Abstract:
BACKGROUND:Studying the intracellular distribution of pharmacological agents, including anticancer compounds, is of central importance in biomedical research. It constitutes a prerequisite for a better understanding of the molecular mechanisms underlying drug action and resistance development. Hyperactivated fibroblast growth factor receptors (FGFRs) constitute a promising therapy target in several types of malignancies including lung cancer. The clinically approved small-molecule FGFR inhibitor nintedanib exerts strong cytotoxicity in FGFR-driven lung cancer cells. However, subcellular pharmacokinetics of this compound and its impact on therapeutic efficacy remain obscure. METHODS:3-dimensional fluorescence spectroscopy was conducted to asses cell-free nintedanib fluorescence properties. MTT assay was used to determine the impact of the lysosome-targeting agents bafilomycin A1 and chloroquine combined with nintedanib on lung cancer cell viability. Flow cytometry and live cell as well as confocal microscopy were performed to analyze uptake kinetics as well as subcellular distribution of nintedanib. Western blot was conducted to investigate protein expression. Cryosections of subcutaneous tumor allografts were generated to detect intratumoral nintedanib in mice after oral drug administration. RESULTS:Here, we report for the first time drug-intrinsic fluorescence properties of nintedanib in living and fixed cancer cells as well as in cryosections derived from allograft tumors of orally treated mice. Using this feature in conjunction with flow cytometry and confocal microscopy allowed to determine cellular drug accumulation levels, impact of the ABCB1 efflux pump and to uncover nintedanib trapping into lysosomes. Lysosomal sequestration - resulting in an organelle-specific and pH-dependent nintedanib fluorescence - was identified as an intrinsic resistance mechanism in FGFR-driven lung cancer cells. Accordingly, combination of nintedanib with agents compromising lysosomal acidification (bafilomycin A1, chloroquine) exerted distinctly synergistic growth inhibitory effects. CONCLUSION:Our findings provide a powerful tool to dissect molecular factors impacting organismal and intracellular pharmacokinetics of nintedanib. Regarding clinical application, prevention of lysosomal trapping via lysosome-alkalization might represent a promising strategy to circumvent cancer cell-intrinsic nintedanib resistance.
journal_name
J Exp Clin Cancer Resjournal_title
Journal of experimental & clinical cancer research : CRauthors
Englinger B,Kallus S,Senkiv J,Heilos D,Gabler L,van Schoonhoven S,Terenzi A,Moser P,Pirker C,Timelthaler G,Jäger W,Kowol CR,Heffeter P,Grusch M,Berger Wdoi
10.1186/s13046-017-0592-3subject
Has Abstractpub_date
2017-09-07 00:00:00pages
122issue
1eissn
0392-9078issn
1756-9966pii
10.1186/s13046-017-0592-3journal_volume
36pub_type
杂志文章abstract:BACKGROUND:Anti-angiogenesis remains an attractive strategy for cancer therapy. Some anti-angiogenic reagents have bell-shape dose-response curves with higher than the effective doses yielding lower anti-angiogenic effects. In this study, two different types of anti-angiogenic reagents, a receptor tyrosine kinase inhib...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章,收录出版
doi:10.1186/s13046-019-1324-7
更新日期:2019-08-28 00:00:00
abstract:BACKGROUND:Measurement of prostate-specific antigen (PSA) advanced the diagnostic and prognostic potential for prostate cancer (PCa). However, due to PSA's lack of specificity, novel biomarkers are needed to improve risk assessment and ensure optimal personalized therapy. A set of protein molecules as potential biomark...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:10.1186/s13046-015-0161-6
更新日期:2015-05-14 00:00:00
abstract:BACKGROUND AND AIM:in recent years, Livin, a new member of IAPs family, is found to be a key molecule in cancers. Researchers consider Livin may become a new target for tumor therapy; however, the role of it in bladder cancer is still unclear. The purpose of this article is to investigate Antisense Oligonucleotide (ASO...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:10.1186/1756-9966-29-63
更新日期:2010-06-03 00:00:00
abstract::Escherichia coli cytosine deaminase (CD), which is a prokaryotic enzyme, converts nontoxic prodrug 5-fluorocytosine (5-FC) into the toxic chemotherapeutic agent 5-fluorouracil (5-FU). To investigate an enzyme/prodrug gene therapy for colorectal cancer, using adenoviral gene transfer of the E. coli CD gene associated w...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:
更新日期:2000-03-01 00:00:00
abstract:BACKGROUND:Multinucleated cells are frequently seen in association with a malignant neoplasm. Some of these multinucleated cells are considered to be neoplastic. The mechanism of neoplastic multinucleation remains unknown, but is considered to be induced by either cell-cell fusion or acytokinetic cell division. Myxofib...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:10.1186/1756-9966-28-44
更新日期:2009-03-31 00:00:00
abstract::Since the social and financial impact of AML therapy is becoming more and more relevant we analyzed the cost of induction therapy of two different regimens. The first one is part of the widely employed EORTC-GIMEMA AML-10 and consists often days of therapy. The second (FLANG) is a short (three day), Fludarabine, Ara-C...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:
更新日期:2001-06-01 00:00:00
abstract::A study of laryngeal carcinomas was performed in order to analyze (a) the expression of p53/p21, cyclin D1/cyclin E, p21/p27 (b) the relation of normal and abnormal protein expression, with the proliferation status, as determined by the expression of Ki67 and PCNA and (c) the correlation of our findings with prognosis...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:
更新日期:2005-09-01 00:00:00
abstract::Neoplastic transformation of heterotopic cervical salivary gland tissue is extremely rare. The Authors describe a case of pleomorphic adenoma arising in this tissue, on the right side of the neck in a 40-year old man. The characteristics of salivary heterotipias of the neck, and their diagnostic difficulties and histo...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:
更新日期:2003-12-01 00:00:00
abstract:BACKGROUND:Retinoic acid-inducible gene-I (Rig-I) is an intracellular viral RNA receptor, which specifically recognizes double-stranded viral RNA initiating antiviral innate immunity. Increasing evidences showed that Rig-I had broader roles in antibacterial immunity and cancer protection. However, the potential roles a...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:10.1186/s13046-016-0471-3
更新日期:2017-01-05 00:00:00
abstract::We evaluated the efficacy and toxicity profile of single-agent docetaxel administered in daily clinical practice at low-dose regimen in 37 pre-treated elderly patients with metastatic breast cancer previously exposed to chemotherapy. Docetaxel was employed by physician's preference according to a weekly (8 patients, 2...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 临床试验,杂志文章
doi:
更新日期:2005-03-01 00:00:00
abstract:BACKGROUND:MircoRNAs(miRNAs) are short, endogenously non-coding RNAs. The abnormal expression of miRNAs may be valuable for the diagnosis and treatment of tumors. METHODS:To screening the special miRNAs in gastric carcinoma, expression level of miRNAs in gastric carcinoma and normal gaster samples were detected by miR...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:10.1186/1756-9966-28-82
更新日期:2009-06-16 00:00:00
abstract:BACKGROUND:The disruption of E-cadherin-mediated adhesion is considered an important driver of tumor progression. Nevertheless, numerous studies have demonstrated that E-cadherin promotes growth- or invasion-related signaling, contrary to the prevailing notion. During tumor progression, epithelial ovarian cancer (EOC) ...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:10.1186/s13046-018-0796-1
更新日期:2018-07-11 00:00:00
abstract::Increased expression of sialyl Lewis antigens, sLe(a) and sLe(x), is frequent during malignant transformation and tumor progression of gastrointestinal cancers and it is assumed to be correlated with the increased metastatic potential of tumor cells and, consequently, with poor patient survival. To determine the influ...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:
更新日期:1999-09-01 00:00:00
abstract::The number of colorectal tumors per mouse induced by 1,2-dimethylhydrazine in transgenic (Tg) mice carrying human c-Ha-ras genes was significantly reduced by ingestion of apple pectin (AP) or a culture condensate of Bifidobacterium longum(MB) compared with a control diet and non-Tg mice. However, there were no differe...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:
更新日期:2001-03-01 00:00:00
abstract::Tumours involving the scrotum are rare and primary malignant melanoma is among the rarest of these lesions. Between 1949 and 1996 only 7 cases have been reported. We present two cases of scrotal melanoma. The current recommendations and management strategies are discussed on the basis of a review of the literature. ...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章,评审
doi:
更新日期:1998-03-01 00:00:00
abstract:BACKGROUND:Cancer-associated fibroblasts (CAFs), the primary component of tumor stroma in tumor microenvironments, are well-known contributors to the malignant progression of gallbladder cancer (GBC). Thrombospondins (THBSs or TSPs) comprise a family of five adhesive glycoproteins that are overexpressed in many types o...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:10.1186/s13046-020-01812-7
更新日期:2021-01-06 00:00:00
abstract:BACKGROUND:Interleukin-32 (IL-32) has been associated with various diseases. Previous studies have shown that IL-32 inhibited the development of several tumors. However, the role of IL-32γ, an isotype of IL-32, in skin carcinogenesis remains unknown. METHODS:We compared 7,12-Dimethylbenz[a]anthracene/12-O-Tetradecanoy...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:10.1186/s13046-018-0943-8
更新日期:2018-11-28 00:00:00
abstract:BACKGROUND:Cell cycle checkpoint regulation is crucial for prevention of tumor in mammalian cells. Cyclin-dependant kinase 4 (CDK4) is important in cell cycle regulation, as it controls the G1-S phase of the cell cycle. CDK4 has potential mitogenic properties through phosphorylation of target proteins. We aimed at iden...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:10.1186/1756-9966-28-42
更新日期:2009-03-28 00:00:00
abstract::The role of viruses in the etiology of human oral cancer is critically reviewed. Available evidences show a positive correlation for human oral cancer with human papilloma virus (HPV), herpes simplex virus (HSV) and human herpes virus type-6 (HHV-6), having strongest association with HPV. These viruses may act alone o...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章,评审
doi:
更新日期:1998-03-01 00:00:00
abstract::Increased expression of CD44 variants is often observed in differentiated thyroid carcinomas. To establish a method for gene diagnosis of thyroid without any additional invasions to the patients, RNA in leftover cells inside the needle used for fine needle aspiration biopsies (FNABs) was extracted to detect the expres...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:
更新日期:1997-09-01 00:00:00
abstract:BACKGROUND:Clear cell renal cell carcinoma (ccRCC) is the most frequently encountered tumor in the adult kidney. Many factors are known to take part in the development and progression of this tumor. Nuclear factor kappa B (NF-kappaB) is a family of the genes that includes five members acting in events such as inflammat...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:10.1186/1756-9966-27-53
更新日期:2008-10-19 00:00:00
abstract:BACKGROUND:The aim of this retrospective study was to assess the results concerning the regional and systemic toxicity and complications in 242 chemo-hyperthermal treatments (HILPs) for lower limb melanoma. PATIENTS AND METHODS:60 HILPs (G-A) were performed with mild HT plus L-PAM (10 mg/lt) +/- D-actimomycin; 74 HILP...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:10.1186/1756-9966-27-67
更新日期:2008-11-12 00:00:00
abstract:BACKGROUND:As novel biomarkers for various cancers, microRNAs negatively regulate genes expression via promoting mRNA degradation and suppressing mRNA translation. miR-589 has been reported to be deregulated in several human cancer types. However, its biological role has not been functionally characterized in gastric c...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:10.1186/s13046-018-0821-4
更新日期:2018-07-16 00:00:00
abstract::Colorectal cancer is the third most commonly diagnosed cancer worldwide. Although surgery remains the best treatment for this disease, adjuvant chemotherapy and radiotherapy are also very important in clinical practice. However, the notorious refractory lack of responses to radiochemotherapy greatly limits the applica...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:10.1186/1756-9966-33-13
更新日期:2014-01-29 00:00:00
abstract::Doxorubicin (DOX) has a wide spectrum of antitumor activity with dose-related cardiotoxicity as a major side effect. This cardiotoxicity has been suggested to result from the generation of oxygen-free radicals. The objective of the present study was to investigate the influence of the antioxidant, thymoquinone (TQ) on...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:
更新日期:1998-06-01 00:00:00
abstract:BACKGROUND:It has been suggested that polymorphisms in glutathione-S-transferases (GST) could predispose to prostate cancer through a heritable deficiency in detoxification pathways for environmental carcinogens. Yet, studies linking GST polymorphism and prostate cancer have so far failed to unambiguously establish thi...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:10.1186/1756-9966-28-32
更新日期:2009-03-05 00:00:00
abstract:BACKGROUND:Hepatocellular carcinoma (HCC) develops in a complex microenvironment characterized by chronic inflammation. In recent years, cholesterol metabolic abnormalities have been implicated the importance in cancer cell physiology. This study was designed to investigate the relationship between inflammation and cho...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:10.1186/s13046-017-0490-8
更新日期:2017-01-18 00:00:00
abstract:BACKGROUND:Progranulin (PGRN), as a multifunctional growth factor, is overexpressed in multiple tumors, but the role of PGRN on tumor immunity is still unclear. Here, we studied the effect of PGRN on breast cancer tumor immunity and its possible molecular mechanism. METHODS:The changes of macrophage phenotypes after P...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:10.1186/s13046-020-01786-6
更新日期:2021-01-04 00:00:00
abstract:BACKGROUND:Oxaliplatin belongs to the platinum-based drug family and has shown promise in treating cancer by binding to DNA to induce cytotoxicity. However, individual patients show diverse therapeutic responses toward oxaliplatin due to yet-unknown underlying mechanisms. We recently established that oxaliplatin also e...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:10.1186/s13046-018-0837-9
更新日期:2018-07-20 00:00:00
abstract:BACKGROUND:CD147 plays a critical role in the invasive and metastatic activity of hepatocellular carcinoma (HCC) cells by stimulating the surrounding fibroblasts to express matrix metalloproteinases (MMPs). Tumor cells adhesion to extracellular matrix (ECM) proteins is the first step to the tumor metastasis. MMPs degra...
journal_title:Journal of experimental & clinical cancer research : CR
pub_type: 杂志文章
doi:10.1186/1756-9966-27-50
更新日期:2008-10-11 00:00:00