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Zhu JK, Wang J. Cytochrome P450 3A gene family in gastric cancer: Unveiling diagnostic biomarkers and therapeutic targets for personalized treatment. World J Clin Oncol 2025; 16:101548. [DOI: 10.5306/wjco.v16.i4.101548] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Revised: 01/12/2025] [Accepted: 02/21/2025] [Indexed: 03/26/2025] Open
Abstract
The cytochrome P450 3A (CYP3A) gene family’s role in early progression of gastric cancer was comprehensively investigated. Its potential as a therapeutic target was evaluated. Upon literature review, aberrant expression of the CYP3A gene family has a strong correlation with gastric cancer onset, although the precise underlying mechanisms remain unclear. To assess its potential as a biomarker for early diagnosis and a therapeutic target, we have provided a comprehensive review of the regulatory mechanisms governing CYP3A gene family expression in gastric cancer, as well as its relation with early tumor progression and the tumor microenvironment. The CYP3A gene family is crucial in the proliferation, migration, and invasion of gastric cancer cells and promotes cancer progression by modulating inflammatory responses and oxidative stress within the tumor microenvironment. Furthermore, genetic polymorphisms in CYP3Aenzymes highlight its potential value in personalized medicine. Based on these findings, this paper explores the feasibility of developing inhibitors and activators targeting CYP3A enzymes and discusses potential applications in gene therapy. This research provides crucial theoretical support for the CYP3A gene family as an early diagnostic marker and therapeutic target for gastric cancer. In the future, multi-omics studies and large-scale clinical trials will be essential to advance clinical translation of these findings.
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Affiliation(s)
- Jun-Kun Zhu
- Department of Medicine, The Chinese University of Hong Kong, Hong Kong 999077, China
| | - Jing Wang
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou 510120, Guangdong Province, China
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Choi BK, Jo MH, Shin HJ, Park SJ. Anti-Angiogenic Potential of Marine Streptomyces-Derived Lucknolide A on VEGF/VEGFR2 Signaling in Human Endothelial Cells. Molecules 2025; 30:987. [PMID: 40076212 PMCID: PMC11901821 DOI: 10.3390/molecules30050987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2025] [Revised: 02/16/2025] [Accepted: 02/18/2025] [Indexed: 03/14/2025] Open
Abstract
Angiogenesis, primarily driven by the vascular endothelial growth factor (VEGF) and its receptor, the VEGFR, plays a key role in various pathological processes such as cancer progression. Here, we investigated the anti-angiogenic effects of Lucknolide A (LA), a marine Streptomyces-derived compound, and evaluated its potential as a VEGFR2 inhibitor. LA selectively inhibited the proliferation of human endothelial cells EA.hy926 and HUVEC while exhibiting minimal effects on normal fibroblasts and various tumor cells. LA induced S-phase cell cycle arrest and apoptosis in EA.hy926 cells, increasing apoptotic markers p53, Bax, and p21 and decreasing the anti-apoptotic protein Bcl-2, with these effects being further enhanced under VEGF stimulation. Additionally, LA suppressed VEGFR2 phosphorylation and its downstream signaling pathways, including Akt/mTOR/p70S6K, MEK/ERK, Src, FAK, and p38 MAPK, which are crucial for endothelial survival and angiogenesis. Molecular docking studies revealed that LA binds to both inactive (DFG-out, PDB: 4ASD) and active (DFG-in, PDB: 3B8R) VEGFR2 conformations, with a significantly stronger affinity for the active state (-107.96 kcal/mol) than the inactive state (-33.56 kcal/mol), suggesting its potential as a VEGFR2 kinase inhibitor. Functionally, LA significantly inhibited VEGF-induced endothelial migration, tube formation, and microvessel sprouting in both in vitro and ex vivo rat aortic ring assays. Additionally, LA reduced tumor-associated tube formation induced by human breast tumor cells (MDA-MB-231), indicating its potential to suppress VEGF-dependent tumor angiogenesis. These findings suggest that LA is a promising selective anti-angiogenic agent with potential therapeutic applications in angiogenesis-related diseases such as cancer.
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Affiliation(s)
- Byeoung-Kyu Choi
- Department of Bio-Convergence Engineering, Dongyang Mirae University, Seoul 08221, Republic of Korea;
| | - Min-Hee Jo
- BB21 Plus Program, Department of Chemistry, Pukyong National University, Busan 48513, Republic of Korea;
| | - Hee Jae Shin
- Marine Natural Products Laboratory, Korea Institute of Ocean Science and Technology, Busan 49111, Republic of Korea
- Department of Marine Technology and Convergence Engineering, Korea National University of Science and Technology (UST), Daejeon 34113, Republic of Korea
| | - Sun Joo Park
- BB21 Plus Program, Department of Chemistry, Pukyong National University, Busan 48513, Republic of Korea;
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Xie Q, Luo M, Liu M, Xie Y, Li D, Dai H, Chen X. Discovery of potential VEGFR-2 inhibitors from natural products by virtual screening and molecular dynamics simulation. Phys Chem Chem Phys 2025; 27:3732-3747. [PMID: 39878700 DOI: 10.1039/d4cp03575e] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2025]
Abstract
Hepatocellular carcinoma (HCC) is the most common cancer worldwide and vascular endothelial growth factor receptor-2 (VEGFR-2) is an important target in the development of inhibitors for the treatment of liver cancer. So far, however, there are no effective drugs targeting VEGFR-2 to achieve complete treatment of liver cancer. In this study, we employed molecular docking, molecular dynamics simulations, molecular mechanics generalized Born surface area (MM-GBSA) method, quantum mechanics/molecular mechanics (QM/MM) calculations and steered molecular dynamics simulations to discover the potential inhibitors from COCONUT database targeting VEGFR-2. The molecular docking analyses of 13 743 natural compounds targeting VEGFR-2 identified 96 molecules as promising candidates. Our molecular dynamics simulations revealed that only 5 candidate-docking systems remained stable over 100 ns of production run. Then, steered molecular dynamics simulations showed that CNP0076764, CNP0028810, CNP0177683 and CNP0107283 had higher mean force values than that of sorafenib, reflecting the high potential of candidate molecules. A detailed analysis of the binding modes revealed that Leu840, Val848, Lys868, Glu885, Leu889, Val899, Val916, Leu1035, Cys1045, Asp1046 and Phe1047 play key roles in binding the inhibitors. Overall, this study shows evidence that the four natural products obtained from the COCONUT database could be further used as anti-cancer inhibitors, which provides theoretical guidance for designing new drugs.
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Affiliation(s)
- Qiong Xie
- Chongqing Key Laboratory of Theoretical and Computational Chemistry, School of Chemistry and Chemical Engineering, Chongqing University, Chongqing 401331, P. R. China.
| | - Mengshi Luo
- Chongqing Key Laboratory of Theoretical and Computational Chemistry, School of Chemistry and Chemical Engineering, Chongqing University, Chongqing 401331, P. R. China.
| | - Mingyan Liu
- Chongqing Key Laboratory of Theoretical and Computational Chemistry, School of Chemistry and Chemical Engineering, Chongqing University, Chongqing 401331, P. R. China.
| | - Yuxin Xie
- Chongqing Key Laboratory of Theoretical and Computational Chemistry, School of Chemistry and Chemical Engineering, Chongqing University, Chongqing 401331, P. R. China.
| | - Di Li
- Chongqing Key Laboratory of Theoretical and Computational Chemistry, School of Chemistry and Chemical Engineering, Chongqing University, Chongqing 401331, P. R. China.
| | - Hongjing Dai
- Chongqing Key Laboratory of Theoretical and Computational Chemistry, School of Chemistry and Chemical Engineering, Chongqing University, Chongqing 401331, P. R. China.
- School of Chemistry and Chemical Engineering, Qiannan Normal University for Nationalities, Duyun 558000, P. R. China
| | - Xiaohua Chen
- Chongqing Key Laboratory of Theoretical and Computational Chemistry, School of Chemistry and Chemical Engineering, Chongqing University, Chongqing 401331, P. R. China.
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Gayathri JS, Krishna SS, Rakesh MP. Tyrosine Kinase Inhibitor Induced Proteinuria - A Review. Drug Res (Stuttg) 2025; 75:5-11. [PMID: 39406370 DOI: 10.1055/a-2423-3533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Tyrosine Kinase inhibitor (TKI) is a class of drugs that interfere with protein kinases' signal transduction pathways through an array of inhibitory mechanisms. Tyrosine kinases (TK) have an inevitable role in downstream signal transduction and the proliferation of tumour cells. Hence, tyrosine kinase inhibitors (TKIs) are frequently employed as anti-neoplastic agents in the treatment of colon, breast, kidney, and lung cancers. They can be used as single or combination therapy with other targeted therapies. It is understood that TKIs pose a risk of developing proteinuria in some patients as it can primarily result in dysfunction of the split diaphragm, constriction or blockage of capillary lumens mediated by the basement membrane, acute interstitial nephritis, or acute tubular necrosis. This paper reviews the mechanism of action of TKIs, the pathophysiological mechanism of TKI-induced proteinuria, and its management Fig. 1.
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Affiliation(s)
- J S Gayathri
- Department of Pharmacy Practice, Amrita School of Pharmacy, Amrita Health Science Campus, Amrita Vishwa Vidyapeetham, Ponekkara, Kochi, India
| | - S Swathi Krishna
- Department of Pharmacy Practice, Amrita School of Pharmacy, Amrita Health Science Campus, Amrita Vishwa Vidyapeetham, Ponekkara, Kochi, India
| | - M P Rakesh
- Department of Medical Oncology, Amrita Health Science Campus, Amrita Vishwa Vidyapeetham, Ponekkara, Kochi, India
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Sato MT, Araki T, Yashima H, Ishikawa Y, Morita J, Maeda Y, Ohbayashi M, Kohyama N, Ogawa Y, Fukagai T, Yamamoto K, Kogo M. Variations in serum concentrations of sunitinib and its metabolites in patients receiving long-term sunitinib treatment. Cancer Chemother Pharmacol 2024; 95:14. [PMID: 39724407 DOI: 10.1007/s00280-024-04741-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2024] [Accepted: 12/09/2024] [Indexed: 12/28/2024]
Abstract
PURPOSE The blood concentrations of some tyrosine kinase inhibitors are known to decrease with long-term administration. We evaluated the variability in the serum concentrations of sunitinib and its metabolites in patients receiving long-term sunitinib treatment. METHODS This study prospectively recruited patients who received sunitinib for metastatic renal cell carcinoma at the Showa University Hospital between March 2020 and January 2022. Bivariate correlations between the serum concentration/dose (C/D) ratios of sunitinib and its metabolites (i.e., N-desethyl sunitinib and sunitinib N-oxide) and treatment duration were evaluated using Pearson's correlation coefficient. RESULTS Seven patients were enrolled, and 79 blood samples were collected. Among six patients who received sunitinib for > 1 year, three showed a decreasing trend in the C/D ratio of sunitinib (Pt1: r = -0.608, p = 0.047; Pt2: r = -0.555, p = 0.077; Pt6: r = -0.590, p = 0.073). In these patients, the median annual decrease in the C/D ratio of sunitinib was 55.8% (26.5-63.2%). Additionally, two of the three patients also showed a decrease in the C/D ratio of N-desethyl sunitinib. The ratio of N-desethyl sunitinib/sunitinib concentration at baseline and the end of follow-up was similar between the C/D-decreased and C/D-non-decreased groups. CONCLUSION This study showed that the C/D ratio of sunitinib decreased by half over time in half of the patients who received long-term sunitinib treatment despite continuing the same dose. Therefore, serum concentrations of sunitinib and its metabolites should be monitored periodically in patients receiving long-term treatment to prevent decrease in serum sunitinib concentrations.
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Affiliation(s)
- Miki Takenaka Sato
- Division of Pharmacotherapeutics, Department of Clinical Pharmacy, School of Pharmacy, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan.
| | - Takuya Araki
- Department of Clinical Pharmacology and Therapeutics, Gunma University Graduate School of Medicine, Maebashi, Japan
- Department of Pharmacy, Gunma University Hospital, Maebashi, Japan
| | - Hideaki Yashima
- Department of Clinical Pharmacology and Therapeutics, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Yuya Ishikawa
- Department of Pharmacy, Gunma University Hospital, Maebashi, Japan
| | - Jun Morita
- Department of Urology, Showa University Hospital, Tokyo, Japan
- Department of Urology, Showa University Fujigaoka Hospital, Yokohama, Japan
| | - Yoshiko Maeda
- Department of Urology, Showa University Hospital, Tokyo, Japan
- Pelvic Reconstructive Surgery, Tokyo Women's Medical University, Adachi Medical Center, Tokyo, Japan
| | - Masayuki Ohbayashi
- Division of Pharmacotherapeutics, Department of Clinical Pharmacy, School of Pharmacy, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan
| | - Noriko Kohyama
- Division of Pharmacotherapeutics, Department of Clinical Pharmacy, School of Pharmacy, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan
| | - Yoshio Ogawa
- Department of Urology, Showa University Hospital, Tokyo, Japan
| | - Takashi Fukagai
- Department of Urology, Showa University Hospital, Tokyo, Japan
| | - Koujirou Yamamoto
- Department of Clinical Pharmacology and Therapeutics, Gunma University Graduate School of Medicine, Maebashi, Japan
- Department of Pharmacy, Gunma University Hospital, Maebashi, Japan
| | - Mari Kogo
- Division of Pharmacotherapeutics, Department of Clinical Pharmacy, School of Pharmacy, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan
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Gui M, Wu C, Qi R, Zeng Y, Huang P, Cao J, Chen T, Chen K, Lin L, Han Q, He P, Fu R, Wu Q, Yuan Q, Zhang T, Xia N, Wang G, Chen Y. Swine pseudorabies virus attenuated vaccine reprograms the kidney cancer tumor microenvironment and synergizes with PD-1 blockade. J Med Virol 2024; 96:e29568. [PMID: 38549430 DOI: 10.1002/jmv.29568] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 01/27/2024] [Accepted: 03/02/2024] [Indexed: 04/02/2024]
Abstract
The global incidence rate of kidney cancer (KC) has been steadily increasing over the past 30 years. With the aging global population, kidney cancer has become an escalating concern that necessitates vigilant surveillance. Nowadays, surgical intervention remains the optimal therapeutic approach for kidney cancer, while the availability of efficacious treatments for advanced tumors remains limited. Oncolytic viruses, an emerging form of immunotherapy, have demonstrated encouraging anti-neoplastic properties and are progressively garnering public acceptance. However, research on oncolytic viruses in kidney cancer is relatively limited. Furthermore, given the high complexity and heterogeneity of kidney cancer, it is crucial to identify an optimal oncolytic virus agent that is better suited for its treatment. The present study investigates the oncolytic activity of the Pseudorabies virus live attenuated vaccine (PRV-LAV) against KC. The findings clearly demonstrate that PRV-LAV exhibits robust oncolytic activity targeting KC cell lines. Furthermore, the therapeutic efficacy of PRV-LAV was confirmed in both a subcutaneous tumor-bearing nude mouse model and a syngeneic mouse model of KC. Combined RNA-seq analysis and flow cytometry revealed that PRV-LAV treatment substantially enhances the infiltration of a diverse range of lymphocytes, including T cells, B cells, macrophages, and NK cells. Additionally, PRV-LAV treatment enhances T cell activation and exerts antitumor effects. Importantly, the combination of PRV-LAV with anti-PD-1 antibodies, an approved drug for KC treatment, synergistically enhances the efficacy against KC. Overall, the discovery of PRV-LAV as an effective oncolytic virus holds significant importance for improving the treatment efficacy and survival rates of KC patients.
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Affiliation(s)
- Mengxuan Gui
- State Key Laboratory of Vaccines for Infectious Diseases, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences, School of Public Health, Xiamen University, Xiamen, People's Republic of China
| | - Chongxin Wu
- State Key Laboratory of Vaccines for Infectious Diseases, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences, School of Public Health, Xiamen University, Xiamen, People's Republic of China
| | - Ruoyao Qi
- State Key Laboratory of Vaccines for Infectious Diseases, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences, School of Public Health, Xiamen University, Xiamen, People's Republic of China
| | - Yue Zeng
- State Key Laboratory of Vaccines for Infectious Diseases, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences, School of Public Health, Xiamen University, Xiamen, People's Republic of China
| | - Pengfei Huang
- State Key Laboratory of Vaccines for Infectious Diseases, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences, School of Public Health, Xiamen University, Xiamen, People's Republic of China
| | - Jiali Cao
- Department of Laboratory Medicine, Fujian Key Clinical Specialty of Laboratory Medicine, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen
| | - Tian Chen
- State Key Laboratory of Vaccines for Infectious Diseases, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences, School of Public Health, Xiamen University, Xiamen, People's Republic of China
| | - Kaiyun Chen
- State Key Laboratory of Vaccines for Infectious Diseases, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences, School of Public Health, Xiamen University, Xiamen, People's Republic of China
| | - Lina Lin
- State Key Laboratory of Vaccines for Infectious Diseases, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences, School of Public Health, Xiamen University, Xiamen, People's Republic of China
| | - Qiangyuan Han
- State Key Laboratory of Vaccines for Infectious Diseases, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences, School of Public Health, Xiamen University, Xiamen, People's Republic of China
| | - Peiqing He
- State Key Laboratory of Vaccines for Infectious Diseases, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences, School of Public Health, Xiamen University, Xiamen, People's Republic of China
| | - Rao Fu
- State Key Laboratory of Vaccines for Infectious Diseases, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences, School of Public Health, Xiamen University, Xiamen, People's Republic of China
| | - Qian Wu
- State Key Laboratory of Vaccines for Infectious Diseases, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences, School of Public Health, Xiamen University, Xiamen, People's Republic of China
| | - Quan Yuan
- State Key Laboratory of Vaccines for Infectious Diseases, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences, School of Public Health, Xiamen University, Xiamen, People's Republic of China
| | - Tianying Zhang
- State Key Laboratory of Vaccines for Infectious Diseases, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences, School of Public Health, Xiamen University, Xiamen, People's Republic of China
| | - Ningshao Xia
- State Key Laboratory of Vaccines for Infectious Diseases, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences, School of Public Health, Xiamen University, Xiamen, People's Republic of China
| | - Guosong Wang
- State Key Laboratory of Vaccines for Infectious Diseases, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences, School of Public Health, Xiamen University, Xiamen, People's Republic of China
| | - Yixin Chen
- State Key Laboratory of Vaccines for Infectious Diseases, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences, School of Public Health, Xiamen University, Xiamen, People's Republic of China
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Li D, Wan S, Li W, Cheng C, Xu L, Gu P. Sorafenib exhibits lower toxicity and comparable efficacy to sunitinib as a first-line treatment for metastatic renal cell carcinoma: A systematic review and meta-analysis. Medicine (Baltimore) 2023; 102:e34983. [PMID: 37682147 PMCID: PMC10489528 DOI: 10.1097/md.0000000000034983] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Accepted: 08/07/2023] [Indexed: 09/09/2023] Open
Abstract
BACKGROUND To assess the safety and efficacy of sorafenib and sunitinib as first-line treatments for metastatic renal cell carcinoma (mRCC), to provide evidence-based support for clinical decision-making regarding rational drug use. METHODS Until May 10, 2023, a comprehensive search was conducted across PubMed, EMBASE, Cochrane Library, ClinicalTrials.gov, China National Knowledge Infrastructure, and Wanfang databases to identify clinical studies comparing sorafenib with sunitinib as first-line treatment for mRCC. The literature was screened, data extracted, and quality evaluated independently by 2 researchers. Meta-analysis was conducted using Revman5.4 software. RESULTS A total of 3741 patients were enrolled in 20 studies. The meta-analysis results indicated that there were no significant differences in the 2- and 5-year progression-free survival (PFS) and overall survival (OS) rates between the sorafenib and sunitinib groups (P > .05). The disease control rate (DCR) was comparable between the 2 groups (P > .05), while the objective response rate (ORR) was higher in the sunitinib group (P = .03). However, subgroup analysis revealed no significant differences in ORR, DCR, 2- and 5-year PFS, and OS rates between sorafenib and sunitinib among both Asian populations as well as European and American populations (P > .05). In terms of drug-related adverse events, the incidence of grade ≥ 3 hypertension, leukopenia, neutropenia, thrombocytopenia, anemia, nausea and vomiting were significantly lower in the sorafenib group compared to the sunitinib group (P < .05). CONCLUSION In the first-line treatment of mRCC, sorafenib exhibits comparable efficacy to sunitinib but with lower toxicity.
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Affiliation(s)
- Dailong Li
- Department of Oncology, General Hospital of The Yangtze River Shipping, Wuhan, Hubei, China
| | - Sha Wan
- Department of Anatomy, College of Basic Medicine, Guilin Medical University, Guilin, China
| | - Wanqiang Li
- Department of Urology, The First College of Clinical Medical Science, China Three Gorges University, Yichang Central People’s Hospital, Yichang, China
| | - Chunlai Cheng
- Department of Oncology, General Hospital of The Yangtze River Shipping, Wuhan, Hubei, China
| | - Lu Xu
- Department of Radiation Oncology and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Peng Gu
- Department of Urology, General Hospital of The Yangtze River Shipping, Wuhan, Hubei, China
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Ahmad A, Nawaz MI. Molecular mechanism of VEGF and its role in pathological angiogenesis. J Cell Biochem 2022; 123:1938-1965. [PMID: 36288574 DOI: 10.1002/jcb.30344] [Citation(s) in RCA: 78] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Revised: 09/12/2022] [Accepted: 10/13/2022] [Indexed: 12/24/2022]
Abstract
Over the last seven decades, a significant scientific contribution took place in the delineation of the implications of vascular endothelial-derived growth factor (VEGF) in the processes of angiogenesis. Under pathological conditions, mainly in response to hypoxia or ischemia, elevated VEGF levels promote vascular damage and the growth of abnormal blood vessels. Indeed, the development of VEGF biology has revolutionized our understanding of its role in pathological conditions. Hence, targeting VEGF or VEGF-mediated molecular pathways could be an excellent therapeutic strategy for managing cancers and intraocular neovascular disorders. Although anti-VEGF therapies, such as monoclonal antibodies and small-molecule tyrosine kinase inhibitors, have limited clinical efficacy, they can still significantly improve the overall survival rate. This thus demands further investigation through the development of alternative strategies in the management of VEGF-mediated pathological angiogenesis. This review article focuses on the recent developments toward the delineation of the functional biology of VEGF and the role of anti-VEGF strategies in the management of tumor and eye pathologies. Moreover, therapeutic angiogenesis, an exciting frontier for the treatment of ischemic disorders, is highlighted in this review, including wound healing.
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Affiliation(s)
- Ajmal Ahmad
- Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.,Dr. Nasser Al-Rashid Research Chair in Ophthalmology, Abdulaziz University Hospital, Riyadh, Saudi Arabia
| | - Mohd Imtiaz Nawaz
- Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.,Dr. Nasser Al-Rashid Research Chair in Ophthalmology, Abdulaziz University Hospital, Riyadh, Saudi Arabia
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Brinch CM, Aggerholm-Pedersen N, Hogdall E, Krarup-Hansen A. Medical Oncological Treatment for Patients with Gastrointestinal Stromal Tumour (GIST) - a Systematic Review. Crit Rev Oncol Hematol 2022; 172:103650. [PMID: 35283299 DOI: 10.1016/j.critrevonc.2022.103650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 02/11/2022] [Accepted: 03/07/2022] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Chemotherapy is ineffective in treating patients with Gastrointestinal Stromal Tumour (GIST). However, several types of tyrosine kinase inhibitors have been investigated since the approval of imatinib in 2001. The purpose of this report was to systematically review studies on the efficacy of neoadjuvant, adjuvant, and lifelong medical oncological treatment of GIST. METHODS The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed throughout the review process. The protocol was submitted to the International prospective register of systematic reviews database (ID 251724). A systematic literature search was performed, including phase II- and III studies of biological treatment, reporting on treatment effect in patients with GIST. RESULTS Of 308 identified publications, 42 studies were included in this review. CONCLUSION This review gives an overview of the existing evidence for approved lines of oncological treatments and potential alternatives for patients with GIST in the neoadjuvant-, adjuvant- and life-long setting.
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Affiliation(s)
- Charlotte Margareta Brinch
- Department of Oncology, Copenhagen University Hospital, Herlev and Gentofte Hospital, Borgmester Ib Juuls Vej 1, DK-2730, Herlev.
| | - Ninna Aggerholm-Pedersen
- Department of Oncology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, DK-8200, Aarhus, Denmark.
| | - Estrid Hogdall
- Department of Pathology, Copenhagen University Hospital, Herlev and Gentofte Hospital, Borgmester Ib Juuls Vej 73, DK-2730, Herlev, Denmark.
| | - Anders Krarup-Hansen
- Department of Oncology, Copenhagen University Hospital, Herlev and Gentofte Hospital, Borgmester Ib Juuls Vej 1, DK-2730, Herlev.
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Guo L, Gong H, Tang TL, Zhang BK, Zhang LY, Yan M. Crizotinib and Sunitinib Induce Hepatotoxicity and Mitochondrial Apoptosis in L02 Cells via ROS and Nrf2 Signaling Pathway. Front Pharmacol 2021; 12:620934. [PMID: 33597889 PMCID: PMC7883288 DOI: 10.3389/fphar.2021.620934] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Accepted: 01/04/2021] [Indexed: 12/11/2022] Open
Abstract
Considerable attention has been raised on crizotinib- and sunitinib-induced hepatotoxicity, but the underlying mechanisms need further examination. In addition, limited therapeutic strategies exist to reduce the liver damage caused by crizotinib and sunitinib. This study investigated the mechanisms of crizotinib- and sunitinib-induced hepatotoxicity and the potential mitigation through ROS and Nrf2 signaling. Firstly, crizotinib and sunitinib reduced cell viability in human liver cells (L02 cells) and triggered dramatic liver injury in mice. Subsequently, we found that crizotinib and sunitinib activated the oxidative stress response (decreased level of GPx and SOD, and increased MDA content) in vivo. Crizotinib and sunitinib also stimulated hepatocyte mitochondrial apoptosis and necrosis in L02 cells in a dose-dependent manner. In vivo studies further confirmed that crizotinib and sunitinib decreased mitochondrial membrane potential and activated apoptosis-associated proteins (cleaved-PARP, cleaved caspase3, cytochrome c, Bcl2 and Bax). Furthermore, mechanistic investigations demonstrated that crizotinib and sunitinib accumulated ROS and inhibited Nrf2 signaling, and that ROS scavenger NAC and Nrf2 agonist tBHQ alleviated the extent of cell damage and the mitochondrial apoptosis during crizotinib- and sunitinib-induced hepatotoxicity in L02 cells. Collectively, these findings indicated that NAC and tBHQ play the crucial roles in crizotinib- and sunitinib-induced mitochondrial apoptosis via the regulation of oxidative stress.
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Affiliation(s)
- Lin Guo
- Department of Pharmacy, Second Xiangya Hospital, Central South University, Changsha, China
| | - Hui Gong
- Department of Pharmacy, Second Xiangya Hospital, Central South University, Changsha, China
| | - Ting-Li Tang
- Department of Pharmacy, Second Xiangya Hospital, Central South University, Changsha, China
| | - Bi-Kui Zhang
- Department of Pharmacy, Second Xiangya Hospital, Central South University, Changsha, China
| | - Lei-Yi Zhang
- Department of General Surgery, Second Xiangya Hospital, Central South University, Changsha, China
| | - Miao Yan
- Department of Pharmacy, Second Xiangya Hospital, Central South University, Changsha, China
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11
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Eissa IH, Ibrahim MK, Metwaly AM, Belal A, Mehany ABM, Abdelhady AA, Elhendawy MA, Radwan MM, ElSohly MA, Mahdy HA. Design, molecular docking, in vitro, and in vivo studies of new quinazolin-4(3H)-ones as VEGFR-2 inhibitors with potential activity against hepatocellular carcinoma. Bioorg Chem 2020; 107:104532. [PMID: 33334586 DOI: 10.1016/j.bioorg.2020.104532] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 12/02/2020] [Accepted: 12/03/2020] [Indexed: 02/09/2023]
Abstract
A series of new VEGFR-2 inhibitors were designed, synthesized and evaluated for their anti-proliferative activities against hepatocellular carcinoma (HepG-2 cell line). Compound 29b (IC50 = 4.33 ± 0.2 µg/ml) was found to be the most potent derivative as it has showed to be more active than doxorubicin (IC50 = 4.50 ± 0.2 µg/ml) and 78% of sorafenib activity (IC50 = 3.40 ± 0.25 µg/ml). The inhibitory profiles against VEGFR-2 were also assessed for the most promising candidates (16b, 20c, 22b, 24a, 24b, 28c, 28e, 29a, 29b and 29c). Compounds 29b, 29c and 29a exhibited potent inhibitory activities towards VEGFR-2 at IC50 values of 3.1 ± 0.04, 3.4 ± 0.05 and 3.7 ± 0.06 µM, respectively, comparing sorafenib (IC50 = 2.4 ± 0.05 µM). Furthermorer, compound 29b induced apoptosis and arrested the cell cycle growth at G2/M phase. Additionally, in vivo antitumor experiments revealed that compounds 29b and 29c have significant tumor growth inhibition. The test of immuno-histochemical expression of activated caspase-3 revealed that there is a time-dependent increase in cleaved caspase-3 protein expression upon exposure of HepG-2 cells to compound 29b. Moreover, the fibroblastic proliferative index test revealed that compound 29b could attenuate liver fibrosis. Docking studies also supported the results concluded from the biological screening via prediction of the possible binding interactions of the target compounds with VEGFR-2 active sites using the crystal structure of VEGFR-2 downloaded from the Protein Data Bank, (PDB ID: 2OH4) using Discovery Studio 2.5 software. Further structural optimization of the most active candidates may serve as a useful strategy for getting new lead compounds in search for powerful and selective antineoplastic agents.
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Affiliation(s)
- Ibrahim H Eissa
- Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt.
| | - Mohammed K Ibrahim
- Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt
| | - Ahmed M Metwaly
- Pharmacognosy Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt
| | - Amany Belal
- Medicinal Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt
| | - Ahmed B M Mehany
- Zoology Department, Faculty of Science, Al-Azhar University, Cairo 11884, Egypt
| | | | - Mostafa A Elhendawy
- National Center for Natural Products Research, University of Mississippi, MS 38677, USA; Department of Agriculture Chemistry, Faculty of Agriculture, Damietta University, Damietta, Egypt
| | - Mohamed M Radwan
- National Center for Natural Products Research, University of Mississippi, MS 38677, USA; Department of Pharmacognosy, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt
| | - Mahmoud A ElSohly
- National Center for Natural Products Research, University of Mississippi, MS 38677, USA; Department of Pharmaceutics and Drug Delivery, University of Mississippi, University, MS 38677, USA
| | - Hazem A Mahdy
- Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt.
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12
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Indra R, Vavrová K, Pompach P, Heger Z, Hodek P. Identification of Enzymes Oxidizing the Tyrosine Kinase Inhibitor Cabozantinib: Cabozantinib Is Predominantly Oxidized by CYP3A4 and Its Oxidation Is Stimulated by cyt b 5 Activity. Biomedicines 2020; 8:biomedicines8120547. [PMID: 33260548 PMCID: PMC7759869 DOI: 10.3390/biomedicines8120547] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 11/13/2020] [Accepted: 11/26/2020] [Indexed: 12/24/2022] Open
Abstract
Herein, the in vitro metabolism of tyrosine kinase inhibitor cabozantinib, the drug used for the treatment of metastatic medullary thyroid cancer and advanced renal cell carcinoma, was studied using hepatic microsomal samples of different human donors, human recombinant cytochromes P450 (CYPs), flavin-containing mono-oxygenases (FMOs) and aldehyde oxidase. After incubation with human microsomes, three metabolites, namely cabozantinib N-oxide, desmethyl cabozantinib and monohydroxy cabozantinib, were detected. Significant correlations were found between CYP3A4 activity and generation of all metabolites. The privileged role of CYP3A4 was further confirmed by examining the effect of CYP inhibitors and by human recombinant enzymes. Only four of all tested human recombinant cytochrome P450 were able to oxidize cabozantinib, and CYP3A4 exhibited the most efficient activity. Importantly, cytochrome b5 (cyt b5) stimulates the CYP3A4-catalyzed formation of cabozantinib metabolites. In addition, cyt b5 also stimulates the activity of CYP3A5, whereas two other enzymes, CYP1A1 and 1B1, were not affected by cyt b5. Since CYP3A4 exhibits high expression in the human liver and was found to be the most efficient enzyme in cabozantinib oxidation, we examined the kinetics of this oxidation. The present study provides substantial insights into the metabolism of cabozantinib and brings novel findings related to cabozantinib pharmacokinetics towards possible utilization in personalized medicine.
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Affiliation(s)
- Radek Indra
- Department of Biochemistry, Faculty of Science, Charles University, Albertov 6, 12800 Prague 2, Czech Republic; (K.V.); (P.P.); (P.H.)
- Correspondence: ; Tel.: +420-221-951-285
| | - Katarína Vavrová
- Department of Biochemistry, Faculty of Science, Charles University, Albertov 6, 12800 Prague 2, Czech Republic; (K.V.); (P.P.); (P.H.)
| | - Petr Pompach
- Department of Biochemistry, Faculty of Science, Charles University, Albertov 6, 12800 Prague 2, Czech Republic; (K.V.); (P.P.); (P.H.)
| | - Zbyněk Heger
- Department of Chemistry and Biochemistry, Mendel University in Brno, Zemedelska 1, 61300 Brno, Czech Republic;
- Central European Institute of Technology, Brno University of Technology, Purkynova 656/123, 61200 Brno, Czech Republic
| | - Petr Hodek
- Department of Biochemistry, Faculty of Science, Charles University, Albertov 6, 12800 Prague 2, Czech Republic; (K.V.); (P.P.); (P.H.)
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13
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Park JH, Baek MJ, Lee JY, Kim KT, Cho HJ, Kim DD. Preparation and characterization of sorafenib-loaded microprecipitated bulk powder for enhancing oral bioavailability. Int J Pharm 2020; 589:119836. [PMID: 32946979 DOI: 10.1016/j.ijpharm.2020.119836] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 08/24/2020] [Accepted: 08/27/2020] [Indexed: 12/31/2022]
Abstract
The aim of this study was to prepare and evaluate Eudragit-based microprecipitated bulk powder (MBP) formulations to enhance the oral bioavailability of sorafenib. Cationic Eudragit E PO and anionic Eudragit S100 were selected for MBP preparation. Ursodeoxycholic acid (UDCA)-incorporated MBP was also prepared to study the synergistic effect of UDCA in enhancing the bioavailability of sorafenib. Sorafenib-loaded MBPs were successfully prepared by a pH-controlled precipitation method using an aqueous antisolvent. Submicron-sized particles of MBPs were observed by scanning electron microscopy, and the amorphous form of sorafenib in MBPs was confirmed by powder X-ray diffraction. MBPs of cationic and anionic Eudragits showed different in vitro dissolution and pharmacokinetic profiles in rats. Sorafenib in Eudragit E PO-based MBP (E PO-MBP) was rapidly dissolved at low pH conditions (pH 1.2 and 4.0), but was precipitated again at pH 4.0 within 4 h. Dissolution of sorafenib from Eudragit S100-based MBP (S100-MBP) was high at pH 7.4 and did not precipitate for up to 4 h. After oral administration to rats, all MBPs, compared with powder, improved the oral absorption of sorafenib, with S100-MBP showing 1.5-fold higher relative oral bioavailability than E PO-MBP. Moreover, incorporation of UDCA in S100-MBP (S100-UDCA-MBP) further increased the Cmax and oral bioavailability of sorafenib, although the dissolution was not significantly different from that of S100-MBP. Taken together, Eudragit-based MBP formulations could be a promising strategy for enhancing the oral bioavailability of sorafenib.
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Affiliation(s)
- Ju-Hwan Park
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - Min-Jun Baek
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - Jae-Young Lee
- College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea
| | - Ki-Taek Kim
- College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Jeonnam 58554, Republic of Korea
| | - Hyun-Jong Cho
- College of Pharmacy, Kangwon National University, Gangwon 24341, Republic of Korea
| | - Dae-Duk Kim
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea.
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14
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Gorshkov K, Pradhan M, Xu M, Yang S, Lee EM, Chen CZ, Shen M, Zheng W. Cell-Based No-Wash Fluorescence Assays for Compound Screens Using a Fluorescence Cytometry Plate Reader. J Pharmacol Exp Ther 2020; 374:500-511. [PMID: 32532853 PMCID: PMC7495342 DOI: 10.1124/jpet.120.265207] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Accepted: 06/01/2020] [Indexed: 11/22/2022] Open
Abstract
High-throughput cell-based fluorescent imaging assays often require removal of background fluorescent signal to obtain robust measurements. Processing high-density microplates to remove background signal is challenging because of equipment requirements and increasing variation after multiple plate wash steps. Here, we present the development of a wash-free cell-based fluorescence assay method for high-throughput screening using a laser scanning fluorescence plate cytometer. The cytometry data consisted of cell count and fluorescent intensity measurements for phenotypic screening. We obtained robust screening results by applying this assay methodology to the lysosomal storage disease Niemann-Pick disease type A. We further demonstrated that this cytometry method can be applied to the detection of cholesterol in Niemann-Pick disease type C. Lastly, we used the Mirrorball method to obtain preliminary results for the detection of Zika and Dengue viral envelope protein. The advantages of this assay format include 1) no plate washing, 2) 4-fold faster plate scan and analysis time, 3) high throughput, and 4) >10-fold smaller direct data files. In contrast, traditional imaging assays require multiple plate washes to remove the background signal, long plate scan and data analysis times, and large data files. Therefore, this versatile and broadly applicable Mirrorball-based method greatly improves the throughput and data quality of image-based screening by increasing sensitivity and efficiency while reducing assay artifacts. SIGNIFICANCE STATEMENT: This work has resulted in the development of broadly applicable cell-based fluorescence imaging assays without the requirement of washing out reagents to reduce background signal, which effectively decreases the need for extensive plate processing by the researcher. We demonstrate this high-throughput method for drug screening against lysosomal storage diseases and a commonly used viral titer assay.
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Affiliation(s)
- Kirill Gorshkov
- National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland
| | - Manisha Pradhan
- National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland
| | - Miao Xu
- National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland
| | - Shu Yang
- National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland
| | - Emily M Lee
- National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland
| | - Catherine Z Chen
- National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland
| | - Min Shen
- National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland
| | - Wei Zheng
- National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland
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15
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Pearson H, Marshall LV, Carceller F. Sorafenib in pediatric hepatocellular carcinoma from a clinician perspective. Pediatr Hematol Oncol 2020; 37:412-423. [PMID: 32183592 DOI: 10.1080/08880018.2020.1740844] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Hepatocellular Carcinoma (HCC) is a rare tumor in children and normally carries poor outcomes. The most frequently employed chemotherapy regimen includes cisplatin and doxorubicin (PLADO), but this combination offers limited efficacy. Sorafenib is a multi-tyrosine kinase inhibitor which, following positive studies in adults with HCC, has begun to be introduced in conjunction with PLADO in pediatric oncology with some encouraging results. Based on these findings, the use of sorafenib is become more common in children with unresectable and/or metastatic HCC. The care of patients receiving sorafenib requires appropriate expertise and standardized pediatric guidelines are lacking. An increasing number of children with HCC are expected to receive sorafenib in the years to come. Pediatric oncology clinicians have a key role in identifying side effects early and clinicians caring for children receiving sorafenib need to be familiar with these. This review article provides suitable and practical information on sorafenib for educational development to optimize clinical care and facilitate enhanced patient/parent education. The article addresses specific areas including mechanisms of action, pre-clinical and clinical evidence, dosing and drug administration and toxicities of sorafenib. Clinical research and recommendations for managing sorafenib-related side effects are discussed. Underpinned by research, this article provides pediatric oncology clinicians with the knowledge required to deliver optimal care to children receiving sorafenib.
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Affiliation(s)
- Helen Pearson
- The Royal Marsden NHS Foundation Trust, Sutton, Surrey, United Kingdom
| | - Lynley V Marshall
- The Royal Marsden NHS Foundation Trust, Sutton, Surrey, United Kingdom.,The Institute of Cancer Research, Division of Clinical Studies and Cancer Therapeutics, Sutton, Surrey, United Kingdom
| | - Fernando Carceller
- The Royal Marsden NHS Foundation Trust, Sutton, Surrey, United Kingdom.,The Institute of Cancer Research, Division of Clinical Studies and Cancer Therapeutics, Sutton, Surrey, United Kingdom
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16
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Fontelonga TM, Jordan B, Nunes AM, Barraza-Flores P, Bolden N, Wuebbles RD, Griner LM, Hu X, Ferrer M, Marugan J, Southall N, Burkin DJ. Sunitinib promotes myogenic regeneration and mitigates disease progression in the mdx mouse model of Duchenne muscular dystrophy. Hum Mol Genet 2020; 28:2120-2132. [PMID: 30806670 DOI: 10.1093/hmg/ddz044] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Revised: 01/28/2019] [Accepted: 02/18/2019] [Indexed: 02/07/2023] Open
Abstract
Duchenne muscular dystrophy (DMD) is a lethal, muscle degenerative disease causing premature death of affected children. DMD is characterized by mutations in the dystrophin gene that result in a loss of the dystrophin protein. Loss of dystrophin causes an associated reduction in proteins of the dystrophin glycoprotein complex, leading to contraction-induced sarcolemmal weakening, muscle tearing, fibrotic infiltration and rounds of degeneration and failed regeneration affecting satellite cell populations. The α7β1 integrin has been implicated in increasing myogenic capacity of satellite cells, therefore restoring muscle viability, increasing muscle force and preserving muscle function in dystrophic mouse models. In this study, we show that a Food and Drug Administration (FDA)-approved small molecule, Sunitinib, is a potent α7 integrin enhancer capable of promoting myogenic regeneration by stimulating satellite cell activation and increasing myofiber fusion. Sunitinib exerts its regenerative effects via transient inhibition of SHP-2 and subsequent activation of the STAT3 pathway. Treatment of mdx mice with Sunitinib demonstrated decreased membrane leakiness and damage owing to myofiber regeneration and enhanced support at the extracellular matrix. The decreased myofiber damage translated into a significant increase in muscle force production. This study identifies an already FDA-approved compound, Sunitinib, as a possible DMD therapeutic with the potential to treat other muscular dystrophies in which there is defective muscle repair.
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Affiliation(s)
- Tatiana M Fontelonga
- Department of Pharmacology, University of Nevada, Reno School of Medicine, , Reno, NV, USA
| | - Brennan Jordan
- Department of Pharmacology, University of Nevada, Reno School of Medicine, , Reno, NV, USA
| | - Andreia M Nunes
- Department of Pharmacology, University of Nevada, Reno School of Medicine, , Reno, NV, USA
| | - Pamela Barraza-Flores
- Department of Pharmacology, University of Nevada, Reno School of Medicine, , Reno, NV, USA
| | - Nicholas Bolden
- Department of Pharmacology, University of Nevada, Reno School of Medicine, , Reno, NV, USA
| | - Ryan D Wuebbles
- Department of Pharmacology, University of Nevada, Reno School of Medicine, , Reno, NV, USA
| | - Lesley Mathews Griner
- Division of Pre-clinical Innovation, NIH Center for Advancing Translational Sciences, Rockville, MD, USA
| | - Xin Hu
- Division of Pre-clinical Innovation, NIH Center for Advancing Translational Sciences, Rockville, MD, USA
| | - Marc Ferrer
- Division of Pre-clinical Innovation, NIH Center for Advancing Translational Sciences, Rockville, MD, USA
| | - Juan Marugan
- Division of Pre-clinical Innovation, NIH Center for Advancing Translational Sciences, Rockville, MD, USA
| | - Noel Southall
- Division of Pre-clinical Innovation, NIH Center for Advancing Translational Sciences, Rockville, MD, USA
| | - Dean J Burkin
- Department of Pharmacology, University of Nevada, Reno School of Medicine, , Reno, NV, USA
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17
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Fogli S, Porta C, Del Re M, Crucitta S, Gianfilippo G, Danesi R, Rini BI, Schmidinger M. Optimizing treatment of renal cell carcinoma with VEGFR-TKIs: a comparison of clinical pharmacology and drug-drug interactions of anti-angiogenic drugs. Cancer Treat Rev 2020; 84:101966. [PMID: 32044644 DOI: 10.1016/j.ctrv.2020.101966] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Revised: 01/09/2020] [Accepted: 01/10/2020] [Indexed: 02/07/2023]
Abstract
Anti-angiogenic treatment is an important option that has changed the therapeutic landscape in various tumors, particularly in patients affected by renal cell carcinoma (RCC). Agents that block signaling pathways governing tumor angiogenesis have raised high expectations among clinicians. Vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) comprise a heterogeneous class of drugs with distinct pharmacological profiles, including potency, selectivity, pharmacokinetics and drug-drug interactions. Among them, tivozanib is one of the last TKIs introduced in the clinical practice; this drug selectively targets VEGFRs, it is characterized by a favorable pharmacokinetics and safety profile and has been approved as first-line treatment for patients with metastatic RCC (mRCC). In this article, we describe the clinical pharmacology of selected VEGFR-TKIs used for the treatment of mRCC, highlighting the relevant differences; moreover we aim to define the main pharmacologic characteristics of these drug.
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Affiliation(s)
- Stefano Fogli
- Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Camillo Porta
- Department of Internal Medicine, University of Pavia and Division of Translational Oncology, IRCCS Istituti Clinici Scientifici Maugeri, Pavia, Italy
| | - Marzia Del Re
- Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Stefania Crucitta
- Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Giulia Gianfilippo
- Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Romano Danesi
- Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
| | - Brian I Rini
- Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Manuela Schmidinger
- Clinical Division of Oncology, Department of Medicine I and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
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18
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Jolibois J, Schmitt A, Royer B. A simple and fast LC-MS/MS method for the routine measurement of cabozantinib, olaparib, palbociclib, pazopanib, sorafenib, sunitinib and its main active metabolite in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci 2019; 1132:121844. [DOI: 10.1016/j.jchromb.2019.121844] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Revised: 10/14/2019] [Accepted: 10/17/2019] [Indexed: 02/01/2023]
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19
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Barui AK, Nethi SK, Haque S, Basuthakur P, Patra CR. Recent Development of Metal Nanoparticles for Angiogenesis Study and Their Therapeutic Applications. ACS APPLIED BIO MATERIALS 2019; 2:5492-5511. [DOI: 10.1021/acsabm.9b00587] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Ayan Kumar Barui
- Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad, Telangana 500007, India
- Department of Chemistry, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea
| | - Susheel Kumar Nethi
- Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad, Telangana 500007, India
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota 55455, United States
| | - Shagufta Haque
- Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad, Telangana 500007, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India
| | - Papia Basuthakur
- Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad, Telangana 500007, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India
| | - Chitta Ranjan Patra
- Department of Applied Biology, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad, Telangana 500007, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh 201002, India
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20
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Xiao J, Wang J, Yuan L, Hao L, Wang D. Study on the mechanism and intervention strategy of sunitinib induced nephrotoxicity. Eur J Pharmacol 2019; 864:172709. [PMID: 31586633 DOI: 10.1016/j.ejphar.2019.172709] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Revised: 09/26/2019] [Accepted: 09/30/2019] [Indexed: 12/27/2022]
Abstract
Sunitinib is an oral small molecular tyrosine kinase inhibitor that exhibits potent antiangiogenic and antitumor activity. Unfortunately, sunitinib kidney toxicity limits its clinical use. Renal injury caused by sunitinib treatment can not only lead to the failure of cancer treatment, but also jeopardizes the health and life of patients. Currently, there is no better intervention measure for renal injury caused by sunitinib therapy except reducing the dosage or stopping the medication. In this study, we learned from clinical case report that sunitinib can cause severe renal injury. Subsequently, we compiled the clinical trials data of sunitinib found that sunitinib can cause general renal damage. Based on this finding, we conducted a study on the mechanism of sunitinib-induced renal injury. The results showed that sunitinib can inhibit the survival of HK-2 cells (human tubule epithelial cells) in a dose- and time-dependent manner. The survival inhibition is mainly due to the activation apoptotic signaling pathway by sunitinib in HK-2 cells and induces apoptosis of HK-2 cells. Subsequently, we found that natural compound oxypeucedanin can significantly alleviate the apoptosis of HK-2 cells induced by sunitinib. Through clinical investigation and experimental study of sunitinib, we found that sunitinib can cause extensive renal damage by inducing apoptosis of renal tubular epithelial cells and natural compound oxypeucedanin is a potentially effective intervention for nephrotoxicity of sunitinib. Thus, our research will provide a theoretical basis for the future rational use of sunitinib and the search for appropriate interventions for sunitinib-induced kidney damage.
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Affiliation(s)
- Jianping Xiao
- Department of Nephrology, The Second Affiliated Hospital of Anhui Medical University, 678 Furong Road, Hefei, Anhui, China.
| | - Ju Wang
- Department of Nephrology, The Second Affiliated Hospital of Anhui Medical University, 678 Furong Road, Hefei, Anhui, China
| | - Liang Yuan
- Department of Nephrology, The Second Affiliated Hospital of Anhui Medical University, 678 Furong Road, Hefei, Anhui, China
| | - Li Hao
- Department of Nephrology, The Second Affiliated Hospital of Anhui Medical University, 678 Furong Road, Hefei, Anhui, China
| | - Deguang Wang
- Department of Nephrology, The Second Affiliated Hospital of Anhui Medical University, 678 Furong Road, Hefei, Anhui, China.
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Laengsri V, Nantasenamat C, Schaduangrat N, Nuchnoi P, Prachayasittikul V, Shoombuatong W. TargetAntiAngio: A Sequence-Based Tool for the Prediction and Analysis of Anti-Angiogenic Peptides. Int J Mol Sci 2019; 20:E2950. [PMID: 31212918 PMCID: PMC6628072 DOI: 10.3390/ijms20122950] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Revised: 06/13/2019] [Accepted: 06/14/2019] [Indexed: 11/21/2022] Open
Abstract
Cancer remains one of the major causes of death worldwide. Angiogenesis is crucial for the pathogenesis of various human diseases, especially solid tumors. The discovery of anti-angiogenic peptides is a promising therapeutic route for cancer treatment. Thus, reliably identifying anti-angiogenic peptides is extremely important for understanding their biophysical and biochemical properties that serve as the basis for the discovery of new anti-cancer drugs. This study aims to develop an efficient and interpretable computational model called TargetAntiAngio for predicting and characterizing anti-angiogenic peptides. TargetAntiAngio was developed using the random forest classifier in conjunction with various classes of peptide features. It was observed via an independent validation test that TargetAntiAngio can identify anti-angiogenic peptides with an average accuracy of 77.50% on an objective benchmark dataset. Comparisons demonstrated that TargetAntiAngio is superior to other existing methods. In addition, results revealed the following important characteristics of anti-angiogenic peptides: (i) disulfide bond forming Cys residues play an important role for inhibiting blood vessel proliferation; (ii) Cys located at the C-terminal domain can decrease endothelial formatting activity and suppress tumor growth; and (iii) Cyclic disulfide-rich peptides contribute to the inhibition of angiogenesis and cell migration, selectivity and stability. Finally, for the convenience of experimental scientists, the TargetAntiAngio web server was established and made freely available online.
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Affiliation(s)
- Vishuda Laengsri
- Department of Clinical Microscopy, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand.
- Center for Research and Innovation, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand.
| | - Chanin Nantasenamat
- Center of Data Mining and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand.
| | - Nalini Schaduangrat
- Center of Data Mining and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand.
| | - Pornlada Nuchnoi
- Department of Clinical Microscopy, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand.
- Center for Research and Innovation, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand.
| | - Virapong Prachayasittikul
- Department of Clinical Microbiology and Applied Technology, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand.
| | - Watshara Shoombuatong
- Center of Data Mining and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Thailand.
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22
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Kiseleva AA, Korobeynikov VA, Nikonova AS, Zhang P, Makhov P, Deneka AY, Einarson MB, Serebriiskii IG, Liu H, Peterson JR, Golemis EA. Unexpected Activities in Regulating Ciliation Contribute to Off-target Effects of Targeted Drugs. Clin Cancer Res 2019; 25:4179-4193. [PMID: 30867219 DOI: 10.1158/1078-0432.ccr-18-3535] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2018] [Revised: 02/14/2019] [Accepted: 03/11/2019] [Indexed: 12/14/2022]
Abstract
PURPOSE For many tumors, signaling exchanges between cancer cells and other cells in their microenvironment influence overall tumor signaling. Some of these exchanges depend on expression of the primary cilium on nontransformed cell populations, as extracellular ligands including Sonic Hedgehog (SHH), PDGFRα, and others function through receptors spatially localized to cilia. Cell ciliation is regulated by proteins that are themselves therapeutic targets. We investigated whether kinase inhibitors of clinical interest influence ciliation and signaling by proteins with ciliary receptors in cancer and other cilia-relevant disorders, such as polycystic kidney disease (PKD). EXPERIMENTAL DESIGN We screened a library of clinical and preclinical kinase inhibitors, identifying drugs that either prevented or induced ciliary disassembly. Specific bioactive protein targets of the drugs were identified by mRNA depletion. Mechanism of action was defined, and activity of select compounds investigated. RESULTS We identified multiple kinase inhibitors not previously linked to control of ciliation, including sunitinib, erlotinib, and an inhibitor of the innate immune pathway kinase, IRAK4. For all compounds, activity was mediated through regulation of Aurora-A (AURKA) activity. Drugs targeting cilia influenced proximal cellular responses to SHH and PDGFRα. In vivo, sunitinib durably limited ciliation and cilia-related biological activities in renal cells, renal carcinoma cells, and PKD cysts. Extended analysis of IRAK4 defined a subset of innate immune signaling effectors potently affecting ciliation. CONCLUSIONS These results suggest a paradigm by which targeted drugs may have unexpected off-target effects in heterogeneous cell populations in vivo via control of a physical platform for receipt of extracellular ligands.
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Affiliation(s)
- Anna A Kiseleva
- Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.,Department of Biochemistry and Biotechnology, Kazan Federal University, Kazan, Russian Federation
| | - Vladislav A Korobeynikov
- Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.,Department of Pathology and Cell Biology, Columbia University, New York, New York
| | - Anna S Nikonova
- Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania
| | - Peishan Zhang
- Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.,School of Pharmacy, Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China
| | - Petr Makhov
- Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania
| | - Alexander Y Deneka
- Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.,Department of Biochemistry and Biotechnology, Kazan Federal University, Kazan, Russian Federation
| | - Margret B Einarson
- Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania
| | - Ilya G Serebriiskii
- Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.,Department of Biochemistry and Biotechnology, Kazan Federal University, Kazan, Russian Federation
| | - Hanqing Liu
- School of Pharmacy, Jiangsu University, Zhenjiang, Jiangsu, People's Republic of China
| | - Jeffrey R Peterson
- Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania
| | - Erica A Golemis
- Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.
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23
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Chakraborty AD, Gonano LA, Munro ML, Smith LJ, Thekkedam C, Staudacher V, Gamble AB, Macquaide N, Dulhunty AF, Jones PP. Activation of RyR2 by class I kinase inhibitors. Br J Pharmacol 2019; 176:773-786. [PMID: 30588601 DOI: 10.1111/bph.14562] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Revised: 11/26/2018] [Accepted: 12/09/2018] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND AND PURPOSE Kinase inhibitors are a common treatment for cancer. Class I kinase inhibitors that target the ATP-binding pocket are particularly prevalent. Many of these compounds are cardiotoxic and can cause arrhythmias. Spontaneous release of Ca2+ via cardiac ryanodine receptors (RyR2), through a process termed store overload-induced Ca2+ release (SOICR), is a common mechanism underlying arrhythmia. We explored whether class I kinase inhibitors could modify the activity of RyR2 and trigger SOICR to determine if this contributes to the cardiotoxic nature of these compounds. EXPERIMENTAL APPROACH The impact of class I and II kinase inhibitors on SOICR was studied in HEK293 cells and ventricular myocytes using single-cell Ca2+ imaging. A specific effect on RyR2 was confirmed using single channel recordings. Ventricular myocytes were also used to determine if drug-induced changes in SOICR could be reversed using anti-SOICR agents. KEY RESULTS Class I kinase inhibitors increased the propensity of SOICR. Single channel recording showed that this was due to a specific effect on RyR2. Class II kinase inhibitors decreased the activity of RyR2 at the single channel level but had little effect on SOICR. The promotion of SOICR mediated by class I kinase inhibitors could be reversed using the anti-SOICR agent VK-II-86. CONCLUSIONS AND IMPLICATIONS Part of the cardiotoxicity of class I kinase inhibitors can be assigned to their effect on RyR2 and increase in SOICR. Compounds with anti-SOICR activity may represent an improved treatment option for patients.
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Affiliation(s)
- A D Chakraborty
- Department of Physiology, School of Biomedical Sciences, and HeartOtago, University of Otago, Dunedin, New Zealand
| | - L A Gonano
- Department of Physiology, School of Biomedical Sciences, and HeartOtago, University of Otago, Dunedin, New Zealand.,Centro de Investigaciones Cardiovasculares, CONICET La Plata, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata, Argentina
| | - M L Munro
- Department of Physiology, School of Biomedical Sciences, and HeartOtago, University of Otago, Dunedin, New Zealand
| | - L J Smith
- Department of Physiology, School of Biomedical Sciences, and HeartOtago, University of Otago, Dunedin, New Zealand
| | - C Thekkedam
- Eccles Institute of Neuroscience, John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia
| | - V Staudacher
- School of Pharmacy, University of Otago, Dunedin, New Zealand
| | - A B Gamble
- School of Pharmacy, University of Otago, Dunedin, New Zealand
| | - N Macquaide
- Institute of Cardiovascular and Medical Sciences and School of Life Sciences, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow, UK
| | - A F Dulhunty
- Eccles Institute of Neuroscience, John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia
| | - P P Jones
- Department of Physiology, School of Biomedical Sciences, and HeartOtago, University of Otago, Dunedin, New Zealand
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24
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Sorafenib-induced Prostate Volume Reduction, a New Adverse Effect Detected by Imaging: A Pilot Study. J Belg Soc Radiol 2018; 102:69. [PMID: 30386849 PMCID: PMC6208293 DOI: 10.5334/jbsr.1607] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Background Sorafenib has been used in the treatment of advanced hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC). Sorafenib-associated organ reduction have been reported on imaging, such as thyroid, pancreas and muscle, but there has been no research on prostate volume reduction (PVR). Methods We retrospectively analyzed 26 patients (twenty with HCC and six patients with RCC) who underwent sorafenib therapy for 31 to 1225 days (median, 100 days). PVR was estimated by two independent readers using CT volumetry. Results The sum of all prostate volumes measured by reader 1 was 24.2 ± 13.8 cm3 on the baseline CT and 20.4 ± 10.6 cm3 on the follow-up CT (p < 0.001), and that measured by reader 2 was 22.3 ± 13.9 cm3 on the baseline CT and 19.2 ± 10.6 cm3 on the follow-up CT (p < 0.001). The concordance correlation coefficient for the prostate volume measured by the two readers was 0.95 on the baseline CT scans and 0.94 on the follow-up CT scans. Sorafenib-associated PVR demonstrated slight dependence to the exposure time (r = -0.23). One patient with benign prostatic hyperplasia (BPH) showed PVR (from 80.4 to 61.5 cm3 [reader 1]; 83.4 to 61.6 cm3 [reader 2]) after sorafenib administration. Sorafenib-associated PVR occurred in patients both with and without underlying liver dysfunction with relative prostate volume changes of 86.7 ± 12.0% and 85.0 ± 9.0%, respectively. Conclusion Our study demonstrated significant PVR with sorafenib treatment in patients regardless of the presence of BPH and underlying liver dysfunction.
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25
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Awoonor-Williams E, Rowley CN. How Reactive are Druggable Cysteines in Protein Kinases? J Chem Inf Model 2018; 58:1935-1946. [DOI: 10.1021/acs.jcim.8b00454] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Ernest Awoonor-Williams
- Department of Chemistry, Memorial University of Newfoundland, St. John’s, NL A1B 3X9, Canada
| | - Christopher N. Rowley
- Department of Chemistry, Memorial University of Newfoundland, St. John’s, NL A1B 3X9, Canada
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26
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Robey RW, Pluchino KM, Hall MD, Fojo AT, Bates SE, Gottesman MM. Revisiting the role of ABC transporters in multidrug-resistant cancer. Nat Rev Cancer 2018; 18:452-464. [PMID: 29643473 PMCID: PMC6622180 DOI: 10.1038/s41568-018-0005-8] [Citation(s) in RCA: 1232] [Impact Index Per Article: 176.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Most patients who die of cancer have disseminated disease that has become resistant to multiple therapeutic modalities. Ample evidence suggests that the expression of ATP-binding cassette (ABC) transporters, especially the multidrug resistance protein 1 (MDR1, also known as P-glycoprotein or P-gp), which is encoded by ABC subfamily B member 1 (ABCB1), can confer resistance to cytotoxic and targeted chemotherapy. However, the development of MDR1 as a therapeutic target has been unsuccessful. At the time of its discovery, appropriate tools for the characterization and clinical development of MDR1 as a therapeutic target were lacking. Thirty years after the initial cloning and characterization of MDR1 and the implication of two additional ABC transporters, the multidrug resistance-associated protein 1 (MRP1; encoded by ABCC1)), and ABCG2, in multidrug resistance, interest in investigating these transporters as therapeutic targets has waned. However, with the emergence of new data and advanced techniques, we propose to re-evaluate whether these transporters play a clinical role in multidrug resistance. With this Opinion article, we present recent evidence indicating that it is time to revisit the investigation into the role of ABC transporters in efficient drug delivery in various cancer types and at the blood-brain barrier.
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Affiliation(s)
- Robert W Robey
- Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Kristen M Pluchino
- Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Matthew D Hall
- National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA
| | - Antonio T Fojo
- Division of Hematology/Oncology, Department of Medicine, Columbia University/New York Presbyterian Hospital, Manhattan, NY, USA
- James J. Peters VA Medical Center, Bronx, NY, USA
| | - Susan E Bates
- Division of Hematology/Oncology, Department of Medicine, Columbia University/New York Presbyterian Hospital, Manhattan, NY, USA
- James J. Peters VA Medical Center, Bronx, NY, USA
| | - Michael M Gottesman
- Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
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27
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Marine natural products for multi-targeted cancer treatment: A future insight. Biomed Pharmacother 2018; 105:233-245. [PMID: 29859466 DOI: 10.1016/j.biopha.2018.05.142] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Revised: 05/26/2018] [Accepted: 05/28/2018] [Indexed: 12/28/2022] Open
Abstract
Cancer is world's second largest alarming disease, which involves abnormal cell growth and have potential to spread to other parts of the body. Most of the available anticancer drugs are designed to act on specific targets by altering the activity of involved transporters and genes. As cancer cells exhibit complex cellular machinery, the regeneration of cancer tissues and chemo resistance towards the therapy has been the main obstacle in cancer treatment. This fact encourages the researchers to explore the multitargeted use of existing medicines to overcome the shortcomings of chemotherapy for alternative and safer treatment strategies. Recent developments in genomics-proteomics and an understanding of the molecular pharmacology of cancer have also challenged researchers to come up with target-based drugs. The literature supports the evidence of natural compounds exhibiting antioxidant, antimitotic, anti-inflammatory, antibiotic as well as anticancer activity. In this review, we have selected marine sponges as a prolific source of bioactive compounds which can be explored for their possible use in cancer and have tried to link their role in cancer pathway. To prove this, we revisited the literature for the selection of cancer genes for the multitargeted use of existing drugs and natural products. We used Cytoscape network analysis and Search tool for retrieval of interacting genes/ proteins (STRING) to study the possible interactions to show the links between the antioxidants, antibiotics, anti-inflammatory and antimitotic agents and their targets for their possible use in cancer. We included total 78 pathways, their genes and natural compounds from the above four pharmacological classes used in cancer treatment for multitargeted approach. Based on the Cytoscape network analysis results, we shortlist 22 genes based on their average shortest path length connecting one node to all other nodes in a network. These selected genes are CDKN2A, FH, VHL, STK11, SUFU, RB1, MEN1, HRPT2, EXT1, 2, CDK4, p14, p16, TSC1, 2, AXIN2, SDBH C, D, NF1, 2, BHD, PTCH, GPC3, CYLD and WT1. The selected genes were analysed using STRING for their protein-protein interactions. Based on the above findings, we propose the selected genes to be considered as major targets and are suggested to be studied for discovering marine natural products as drug lead in cancer treatment.
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28
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Ishihara H, Kondo T, Fukuda H, Yoshida K, Omae K, Takagi T, Iizuka J, Kobayashi H, Tanabe K. Evaluation of renal function change during first-line tyrosine kinase inhibitor therapy for metastatic renal cell carcinoma. Jpn J Clin Oncol 2018; 47:1175-1181. [PMID: 29140528 PMCID: PMC5896698 DOI: 10.1093/jjco/hyx161] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Accepted: 10/23/2017] [Indexed: 11/13/2022] Open
Abstract
Background The change in renal function induced by first-line tyrosine kinase inhibitor therapy for metastatic renal cell carcinoma remains unclear. Methods One hundred and thirty-four patients were evaluated. Sunitinib (SU) and sorafenib (SO) were administered to 91 (67.9%) and 43 (32.1%) patients, respectively. The change in estimated glomerular filtration rate (ΔeGFR) was calculated as [(eGFR at each time point - pre-treatment eGFR)/pre-treatment eGFR] × 100. ΔeGFR was compared between SU- and SO users using a mixed-effects model for repeated measures data with two or greater. Additionally, predictors for ΔeGFR ≤ -10% at 6 months after therapy initiation were evaluated using multivariate logistic regression analysis. Results Throughout the 24 months after therapy initiation, ΔeGFR was negatively greater in SU users, compared with that in SO users (P < 0.0001). In SU users, renal dysfunction was observed regardless of pre-treatment chronic kidney disease (CKD) status, whereas the magnitude of renal dysfunction was milder in SO users. In SO users without pre-treatment CKD, renal function did not significantly deteriorate. Moreover, ΔeGFR ≤ -10% was more frequently observed in SU users after 3 months (P = 0.0121) and 6 months (P = 0.0009). Finally, SU usage was an independent predictor for ΔeGFR ≤ -10% at 6 months (odds ratio 8.87, P = 0.0053), along with pre-treatment hypertension (odds ratio 4.69, P = 00072). Conclusions Deterioration of renal function was stronger with SU than SO. During SU therapy, renal function should be monitored and pre-treatment kidney function should be taken into consideration for therapy selection.
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Affiliation(s)
- Hiroki Ishihara
- Department of Urology, Kidney Center, Tokyo Women's Medical University
| | - Tsunenori Kondo
- Department of Urology, Kidney Center, Tokyo Women's Medical University.,Department of Urology, Tokyo Women's Medical University Medical Center East, Tokyo
| | - Hironori Fukuda
- Department of Urology, Kidney Center, Tokyo Women's Medical University
| | - Kazuhiko Yoshida
- Department of Urology, Kidney Center, Tokyo Women's Medical University
| | - Kenji Omae
- Department of Urology, Kidney Center, Tokyo Women's Medical University.,Department of Healthcare Epidemiology, Kyoto University Graduate School of Medicine/ School of Public Health, Kyoto.,Center for Innovative Research for Communities and Clinical Excellence, Fukushima Medical University, Fukushima, Japan
| | - Toshio Takagi
- Department of Urology, Kidney Center, Tokyo Women's Medical University
| | - Junpei Iizuka
- Department of Urology, Kidney Center, Tokyo Women's Medical University
| | | | - Kazunari Tanabe
- Department of Urology, Kidney Center, Tokyo Women's Medical University
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Abstract
Osteosarcoma (OS), the most common type of primary malignant bone tumor, is defined by the presence of malignant mesenchymal cells producing osteoid or immature bone. The peak incidence of the most frequent type of OS, i.e., high-grade central OS, occurs in the second decade of life during the adolescent growth spurt. Most patients suffer from the pain and swelling in the involved region and, usually, seek medical attention. Diagnosis is carried out by conventional radiographs, computed tomography, and magnetic resonance image (MRI). In addition, three-phase bone scans, thallium scintigraphy, dynamic MRI, and positron emission spectroscopy are new innovative promising tools. OS can be treated with surgery, radiotherapy, and chemotherapy. There is a clear need for newer effective agents for patients with OS, especially for patients who afflicted with metastatic and recurrence tumor. Monoclonal antibodies directed against OS may prove useful as treatment, either for drug delivery or for radiopharmaceuticals.
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Affiliation(s)
- Shachi Jain Taran
- From the Department of Pediatrics, Sri Aurobindo Medical College and Postgraduate Institute, Indore, Madhya Pradesh, India
| | - Rakesh Taran
- Department of Medical Oncology, Sri Aurobindo Medical College and Postgraduate Institute, Indore, Madhya Pradesh, India
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30
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Mishra S, Katare DP. Synergistic Combination for Chemoprevention of Hepatocellular Carcinoma: An In Silico and In Vitro Approach. Basic Clin Pharmacol Toxicol 2016; 120:532-540. [PMID: 27987371 DOI: 10.1111/bcpt.12730] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Accepted: 11/29/2016] [Indexed: 01/11/2023]
Abstract
Combination therapy is one of the best methods to manage the fatality rate in hepatocellular carcinoma (HCC). This study aimed to formulate a synergistic combination of synthetic and herbal compounds for the treatment of HCC as well as to elucidate a possible signalling mechanism. MTT and enzymatic assay were performed to determine the synergistic effect of drug combination (sorafenib, vitamin K1 and trans-chalcone) on HepG2 cell lines after intoxication with H2 O2 . Protein-protein interaction and docking studies were performed using Pathwaylinker2.0 and Schrödinger's software application to find out the mechanism of action and major targets for drug combination. The overall in vitro result showed that combination of trans-chalcone, vitamin K1 and sorafenib (10, 5 and 5 μM concentration, respectively) enhanced the resistance against oxidative stress generated by H2 O2 . The interaction studies helped in identification of few targets for docking of ligands (trans-chalcone, vitamin K1 and sorafenib). The study reports the synergistic effects of the formulation that can protect the cells from oxidative stress and restore normal levels of cellular enzymes in HepG2 cell line. We were able to determine the mechanism of action of herbal and synthetic formulation through in silico studies. Finally, docking studies confirmed potential targets for inhibition of hepatocarcinogenesis.
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Affiliation(s)
- Savita Mishra
- Proteomics & Translational Research Lab, Centre for Medical Biotechnology, Institute of Biotechnology, Amity University Uttar Pradesh, Noida, India
| | - Deepshikha Pande Katare
- Proteomics & Translational Research Lab, Centre for Medical Biotechnology, Institute of Biotechnology, Amity University Uttar Pradesh, Noida, India
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31
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Takahashi H, Nasu K, Minami M, Kojima T, Nishiyama H, Ishiguro T, Konishi T. Organ Atrophy Induced by Sorafenib and Sunitinib - Quantitative Computed Tomography (CT) Evaluation of the Pancreas, Thyroid Gland and Spleen. Pol J Radiol 2016; 81:557-565. [PMID: 27956943 PMCID: PMC5129701 DOI: 10.12659/pjr.898936] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Accepted: 06/08/2016] [Indexed: 11/13/2022] Open
Abstract
Background To evaluate organ atrophy induced by sorafenib and sunitinib, we retrospectively reviewed the CT scans of renal cell carcinoma (RCC) patients receiving molecular targeted therapy (MTT) using sorafenib or sunitinib, and performed volumetric analysis of the pancreas, thyroid gland, and spleen. Material/Methods Thirteen RCC patients receiving MTT were assigned as the evaluation cases (MTT group), while thirteen additional RCC patients not receiving MTT were retrieved as the Control group. We evaluated the baseline and follow-up CT studies. The volume of the three organs estimated by CT volumetry was compared between the baseline and follow-up CTs. The atrophic ratio of the organ volume in the follow-up CT to that in the baseline CT was calculated, and compared between the MTT and Control groups. Results All measured organs in the MTT group showed statistically significant volume loss, while no significant change was observed in the Control group. Mean atrophic ratio in the MTT group was 0.74, 0.58, and 0.82 for the pancreas, thyroid and spleen, respectively. The differences in atrophic ratios between both groups were all statistically significant (P<0.05). Conclusions Single-agent sorafenib or sunitinib therapy induced statistically significant atrophy in the pancreas, thyroid, and spleen.
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Affiliation(s)
- Hiroaki Takahashi
- Department of Diagnostic and Interventional Radiology, University of Tsukuba, Faculty of Medicine, Ibaraki, Japan
| | - Katsuhiro Nasu
- Department of Diagnostic and Interventional Radiology, University of Tsukuba, Faculty of Medicine, Ibaraki, Japan
| | - Manabu Minami
- Department of Diagnostic and Interventional Radiology, University of Tsukuba, Faculty of Medicine, Ibaraki, Japan
| | - Takahiro Kojima
- Department of Urology, University of Tsukuba, Faculty of Medicine, Ibaraki, Japan
| | - Hiroyuki Nishiyama
- Department of Urology, University of Tsukuba, Faculty of Medicine, Ibaraki, Japan
| | - Toshitaka Ishiguro
- Department of Diagnostic and Interventional Radiology, University of Tsukuba, Faculty of Medicine, Ibaraki, Japan
| | - Takahiro Konishi
- Department of Diagnostic and Interventional Radiology, University of Tsukuba, Faculty of Medicine, Ibaraki, Japan
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32
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Bourlon MT, Gao D, Trigero S, Clemons JE, Breaker K, Lam ET, Flaig TW. Clinical significance of sunitinib-associated macrocytosis in metastatic renal cell carcinoma. Cancer Med 2016; 5:3386-3393. [PMID: 27758076 PMCID: PMC5224865 DOI: 10.1002/cam4.919] [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: 05/10/2016] [Revised: 08/11/2016] [Accepted: 08/18/2016] [Indexed: 12/12/2022] Open
Abstract
Increases in the mean corpuscular volume (MCV) have been observed in patients with metastatic renal cell carcinoma (mRCC) on tyrosine kinase inhibitor (TKI) treatment; however, its association with progression‐free‐survival (PFS) is unknown. We aimed to characterize TKI‐associated macrocytosis in mRCC and its relationship with PFS. Retrospective review of data on macrocytosis and thyroid dysfunction on mRCC patients treated with sunitinib and/or sorafenib. These results are evaluated in the context of our previous report on the association of hypothyroidism in this setting. We assessed PFS as clinically defined by the treating physician. Seventy‐four patients, 29 of whom received both drugs, were included. A treatment period was defined as time from initiation to discontinuation of either sunitinib or sorafenib; 103 treatment periods [sorafenib (47), sunitinib (56)] were analyzed. Macrocytosis was found in 55 and 8% of sunitinib‐ and sorafenib‐treated patients, respectively, P < 0.001. The median time to developing macrocytosis was 3 months (m, range 1–7). Median PFS in sunitinib‐treated patients was 11 m (95% CI: 6–19). Median PFS was higher among those with macrocytosis compared to normocytosis (21 m [95% CI: 11–25] vs. 4 m [95% CI: 3–8] P = 0.0001). Macrocytosis and hypothyroidism were two significant predictors of PFS. The greatest difference in PFS among all patients was observed in patients with both macrocytosis and hypothyroidism (25 m), compared to the normocytic and euthyroid patients (5 m) (P < 0.0001). Sunitinib‐related macrocytosis was associated with prolonged PFS, and concurrent development of hypothyroidism and macrocytosis further prolonged PFS. Increased MCV may have a role as a predictive biomarker for sunitinib. Prospective studies accounting for other known prognostic factors are needed to confirm this finding.
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Affiliation(s)
- Maria T Bourlon
- Division of Medical Oncology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Dexiang Gao
- Department of Biostatistics and Informatics, University of Colorado, Denver, Colorado
| | - Sara Trigero
- School of Medicine, University of Colorado Denver, Aurora, Colorado
| | - Julia E Clemons
- School of Medicine, University of Colorado Denver, Aurora, Colorado
| | - Kathryn Breaker
- Division of Medical Oncology, Department of Medicine, School of Medicine, University of Colorado, Aurora, Colorado.,University of Colorado Cancer Center, Aurora, Colorado
| | - Elaine T Lam
- Division of Medical Oncology, Department of Medicine, School of Medicine, University of Colorado, Aurora, Colorado.,University of Colorado Cancer Center, Aurora, Colorado
| | - Thomas W Flaig
- Division of Medical Oncology, Department of Medicine, School of Medicine, University of Colorado, Aurora, Colorado.,University of Colorado Cancer Center, Aurora, Colorado
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Mukherjee S, Patra CR. Therapeutic application of anti-angiogenic nanomaterials in cancers. NANOSCALE 2016; 8:12444-12470. [PMID: 27067119 DOI: 10.1039/c5nr07887c] [Citation(s) in RCA: 85] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/05/2023]
Abstract
Angiogenesis, the formation of new blood vessels from pre-existing vasculature, plays a vital role in physiological and pathological processes (embryonic development, wound healing, tumor growth and metastasis). The overall balance of angiogenesis inside the human body is maintained by pro- and anti-angiogenic signals. The processes by which drugs inhibit angiogenesis as well as tumor growth are called the anti-angiogenesis technique, a most promising cancer treatment strategy. Over the last couple of decades, scientists have been developing angiogenesis inhibitors for the treatment of cancers. However, conventional anti-angiogenic therapy has several limitations including drug resistance that can create problems for a successful therapeutic strategy. Therefore, a new comprehensive treatment strategy using antiangiogenic agents for the treatment of cancer is urgently needed. Recently researchers have been developing and designing several nanoparticles that show anti-angiogenic properties. These nanomedicines could be useful as an alternative strategy for the treatment of various cancers using anti-angiogenic therapy. In this review article, we critically focus on the potential application of anti-angiogenic nanomaterial and nanoparticle based drug/siRNA/peptide delivery systems in cancer therapeutics. We also discuss the basic and clinical perspectives of anti-angiogenesis therapy, highlighting its importance in tumor angiogenesis, current status and future prospects and challenges.
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Affiliation(s)
- Sudip Mukherjee
- Biomaterials Group, CSIR-Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad - 500007, Telangana, India.
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Okada K, Nakano Y, Yamasaki K, Nitani C, Fujisaki H, Hara J. Sorafenib treatment in children with relapsed and refractory neuroblastoma: an experience of four cases. Cancer Med 2016; 5:1947-9. [PMID: 27264843 PMCID: PMC4898977 DOI: 10.1002/cam4.784] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2015] [Revised: 05/03/2016] [Accepted: 05/05/2016] [Indexed: 12/23/2022] Open
Abstract
Metastatic neuroblastoma is an aggressive malignancy with a poor prognosis. Recent findings have shown that sorafenib decreases cell viability and increases apoptosis in human neuroblastoma cell lines. We report an experience of compassionate use of sorafenib in children with treatment‐refractory neuroblastoma. Sorafenib showed transient anti‐tumor activity in all four patients without adverse effects. However, progression was observed after a short stabilization phase. While sorafenib showed minimal anti‐tumor activity in our patients, it might still be effective in patients with neuroblastoma in an earlier stage.
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Affiliation(s)
- Keiko Okada
- Department of Pediatric Hematology/Oncology, Osaka City General Hospital, Osaka, Japan
| | - Yoshiko Nakano
- Department of Pediatric Hematology/Oncology, Osaka City General Hospital, Osaka, Japan
| | - Kai Yamasaki
- Department of Pediatric Hematology/Oncology, Osaka City General Hospital, Osaka, Japan
| | - Chika Nitani
- Department of Pediatric Hematology/Oncology, Osaka City General Hospital, Osaka, Japan
| | - Hiroyuki Fujisaki
- Department of Pediatric Hematology/Oncology, Osaka City General Hospital, Osaka, Japan
| | - Junichi Hara
- Department of Pediatric Hematology/Oncology, Osaka City General Hospital, Osaka, Japan
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Li DL, Wang ZV, Ding G, Tan W, Luo X, Criollo A, Xie M, Jiang N, May H, Kyrychenko V, Schneider JW, Gillette TG, Hill JA. Doxorubicin Blocks Cardiomyocyte Autophagic Flux by Inhibiting Lysosome Acidification. Circulation 2016; 133:1668-87. [PMID: 26984939 DOI: 10.1161/circulationaha.115.017443] [Citation(s) in RCA: 342] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2015] [Accepted: 03/03/2016] [Indexed: 11/16/2022]
Abstract
BACKGROUND The clinical use of doxorubicin is limited by cardiotoxicity. Histopathological changes include interstitial myocardial fibrosis and the appearance of vacuolated cardiomyocytes. Whereas dysregulation of autophagy in the myocardium has been implicated in a variety of cardiovascular diseases, the role of autophagy in doxorubicin cardiomyopathy remains poorly defined. METHODS AND RESULTS Most models of doxorubicin cardiotoxicity involve intraperitoneal injection of high-dose drug, which elicits lethargy, anorexia, weight loss, and peritoneal fibrosis, all of which confound the interpretation of autophagy. Given this, we first established a model that provokes modest and progressive cardiotoxicity without constitutional symptoms, reminiscent of the effects seen in patients. We report that doxorubicin blocks cardiomyocyte autophagic flux in vivo and in cardiomyocytes in culture. This block was accompanied by robust accumulation of undegraded autolysosomes. We go on to localize the site of block as a defect in lysosome acidification. To test the functional relevance of doxorubicin-triggered autolysosome accumulation, we studied animals with diminished autophagic activity resulting from haploinsufficiency for Beclin 1. Beclin 1(+/-) mice exposed to doxorubicin were protected in terms of structural and functional changes within the myocardium. Conversely, animals overexpressing Beclin 1 manifested an amplified cardiotoxic response. CONCLUSIONS Doxorubicin blocks autophagic flux in cardiomyocytes by impairing lysosome acidification and lysosomal function. Reducing autophagy initiation protects against doxorubicin cardiotoxicity.
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Affiliation(s)
- Dan L Li
- From Division of Cardiology (D.L.L., Z.V.W., G.D., X.L., A.C., M.X., N.J., H.M., V.K., J.W.S., T.G.G., J.A.H.) and Department of Molecular Biology (W.T., J.A.H.), UT Southwestern Medical Center, Dallas, TX
| | - Zhao V Wang
- From Division of Cardiology (D.L.L., Z.V.W., G.D., X.L., A.C., M.X., N.J., H.M., V.K., J.W.S., T.G.G., J.A.H.) and Department of Molecular Biology (W.T., J.A.H.), UT Southwestern Medical Center, Dallas, TX
| | - Guanqiao Ding
- From Division of Cardiology (D.L.L., Z.V.W., G.D., X.L., A.C., M.X., N.J., H.M., V.K., J.W.S., T.G.G., J.A.H.) and Department of Molecular Biology (W.T., J.A.H.), UT Southwestern Medical Center, Dallas, TX
| | - Wei Tan
- From Division of Cardiology (D.L.L., Z.V.W., G.D., X.L., A.C., M.X., N.J., H.M., V.K., J.W.S., T.G.G., J.A.H.) and Department of Molecular Biology (W.T., J.A.H.), UT Southwestern Medical Center, Dallas, TX
| | - Xiang Luo
- From Division of Cardiology (D.L.L., Z.V.W., G.D., X.L., A.C., M.X., N.J., H.M., V.K., J.W.S., T.G.G., J.A.H.) and Department of Molecular Biology (W.T., J.A.H.), UT Southwestern Medical Center, Dallas, TX
| | - Alfredo Criollo
- From Division of Cardiology (D.L.L., Z.V.W., G.D., X.L., A.C., M.X., N.J., H.M., V.K., J.W.S., T.G.G., J.A.H.) and Department of Molecular Biology (W.T., J.A.H.), UT Southwestern Medical Center, Dallas, TX
| | - Min Xie
- From Division of Cardiology (D.L.L., Z.V.W., G.D., X.L., A.C., M.X., N.J., H.M., V.K., J.W.S., T.G.G., J.A.H.) and Department of Molecular Biology (W.T., J.A.H.), UT Southwestern Medical Center, Dallas, TX
| | - Nan Jiang
- From Division of Cardiology (D.L.L., Z.V.W., G.D., X.L., A.C., M.X., N.J., H.M., V.K., J.W.S., T.G.G., J.A.H.) and Department of Molecular Biology (W.T., J.A.H.), UT Southwestern Medical Center, Dallas, TX
| | - Herman May
- From Division of Cardiology (D.L.L., Z.V.W., G.D., X.L., A.C., M.X., N.J., H.M., V.K., J.W.S., T.G.G., J.A.H.) and Department of Molecular Biology (W.T., J.A.H.), UT Southwestern Medical Center, Dallas, TX
| | - Viktoriia Kyrychenko
- From Division of Cardiology (D.L.L., Z.V.W., G.D., X.L., A.C., M.X., N.J., H.M., V.K., J.W.S., T.G.G., J.A.H.) and Department of Molecular Biology (W.T., J.A.H.), UT Southwestern Medical Center, Dallas, TX
| | - Jay W Schneider
- From Division of Cardiology (D.L.L., Z.V.W., G.D., X.L., A.C., M.X., N.J., H.M., V.K., J.W.S., T.G.G., J.A.H.) and Department of Molecular Biology (W.T., J.A.H.), UT Southwestern Medical Center, Dallas, TX
| | - Thomas G Gillette
- From Division of Cardiology (D.L.L., Z.V.W., G.D., X.L., A.C., M.X., N.J., H.M., V.K., J.W.S., T.G.G., J.A.H.) and Department of Molecular Biology (W.T., J.A.H.), UT Southwestern Medical Center, Dallas, TX
| | - Joseph A Hill
- From Division of Cardiology (D.L.L., Z.V.W., G.D., X.L., A.C., M.X., N.J., H.M., V.K., J.W.S., T.G.G., J.A.H.) and Department of Molecular Biology (W.T., J.A.H.), UT Southwestern Medical Center, Dallas, TX.
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Abstract
Sorafenib is a multiple kinase inhibitor (MKI) approved for the treatment of primary advanced renal cell carcinoma and advanced primary liver cancer. It was recently approved by several health agencies around the world as the first available MKI treatment for radioactive iodine-refractory advanced and progressive differentiated thyroid cancer. Sorafenib targets C-RAF, B-RAF, VEGF receptor-1, -2, -3, PDGF receptor-β, RET, c-kit, and Flt-3. As a multifunctional inhibitor, sorafenib has the potential of inhibiting tumor growth, progression, metastasis, and angiogenesis and downregulating mechanisms that protect tumors from apoptosis and has shown to increase the progression-free survival in several Phase II trials. This led to the Phase III trial (DECISION) which showed that there was an improvement in progression-free survival of 5 months for patients on sorafenib when compared to those on placebo. Adverse events with this drug are common but usually manageable. The development of resistance after 1 or 2 years is almost a rule in most patients who showed partial response or stabilization of the disease while on sorafenib, which makes it necessary to think of a plan for subsequent therapies. These may include the use of another MKI, such as lenvatinib, the second approved MKI for advanced differentiated thyroid cancer, or include patients in clinical trials or the off-label use of other MKIs. Given sorafenib's earlier approval, most centers now have access to its prescription. The goal of this review was to improve the care of these patients by describing key aspects that all prescribers will need to master in order to optimize outcomes.
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Affiliation(s)
- Fabián Pitoia
- Division of Endocrinology, Hospital de Clinicas – University of Buenos Aires, Buenos Aires, Argentina
| | - Fernando Jerkovich
- Division of Endocrinology, Hospital de Clinicas – University of Buenos Aires, Buenos Aires, Argentina
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Korashy HM, Ansari MA, Maayah ZH, Imam F, Raish M, Attafi IM, Alharbi NO, Moraished BA. Differential Effects of Sunitinib on the Expression Profiles of Xenobiotic-Metabolizing Enzymes and Transporters in Rat Liver and Kidneys. Basic Clin Pharmacol Toxicol 2016; 119:173-83. [DOI: 10.1111/bcpt.12555] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2015] [Accepted: 01/05/2016] [Indexed: 01/09/2023]
Affiliation(s)
- Hesham M. Korashy
- Department of Pharmacology and Toxicology; College of Pharmacy; King Saud University; Riyadh Saudi Arabia
| | - Mushtaq A. Ansari
- Department of Pharmacology and Toxicology; College of Pharmacy; King Saud University; Riyadh Saudi Arabia
| | - Zaid H. Maayah
- Department of Pharmacology and Toxicology; College of Pharmacy; King Saud University; Riyadh Saudi Arabia
| | - Faisal Imam
- Department of Pharmacology and Toxicology; College of Pharmacy; King Saud University; Riyadh Saudi Arabia
| | - Mohammad Raish
- Department of Pharmaceutics; College of Pharmacy; King Saud University; Riyadh Saudi Arabia
| | - Ibraheem M. Attafi
- Department of Pharmacology and Toxicology; College of Pharmacy; King Saud University; Riyadh Saudi Arabia
| | - Naif O. Alharbi
- Department of Pharmacology and Toxicology; College of Pharmacy; King Saud University; Riyadh Saudi Arabia
| | - Bader A. Moraished
- Department of Pharmacology and Toxicology; College of Pharmacy; King Saud University; Riyadh Saudi Arabia
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Abstract
OPINION STATEMENT A paradigm shift towards molecular-based, personalized cancer therapeutics has occurred in recent years and a number of targeted drugs have emerged. Various targeted therapies like erlotinib, trastuzumab, and cetuximab have been approved in lung, breast, and colon cancers, respectively. Numerous clinical trials involving targeted drugs in biliary tract cancers are currently in progress, though none have been approved for this disease. Biliary tract cancers are divided into separate entities both anatomically and in terms of pathogenesis but are grouped together in most trials given their rarity. Combination chemotherapy involving cisplatin and gemcitabine is the current standard of care in the metastatic setting. In this review, we will discuss the various molecular pathways implicated in biliary tract cancers and potential therapeutic targets.
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Affiliation(s)
- Amartej Merla
- Department of Medical Oncology, Montefiore Medical Center, 1695 Eastchester Road, 2nd Floor, Bronx, NY 10461 USA
| | - Kenneth G. Liu
- Department of Medical Oncology, Montefiore Medical Center, 1695 Eastchester Road, 2nd Floor, Bronx, NY 10461 USA
| | - Lakshmi Rajdev
- Department of Medical Oncology, Montefiore Medical Center, 1695 Eastchester Road, 2nd Floor, Bronx, NY 10461 USA
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McKay RR, Rodriguez GE, Lin X, Kaymakcalan MD, Hamnvik OPR, Sabbisetti VS, Bhatt RS, Simantov R, Choueiri TK. Angiotensin system inhibitors and survival outcomes in patients with metastatic renal cell carcinoma. Clin Cancer Res 2015; 21:2471-9. [PMID: 25724518 PMCID: PMC4566854 DOI: 10.1158/1078-0432.ccr-14-2332] [Citation(s) in RCA: 94] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2014] [Accepted: 02/07/2015] [Indexed: 11/16/2022]
Abstract
PURPOSE The renin-angiotensin system may play a role in carcinogenesis. The purpose of this study was to evaluate the impact of angiotensin system inhibitors (ASI) on outcomes in metastatic renal cell carcinoma (mRCC) patients treated in the targeted therapy era. EXPERIMENTAL DESIGN We conducted a pooled analysis of mRCC patients treated on phase II and III clinical trials. Statistical analyses were performed using Cox regression adjusted for several risk factors and the Kaplan-Meier method. RESULTS A total of 4,736 patients were included, of whom 1,487 received ASIs and 783 received other antihypertensive agents. Overall, ASI users demonstrated improved overall survival (OS) compared with users of other antihypertensive agents (adjusted HR, 0.838, P = 0.0105, 26.68 vs. 18.07 months) and individuals receiving no antihypertensive therapy (adjusted HR, 0.810, P = 0.0026, 26.68 vs. 16.72 months). When stratified by therapy type, a benefit in OS was demonstrated in ASI users compared with nonusers in individuals receiving VEGF therapy (adjusted HR, 0.737, P < 0.0001, 31.12 vs. 21.94 months) but not temsirolimus or IFNα. An in vitro cell viability assay demonstrated that sunitinib in combination with an ASI significantly decreased RCC cell viability compared with control at physiologically relevant doses. This effect was not observed with either agent alone or with other non-ASI antihypertensives or temsirolimus. CONCLUSIONS In the largest analysis to date, we demonstrate that ASI use improved survival in mRCC patients treated in the targeted therapy era. Further studies are warranted to investigate the mechanism underlying this interaction and verify our observations to inform clinical practice.
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Affiliation(s)
- Rana R McKay
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | | | - Xun Lin
- Division of Endocrinology, Diabetes, and Hypertension, Brigham and Woman's Hospital, Boston, Massachusetts
| | - Marina D Kaymakcalan
- Department of Pharmacy and Clinical Support, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Ole-Petter R Hamnvik
- Division of Endocrinology, Diabetes, and Hypertension, Brigham and Woman's Hospital, Boston, Massachusetts
| | | | - Rupal S Bhatt
- Division of Hematology-Oncology and Cancer Biology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | | | - Toni K Choueiri
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
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Adamson PC. Improving the outcome for children with cancer: Development of targeted new agents. CA Cancer J Clin 2015; 65:212-20. [PMID: 25754421 PMCID: PMC4629487 DOI: 10.3322/caac.21273] [Citation(s) in RCA: 93] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2015] [Revised: 02/09/2015] [Accepted: 02/09/2015] [Indexed: 01/27/2023] Open
Abstract
The outcome for children with cancer has improved significantly over the past 60 years, with greater than 80% of patients today becoming 5-year survivors. Despite this progress, cancer remains the leading cause of death from disease in children in the United States, and significant short-term and long-term treatment toxicities continue to impact the majority of children with cancer. The development of targeted new agents offers the prospect of potentially more effective and less toxic treatment for children. More than a decade since imatinib mesylate was introduced into the treatment of children with Philadelphia chromosome-positive acute lymphoblastic leukemia, transforming its outcome, a range of targeted agents has undergone study in pediatric cancer patients. Early lessons learned from these studies include a better understanding of the adverse event profile of these drugs in children, the challenge of developing pediatric-specific formulations, and the continued reliance on successful development for adult cancer indications on pediatric drug development. The collaborative research infrastructure for children with cancer in the United States is well positioned to advance novel treatments into clinical investigations for a spectrum of rare and ultra-rare childhood cancers. A greater investment of resources in target discovery and validation can help drive much needed development of new, more effective treatments for children with cancer.
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Affiliation(s)
- Peter C. Adamson
- Corresponding author: Peter C. Adamson, MD, Chair, Children’s Oncology Group, The Children’s Hospital of Philadelphia, 3501 Civic Center Boulevard, CRTB 10060, Philadelphia, PA 19104;
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Pitoia F. Response to sorafenib treatment in advanced metastatic thyroid cancer. ACTA ACUST UNITED AC 2015; 58:37-41. [PMID: 24728162 DOI: 10.1590/0004-2730000002839] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2013] [Accepted: 08/31/2013] [Indexed: 01/26/2023]
Abstract
OBJECTIVE To investigate the efficacy of sorafenib in progressive radioiodine resistant metastatic thyroid carcinoma. SUBJECTS AND METHODS Off-label observational study. Sorafenib 400 mg twice daily was evaluated. Therapy duration was 12 ± 3 months (range 6-16 months). RESULTS Eight patients were included (seven papillary, one insular variant). The eight patients meeting study criteria received sorafenib 400 mg orally twice a day until disease progression or unacceptable toxicity developed. One patient showed a partial response with tumor regression of -35%, six months after the beginning of the treatment; five patients exhibited stable disease and two patients had progressive disease and died. Thyroglobulin decreased within 4 weeks in all patients by 50% ± 23%. Adverse events: one patient had heart failure, and recovered after sorafenib withdrawal. However, she died five months later of sudden death. CONCLUSION These data suggest a possible role for sorafenib in the treatment of progressive metastatic DTC. Adverse event are usually manageable, but severe ones may appear and these patients should be strictly controlled.
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Affiliation(s)
- Fabian Pitoia
- Private Office and Division of Endocrinology, Hospital de Clínicas, University of Buenos Aires, Buenos Aires, Argentina
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42
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Chee ELC, Lim AYL, Modamio P, Fernandez-Lastra C, Segarra I. Sunitinib tissue distribution changes after coadministration with ketoconazole in mice. Eur J Drug Metab Pharmacokinet 2015; 41:309-19. [PMID: 25656737 DOI: 10.1007/s13318-015-0264-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2014] [Accepted: 01/30/2015] [Indexed: 12/27/2022]
Abstract
Sunitinib is a multitargeted tyrosine kinase inhibitor approved for gastrointestinal stromal tumor (GIST), advanced renal cell carcinoma (RCC) and pancreatic neuroendocrine tumors. It is metabolized via CYP3A4 and has low brain penetration due to efflux transporters ABCB1B and ABCG2. We studied the interaction with ketoconazole (50 mg/kg), antifungal drug which shares metabolic pathways and efflux transporters, in ICR female mice after oral coadministration (30 min apart) of 60 mg/kg sunitinib (study group) versus sunitinib alone (control group). Plasma, liver, kidney and brain sunitinib concentrations were measured by HPLC at 2, 5, 10, 20, 40 min, 1, 2, 4, 6, 12 h post-sunitinib administration, and non-compartmental pharmacokinetic parameters estimated. In plasma, ketoconazole coadministration increased plasma maximum concentration (C MAX) 60 %, delayed time to C MAX (T MAX); 1.6-fold greater area under the curve AUC0→∞ (p < 0.001); lower apparent steady-state volume of distribution (V SS/F) and oral clearance (Cl/F) 40 and 61 %, respectively; and shorter elimination half-life (t 1/2). Sunitinib exhibited extensive tissue distribution which increased after ketoconazole coadministration: total area under the curve (AUC0→∞) increased 1.8-, 2.8- and 1.2-fold in kidney, liver and brain, respectively (all p < 0.001). Sunitinib presented high tissue-to-plasma AUC0→∞ ratio in liver (17.8 ± 1.2), kidney (14.6 ± 1.52) and brain (2.25 ± 0.18) which was modified after coadministration: AUC0→∞ ratio increased in liver (31.4 ± 4.7; p < 0.001), kidney (17.1 ± 2.2; p > 0.05) and decreased in brain (1.70 ± 0.23, p > 0.05). The results showed a significant ketoconazole-sunitinib interaction that affected plasma, tissue pharmacokinetics and tissue uptake mechanisms. The study portrays the risk to increase toxicity and potential clinical translatability to treat tumors in tissues.
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Affiliation(s)
- Evelyn Li-Ching Chee
- Department of Pharmaceutical Technology, School of Pharmacy and Health Sciences, International Medical University, Jalan 19/155B, Bukit Jalil, 57000, Kuala Lumpur, Malaysia
| | - Adeline Yi Ling Lim
- Department of Human Biology, School of Medicine, International Medical University, Jalan 19/155B, Bukit Jalil, 57000, Kuala Lumpur, Malaysia.,Department of Medicine, Alfred Hospital, 55 Commercial Road, Prahran, VIC, 3181, Australia
| | - Pilar Modamio
- Clinical Pharmacy and Pharmacotherapy Unit, Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Barcelona, Av. Joan XXIII s/n, Barcelona, 08028, Spain
| | - Cecilia Fernandez-Lastra
- Clinical Pharmacy and Pharmacotherapy Unit, Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Barcelona, Av. Joan XXIII s/n, Barcelona, 08028, Spain
| | - Ignacio Segarra
- Department of Pharmaceutical Technology, School of Pharmacy and Health Sciences, International Medical University, Jalan 19/155B, Bukit Jalil, 57000, Kuala Lumpur, Malaysia. .,Clinical Pharmacy and Pharmacotherapy Unit, Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Barcelona, Av. Joan XXIII s/n, Barcelona, 08028, Spain. .,, C/Sant Albert 4, Valldoreix, 08197, Barcelona, Spain.
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Alao JP, Michlikova S, Dinér P, Grøtli M, Sunnerhagen P. Selective inhibition of RET mediated cell proliferation in vitro by the kinase inhibitor SPP86. BMC Cancer 2014; 14:853. [PMID: 25409876 PMCID: PMC4252022 DOI: 10.1186/1471-2407-14-853] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2014] [Accepted: 11/10/2014] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND The RET tyrosine kinase receptor has emerged as a target in thyroid and endocrine resistant breast cancer. We previously reported the synthesis of kinase inhibitors with potent activity against RET. Herein, we have further investigated the effect of the lead compound SPP86 on RET mediated signaling and proliferation. Based on these observations, we hypothesized that SPP86 may be useful for studying the cellular activity of RET. METHODS We compared the effects of SPP86 on RET-induced signaling and proliferation in thyroid cancer cell lines expressing RET-PTC1 (TPC1), or the activating mutations BRAFV600E (8505C) and RASG13R (C643). The effect of SPP86 on RET- induced phosphatidylinositide 3-kinases (PI3K)/Akt and MAPK pathway signaling and cell proliferation in MCF7 breast cancer cells was also investigated. RESULTS SPP86 inhibited MAPK signaling and proliferation in RET/PTC1 expressing TPC1 but not 8505C or C643 cells. In TPC1 cells, the inhibition of RET phosphorylation required co-exposure to SPP86 and the focal adhesion kinase (FAK) inhibitor PF573228. In MCF7 cells, SPP86 inhibited RET- induced phosphatidylinositide 3-kinases (PI3K)/Akt and MAPK signaling and estrogen receptorα (ERα) phosphorylation, and inhibited proliferation to a similar degree as tamoxifen. Interestingly, SPP86 and PF573228 inhibited RET/PTC1 and GDNF- RET induced activation of Akt and MAPK signaling to a similar degree. CONCLUSION SPP86 selectively inhibits RET downstream signaling in RET/PTC1 but not BRAFV600E or RASG13R expressing cells, indicating that downstream kinases were not affected. SPP86 also inhibited RET signaling in MCF7 breast cancer cells. Additionally, RET- FAK crosstalk may play a key role in facilitating PTC1/RET and GDNF- RET induced activation of Akt and MAPK signaling in TPC1 and MCF7 cells.
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Affiliation(s)
- John P Alao
- Department of Chemistry and Molecular Biology, University of Gothenburg, Box 462, SE-405 30 Göteborg, Sweden.
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The effect of sunitinib on the plasma exposure of intravenous paracetamol and its major metabolite: paracetamol glucuronide. Eur J Drug Metab Pharmacokinet 2014; 40:163-70. [PMID: 24676873 PMCID: PMC4426134 DOI: 10.1007/s13318-014-0191-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2014] [Accepted: 03/08/2014] [Indexed: 12/04/2022]
Abstract
The study aimed to examine the effect of sunitinib on the plasma exposure of intravenous paracetamol and its major metabolite, paracetamol glucuronide. Both drugs share metabolic pathways in the liver, and the drug interactions between sunitinib and paracetamol administered in higher doses were reported. These interactions resulted in hepatotoxicity. The adult New Zealand male rabbits were divided into three groups (6 animals each): rabbits receiving sunitinib and paracetamol (SUN + PC), rabbits receiving sunitinib (SUN), and a control group receiving paracetamol (PC). Sunitinib was administered orally (25 mg) and paracetamol was administrated intravenously (35 mg/kg). Blood samples for sunitinib and SU12662 assays were collected up to 96 h after drug administration and for paracetamol and paracetamol glucuronide up to 300 min after drug administration. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and bilirubin were analysed before and after drug administration. A number of pharmacokinetic parameters were analysed. There were no differences in the levels of AST, ALT, and bilirubin among the groups at either time point. Significantly higher values of AUC0–t, AUC0–∞, and Cmax and lower clearance and volume of distribution of paracetamol were observed in group PC vs. group SUN + PC (p < 0.01). The maximum plasma concentration of paracetamol glucuronide tended to be higher in group PC 213.27 μg/mL (90 % CI 1.06, 1.25; p = 0.0267). Statistically significant differences were revealed for paracetamol glucuronide mean residence time (MRT); MRT was higher in group SUN + PC than in group PC (p = 0.0375). The mean tmax of paracetamol glucuronide was similar in both groups: SUN + PC and group PC (15 and 20 min, respectively). The mean tmax of sunitinib was different in groups SUN + PC and SUN (10.0 and 7.0, respectively; p = 0.0134). At the studied doses, neither of the drugs, whether administered alone or together, had hepatotoxic effects. The present study was not able to confirm that sunitinib, administered at low doses in conjunction with paracetamol, displays a hepatoprotective effect. Significant differences were observed in some pharmacokinetic parameters of paracetamol.
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Xie C, Zhou J, Guo Z, Diao X, Gao Z, Zhong D, Jiang H, Zhang L, Chen X. Metabolism and bioactivation of famitinib, a novel inhibitor of receptor tyrosine kinase, in cancer patients. Br J Pharmacol 2013; 168:1687-706. [PMID: 23126373 DOI: 10.1111/bph.12047] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2012] [Revised: 10/30/2012] [Accepted: 10/31/2012] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND AND PURPOSE Famitinib is a novel multi-targeted receptor tyrosine kinase inhibitor under development for cancer treatment. This study aims to characterize the metabolic and bioactivation pathways of famitinib. EXPERIMENTAL APPROACH The metabolites in human plasma, urine and feces were identified via ultra-high performance liquid chromatography-quadrupole-time of flight-mass spectrometry and confirmed using synthetic standards. Biotransformation and bioactivation mechanisms were investigated using microsomes, recombinant metabolic enzymes and hepatocytes. KEY RESULTS Famitinib was extensively metabolized after repeated oral administrations. Unchanged famitinib was the major circulating material, followed by N-desethylfaminitib (M3), whose steady-state exposure represented 7.2 to 7.5% that of the parent drug. Metabolites in the excreta were mainly from oxidative deamination (M1), N-desethylation (M3), oxidative defluorination (M7), indolylidene hydroxylation (M9-1 and M9-5) and secondary phase-II conjugations. CYP3A4/5 was the major contributor to M3 formation, CYP3A4/5 and aldehyde dehydrogenase to M1 formation and CYP1A1/2 to M7, M9-1 and M9-5 formations. Minor cysteine conjugates were observed in the plasma, urine and feces, implying the formation of reactive intermediate(s). In vitro microsomal studies proved that famitinib was bioactivated through epoxidation at indolylidene by CYP1A1/2 and spontaneously defluorinated rearrangement to afford a quinone-imine species. A correlation between famitinib hepatotoxicity and its bioactivation was observed in the primary human hepatocytes. CONCLUSION AND IMPLICATIONS Famitinib is well absorbed and extensively metabolized in cancer patients. Multiple enzymes, mainly CYP3A4/5 and CYP1A1/2, are involved in famitinib metabolic clearance. The quinone-imine intermediate formed through bioactivation may be associated with famitinib hepatotoxicity. Co-administered CYP1A1/2 inducers or inhibitors may potentiate or suppress its hepatotoxicity.
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Affiliation(s)
- Cen Xie
- Centre for Drug Metabolism and Pharmacokinetics Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
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Chen YY, Brown NJ, Jones R, Lewis CE, Mujamammi AH, Muthana M, Seed MP, Barker MD. A peptide derived from TIMP-3 inhibits multiple angiogenic growth factor receptors and tumour growth and inflammatory arthritis in mice. Angiogenesis 2013; 17:207-19. [PMID: 24129822 PMCID: PMC3898417 DOI: 10.1007/s10456-013-9389-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2012] [Accepted: 09/23/2013] [Indexed: 11/30/2022]
Abstract
The binding of vascular endothelial growth factor (VEGF) to VEGF receptor-2 (VEGFR-2) on the surface of vascular endothelial cells stimulates many steps in the angiogenic pathway. Inhibition of this interaction is proving of value in moderating the neovascularization accompanying age-related macular degeneration and in the treatment of cancer. Tissue inhibitor of metalloproteinases-3 (TIMP-3) has been shown to be a natural VEGFR-2 specific antagonist-an activity that is independent of its ability to inhibit metalloproteinases. In this investigation we localize this activity to the C-terminal domain of the TIMP-3 molecule and characterize a short peptide, corresponding to part of this domain, that not only inhibits all three VEGF-family receptors, but also fibroblast growth factor and platelet-derived growth factor receptors. This multiple-receptor inhibition may explain why the peptide was also seen to be a powerful inhibitor of tumour growth and also a partial inhibitor of arthritic joint inflammation in vivo.
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Affiliation(s)
- Yung-Yi Chen
- Department of Oncology, Medical School, University of Sheffield, Beech Hill Road, Sheffield, S10 2RX, UK
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Krikorian SA, Shamim K. Adherence Issues for Oral Antineoplastics. Am J Lifestyle Med 2013. [DOI: 10.1177/1559827612466996] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Nonadherence to antineoplastics is a growing concern because of the increasing number of novel oral targeted anticancer therapies. Many of these agents are administered on a chronic continuous schedule for an indefinite period of time where adherence is crucial to achieve optimal disease control and prolong survival. Many factors are known to contribute to medication nonadherence. Prevention, early detection, and management of adverse drug reactions associated with oral targeted therapies require close vigilance. Knowing how to prevent and manage adverse drug reactions will help clinicians develop strategies to promote patient adherence to oral anticancer treatment regimens. Optimal adherence requires a dynamic patient-provider alliance through education, communication, ongoing monitoring, and follow-up.
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Affiliation(s)
- Susan A. Krikorian
- Massachusetts College of Pharmacy and Health Sciences, Boston, Massachusetts (SAK, KS)
- Mount Auburn Hospital, Cambridge, Massachusetts (SAK)
| | - Kanza Shamim
- Massachusetts College of Pharmacy and Health Sciences, Boston, Massachusetts (SAK, KS)
- Mount Auburn Hospital, Cambridge, Massachusetts (SAK)
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Pacini F, Ito Y, Luster M, Pitoia F, Robinson B, Wirth L. Radioactive iodine-refractory differentiated thyroid cancer: unmet needs and future directions. Expert Rev Endocrinol Metab 2012; 7:541-554. [PMID: 30780891 DOI: 10.1586/eem.12.36] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Approximately 90% of thyroid cancers are differentiated (DTCs) and have papillary, follicular or Hürthle cell morphology. Although treatment with surgery and radioactive iodine (I-131; RAI), as appropriate, is associated with significant cure rates and survival benefits, clonal disease progression with development of refractoriness to RAI poses a major therapeutic challenge in about 15% of patients. Traditional chemotherapeutic agents are relatively ineffective and are associated with significant toxicities. Molecular studies have demonstrated that the development and progression of DTC are associated with a series of consistent abnormalities in pathways such as MAPK/ERK and PI3/Akt, which govern cellular growth, proliferation, apoptosis and angiogenesis. Small molecular inhibitors that target these pathogenic pathways, without many of the impairments associated with cytotoxic chemotherapy, have demonstrated efficacy in a variety of malignancies, including renal cell carcinoma, hepatocellular carcinoma, non-small-cell lung cancer and chronic myelogenous leukemia. Several targeted therapeutic agents are in development for the treatment of RAI-refractory DTC. Sorafenib and lenvatinib are being studied in placebo-controlled Phase III trials based on encouraging efficacy results observed in single-arm Phase II studies.
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Affiliation(s)
| | | | | | - Fabian Pitoia
- d University of Buenos Aires, Buenos Aires, Argentina
| | | | - Lori Wirth
- f Massachusetts General Hospital, Boston, MA, USA
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Liu LP, Ho RLK, Chen GG, Lai PBS. Sorafenib inhibits hypoxia-inducible factor-1α synthesis: implications for antiangiogenic activity in hepatocellular carcinoma. Clin Cancer Res 2012; 18:5662-71. [PMID: 22929805 DOI: 10.1158/1078-0432.ccr-12-0552] [Citation(s) in RCA: 97] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
PURPOSE The overexpression of hypoxia-inducible factor 1α (HIF-1α) is a common finding in hepatocellular carcinoma (HCC), and it leads to angiogenesis and poor prognosis. Sorafenib, a multikinase inhibitor, has shown significant improvement in survival in patients with advanced HCC in clinical trials. However, the mechanisms that account for the antiangiogenic efficiency of sorafenib have not been fully elucidated. The present study aims to explore the effect of sorafenib on HIF-1α expression and activation in HCC cells and xenografts. EXPERIMENTAL DESIGN HCC cells and xenografts were treated with sorafenib or vehicles. Western blotting and quantitative PCR array were used to determine protein and mRNA expression, respectively. HIF-1α activity, de novo protein synthesis, and VEGF secretions were determined using assay kits. RESULTS Sorafenib dose dependently decreased the hypoxia-induced accumulation and activation of HIF-1α protein. Further analysis revealed that such reduction of HIF-1α was associated with the inhibition of HIF-1α protein synthesis rather than the promotion of HIF-1α protein degradation or the reduction of HIF-1α mRNA. Moreover, the phosphorylation levels of mTOR, extracellular signal-regulated kinase (ERK), p70S6K, RP-S6, 4E-BP1, and eIF4E were significantly suppressed by sorafenib. In vivo studies further confirmed the inhibitory effect of sorafenib on the expression of HIF-1α and VEGF proteins, leading to a decrease in tumor vascularization and growth of the xenografts. CONCLUSIONS Sorafenib-mediated inhibition of HIF-1α synthesis is associated with previously undefined pathways in which mTOR/p70S6K/4E-BP1 and ERK phosphorylation are downregulated. Our preclinical data expand our understanding of sorafenib's antiangiogenic mechanism of action by inhibiting HIF-1α and VEGF protein expression.
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Affiliation(s)
- Li-ping Liu
- Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China
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Abstract
OBJECTIVES To review oral agents approved for cancer, discuss their mechanism of action and/or molecular targets, and outline side effects and challenges that impact adherence. DATA SOURCES Peer reviewed literature and on-line drug information. CONCLUSION Oral agents to treat cancer, although not new, are common and increasing dramatically. The context of adherence to oral agents is complicated by increased knowledge of food-drug interactions and combinations of agents with overlapping or synergistic toxicity profiles. IMPLICATIONS FOR NURSING PRACTICE The role of nursing in the administration and education of oral cancer treatments is critical to optimal treatment outcomes.
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Affiliation(s)
- Debra Barton
- Oncology, Mayo Clinic, 200 First Street SW, Charlton 6-133, Rochester, MN 55905, USA.
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