan. The median follow-up was 65 months. SMs developed in 14 patients (4.1%, 10 men, 4 women) after the start of TKIs...
May 30, 2018: Medical Oncology
Massimo Breccia, Fabio Efficace, Alessandra Iurlo, Luigiana Luciano, Elisabetta Abruzzese, Antonella Gozzini, Patrizia Pregno, Mario Tiribelli, Gianantonio Rosti, Giorgio Minotti
In spite of the proven efficacy of the tyrosine kinase inhibitor (TKI), imatinib, in chronic myeloid leukemia (CML), many patients develop intolerance and discontinue therapy in the long-term. Second-generation TKIs (dasatinib, nilotinib, bosutinib) and the third-generation TKI, ponatinib, have added opportunities but also complexity in the settings of CML treatment. Areas covered: Different definitions of intolerance have been used through several clinical trials, making the published data non homogenous. In most cases, only the severity of acute adverse events (AEs), graded by conventional scales such as Common Terminology Criteria for Adverse Events, was reported...
June 2018: Expert Opinion on Drug Safety
Shuichi Mizuta, Masashi Sawa, Hisashi Tsurumi, Kana Matsumoto, Kotaro Miyao, Takeshi Hara, Takeshi Takahashi, Reona Sakemura, Hiroshi Kojima, Akio Kohno, Mari S Oba, Satoshi Morita, Junichi Sakamoto, Nobuhiko Emi
BACKGROUND: Dasatinib has shown promising anti-leukemic activity against chronic myeloid leukemia (CML). However, patients receiving dasatinib frequently require dose reductions and treatment interruptions (treatment alteration). METHODS: We prospectively analyzed the frequency and significance of treatment alteration during dasatinib therapy in patients with CML. In all patients, trough plasma concentrations of dasatinib (Cmin ) at steady state were assessed on day 28 of therapy...
May 29, 2018: International Journal of Clinical Oncology
Yang Fu, Ge Yang, Peipei Xue, Luwei Guo, Yuhan Yin, Zhiqiang Ye, Sanfei Peng, Yanru Qin, Qiuhong Duan, Feng Zhu
Preclinical data have revealed the inhibitory effect of dasatinib on colon cancer. However, a combination of dasatinib and conventional chemotherapy has failed to show any meaningful outcome in a series of clinical trials. We, therefore, wondered whether Src kinase inhibitors were suitable for treating colon cancer in combination with chemotherapy drugs. This study was designed to explore whether dasatinib disturbed 5-Fu-triggered apoptosis in colon carcinoma. As a result, we established that Src was able to directly phosphorylate caspase-9 at tyrosine 251, leading to elevated caspase-9 activity...
2018: Cell Death Discovery
William B Slayton, Kirk R Schultz, John A Kairalla, Meenakshi Devidas, Xinlei Mi, Michael A Pulsipher, Bill H Chang, Charles Mullighan, Ilaria Iacobucci, Lewis B Silverman, Michael J Borowitz, Andrew J Carroll, Nyla A Heerema, Julie M Gastier-Foster, Brent L Wood, Sherri L Mizrahy, Thomas Merchant, Valerie I Brown, Lance Sieger, Marilyn J Siegel, Elizabeth A Raetz, Naomi J Winick, Mignon L Loh, William L Carroll, Stephen P Hunger
Purpose Addition of imatinib to intensive chemotherapy improved survival for children and young adults with Philadelphia chromosome-positive acute lymphoblastic leukemia. Compared with imatinib, dasatinib has increased potency, CNS penetration, and activity against imatinib-resistant clones. Patients and Methods Children's Oncology Group (COG) trial AALL0622 (Bristol Myers Squibb trial CA180-204) tested safety and feasibility of adding dasatinib to intensive chemotherapy starting at induction day 15 in patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia age 1 to 30 years...
May 29, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Matteo Molica, Emilia Scalzulli, Gioia Colafigli, Danilo Alunni Fegatelli, Fulvio Massaro, Roberto Latagliata, Robin Foà, Massimo Breccia
We investigated the median estimated glomerular filtration rate (eGFR) changes in chronic myeloid leukemia (CML) patients treated front line with tyrosine kinase inhibitors (TKIs). A large cohort of 397 patients-320 treated front line with imatinib, 25 with dasatinib, and 53 with nilotinib-was retrospectively analyzed at a single institution. The eGFR was calculated according to the Chronic Kidney Disease Epidemiology Collaboration equation for all patients at baseline and then at 6 and 12 months, and at the last follow-up...
May 27, 2018: Annals of Hematology
Wai Yin Chan, Pui Man Lau, Ka Wing Yeung, Siu Kai Kong
Dasatinib, a new tyrosine kinase inhibitor, is used clinically to kill chronic myelogenous leukemia and acute lymphoblastic leukemia through apoptosis. Obviously, anemia is developed in many patients receiving dasatinib for treatment. Until now, the mechanism for the cytotoxic effects of dasatinib in human erythrocytes is not fully understood. As many tyrosine kinases are found in human erythrocytes, it is therefore logical to hypothesize that dasatinib is able to induce apoptosis (or eryptosis) in human erythrocytes...
May 24, 2018: Toxicology Letters
Lisa S Rotenstein, Stacie B Dusetzina, Nancy L Keating
BACKGROUND: With total and out-of-pocket spending for oral oncolytics rising, there is increased interest in choosing oncology treatments based on their clinical value relative to cost. OBJECTIVE: To determine if out-of-pocket spending varied for higher versus lower benefit oral oncology drugs reimbursed by commercial insurers. METHODS: This study was a retrospective analysis of commercial insurer prescription drug claims filed between 2007 and 2014 for 13 oral oncolytics approved before 2009...
June 2018: Journal of Managed Care & Specialty Pharmacy
Philipp Berning, Christiane Schaefer, Dagmar Clemens, Eberhard Korsching, Uta Dirksen, Jenny Potratz
BACKGROUND: The CXCR4 receptor antagonist plerixafor (AMD3100) is raising interest as an anti-cancer agent that disrupts the CXCL12-CXCR4 chemokine - receptor interaction between neoplastic cells and their microenvironment in tumor progression and metastasis. Here, we investigated plerixafor for anti-cancer activity in Ewing sarcoma, a rare and aggressive cancer of bone and soft tissues. METHODS: We used a variety of methods such as cell viability and migration assays, flow cytometry, phospho-tyrosine arrays and western blotting to determine plerixafor effects on five characterized Ewing sarcoma cell lines and a low-passage culture in vitro...
May 18, 2018: Cell Communication and Signaling: CCS
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