The pan-ErbB tyrosine kinase inhibitor canertinib induces caspase-mediated cell death in human T-cell leukemia (Jurkat) cells

Trinks, Cecilia; Severinsson, Emelie; Holmlund, Birgitta; Gréen, Anna; Gréen, Henrik; Jönsson, Jan‐Ingvar; Hallbeck, Anna-Lotta; Walz, Thomas

doi:10.1016/j.bbrc.2011.05.148

Cited by 8 publications

(4 citation statements)

References 21 publications

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“…We observed that ERK/MAPK, STAT3 and CREB were inhibited in both sensitive and resistant breast cancer cell lines, whereas JNK and STAT5A/B were only inhibited in the sensitive cell line SKBR3, which suggests that in addition to hyperactivity of HER and of downstream PI3K signaling [ 24 ] these two parameters also contribute to the development of resistance of breast cancer cells against HER-TKIs. This hypothesis is supported by studies in pancreatic and prostate cancer, which also suggest a role for JNK activation in the development of resistance to HER targeting [ 16 , 17 , 29 – 31 ].…”

Section: Discussionmentioning

confidence: 99%

“…Cells plated in media containing 5% FCS at 5 x 10 5 in 60 mm dishes were allowed to adhere and were exposed for 48 or 72 hours to various concentrations of canertinib. Cells were then lysed, and protein fractions (30 μg/lane) were subjected to SDS-PAGE, blotted onto PVDF membranes, and immunostained as described [ 24 ] using antibodies against full length and cleaved PARP-1 (Cell Signaling Technology, Boston, MA) or against actin (I-19, Santa Cruz Biotechnology, Santa Cruz, CA) at 1:1,000. Membranes were then incubated with peroxidase-tagged secondary antibodies.…”

Section: Methodsmentioning

confidence: 99%

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HER Specific TKIs Exert Their Antineoplastic Effects on Breast Cancer Cell Lines through the Involvement of STAT5 and JNK

et al. 2016

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BackgroundHER-targeted tyrosine kinase inhibitors (TKIs) have demonstrated pro-apoptotic and antiproliferative effects in vitro and in vivo. The exact pathways through which TKIs exert their antineoplastic effects are, however, still not completely understood.MethodsUsing Milliplex assays, we have investigated the effects of the three panHER-TKIs lapatinib, canertinib and afatinib on signal transduction cascade activation in SKBR3, T47D and Jurkat neoplastic cell lines. The growth-inhibitory effect of blockade of HER and of JNK and STAT5 signaling was measured by proliferation- and apoptosis-assays using formazan dye labeling of viable cells, Western blotting for cleaved PARP-1 and immunolabeling for active caspase 3, respectively.ResultsAll three HER-TKIs clearly inhibited proliferation and increased apoptosis in HER2 overexpressing SKBR3 cells, while their effect was less pronounced on HER2 moderately expressing T47D cells where they exerted only a weak antiproliferative and essentially no pro-apoptotic effect. Remarkably, phosphorylation/activation of JNK and STAT5A/B were inhibited by HER-TKIs only in the sensitive, but not in the resistant cells. In contrast, phosphorylation/activation of ERK/MAPK, STAT3, CREB, p70 S6 kinase, IkBa, and p38 were equally affected by HER-TKIs in both cell lines. Moreover, we demonstrated that direct pharmacological blockade of JNK and STAT5 abrogates cell growth in both HER-TKI-sensitive as well as -resistant breast cancer cells, respectively.ConclusionWe have shown that HER-TKIs exert a HER2 expression-dependent anti-cancer effect in breast cancer cell lines. This involves blockade of JNK and STAT5A/B signaling, which have been found to be required for in vitro growth of these cell lines.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

HER Specific TKIs Exert Their Antineoplastic Effects on Breast Cancer Cell Lines through the Involvement of STAT5 and JNK

et al. 2016

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“…Therefore it is not surprising that canertinib was not truly selective for FLT3 and also inhibited KIT signalling, although at significantly higher concentrations. In addition, we have recently found that canertinib inhibits other tyrosine kinases, such as LCK and ZAP70, associated with the T‐cell receptor complex (Trinks et al , 2011). This adds the possibility that canertinib, besides some degree of FLT3 selectivity, could also act by kinase multi‐targeting, providing the drug with further therapeutic advantages.…”

Section: Discussionmentioning

confidence: 99%

Irreversible pan‐ERBB inhibitor canertinib elicits anti‐leukaemic effects and induces the regression of FLT3‐ITD transformed cells in mice

et al. 2011

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Summary Recent findings have indicated that tyrosine kinase inhibitors (TKIs) targeting the ERBB receptor family display anti‐leukaemic effects, despite the lack of receptor expression on human leukaemic cells. The occurrence of activating mutations in the gene encoding FMS‐like tyrosine kinase 3 (FLT3) in patients with acute myeloid leukaemia (AML) has rendered inhibition of this receptor a promising therapeutic target. Due to possibility of cross‐reactivity, we investigated the effect of the irreversible pan‐ERBB inhibitor canertinib (CI‐1033) on leukaemic cells expressing FLT3. The drug had anti‐proliferative and apoptotic effects on primary AML cells and human leukaemic cell lines expressing mutated FLT3. In several AML patient samples, a blast cell population expressing FLT3‐internal tandem duplication (ITD) was eradicated by canertinib. Canertinib inhibited receptor autophosphorylation and kinase activity of both mutated and FLT3 ligand stimulated wildtype FLT3, leading to inhibition of the PI3‐kinase and MAP kinase pathways. Apoptotic induction was dependent on pro‐apoptotic BH3‐only protein BCL2L11/BIM because siRNA silencing attenuated apoptosis. Moreover, the drug induced regression of cells expressing FLT3‐ITD in a murine in vivo‐transplantation model at previously described tolerated doses. These results indicate that canertinib, as an irreversible TKI, could constitute a novel treatment regimen in patients with mutated or overexpressed FLT3.

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“…Its derivatives display a wide spectrum of pharmaceutical activities, including anticancer, antimicrobial, anti-inflammatory, antiadenovirus, antioxidative, and other activities. − Because the quinazoline fragment owns a vital status in predicting the biological behaviors of a title molecule, considerable investigations have been performed on this flexible motif, which have led to an array of quinazoline-tailored compounds with practical and substantial applications in many fields (Figure a). For instance, gefitinib, erlotinib, canertinib, and lapatinib ditosylate with quinazoline patterns have already been introduced into the market for the treatment of human cancers. Fluquinconazole has been successfully developed as a powerful systemic fungicide against plant fungal diseases caused by pathogenic Basidiomycetes, Hymenomycetes, and Ascomycetes .…”

Section: Introductionmentioning

confidence: 99%

Fabrication of Furan-Functionalized Quinazoline Hybrids: Their Antibacterial Evaluation, Quantitative Proteomics, and Induced Phytopathogen Morphological Variation Studies

Long

Liu

Zhao

et al. 2019

J. Agric. Food Chem.

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The limited number of agrochemicals targeting plant bacterial diseases has driven us to develop highly efficient, low-cost, and versatile antibacterial alternatives. Herein, a novel type of simple furan-functionalized quinazolin-4-amines was systematically fabricated and screened for their antibacterial activity. Bioassay results revealed that compounds C 1 and E 4 could substantially block the growth of two frequently mentioned pathogens Xanthomonas oryzae pv oryzae and X. axonopodis pv citri in vitro, displaying appreciable EC 50 values of 7.13 and 10.3 mg/L, respectively. This effect was prominently improved by comparing those of mainly used agrochemicals. An in vivo experiment against bacterial blight further illustrated their viable applications as antimicrobial ingredients. Quantitative proteomics demonstrated that C 1 possessed a remarkable ability to manipulate the upregulation and downregulation of expressed proteins, which probably involved D-glucose and biotin metabolic pathways. This finding was substantially verified by parallel reaction monitoring analysis. Scanning electron microscopy images and fluorescence spectra also indicated that the designed compounds had versatile capacities for destroying the integrity of bacteria. Given these remarkable characteristics, furan-functionalized quinazoline hybrids can serve as a viable platform for developing innovative antibiotic alternatives against bacterial infections.

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The pan-ErbB tyrosine kinase inhibitor canertinib induces caspase-mediated cell death in human T-cell leukemia (Jurkat) cells

Cited by 8 publications

References 21 publications

HER Specific TKIs Exert Their Antineoplastic Effects on Breast Cancer Cell Lines through the Involvement of STAT5 and JNK

HER Specific TKIs Exert Their Antineoplastic Effects on Breast Cancer Cell Lines through the Involvement of STAT5 and JNK

Irreversible pan‐ERBB inhibitor canertinib elicits anti‐leukaemic effects and induces the regression of FLT3‐ITD transformed cells in mice

Fabrication of Furan-Functionalized Quinazoline Hybrids: Their Antibacterial Evaluation, Quantitative Proteomics, and Induced Phytopathogen Morphological Variation Studies

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