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Studies on the effect of ErbB tyrosine kinase inhibitors on malignant melanoma growth and survival in vitro
Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
2009 (English)Licentiate thesis, comprehensive summary (Other academic)
Abstract [en]

Malignant melanoma has one of the fastest increasing incidences among the different types of cancerin the Western world. This raise can partly be ascribed to the change in sun habits that has takenplace during the last decades, since the major external risk factor for melanoma is exposure toultraviolet radiation. Patients with early stages of melanoma can often be cured by surgery, howeverfor patients suffering from metastatic melanoma there are only a few treatment options available.Unfortunately malignant melanoma is often resistant to radio-, bio- and chemotherapy and treatmentwith the currently most frequently used agent, dacarbazine, is characterized by a very low clinicalresponse rate. Therefore, there is an urgent need for new treatment strategies which can increase theoverall survival and cause less severe side effects.

The aim of this thesis was to investigate the anti-tumor effect of two different tyrosine kinaseinhibitors (TKIs), gefitinib and canertinib, on two different human malignant melanoma (RaH3 andRaH5) cell lines. We investigate the effect of these two drugs on cell proliferation and survival andstudied the effect of gefitinib and canertinib on ErbB1-4 receptor phosphorylation, as well as Akt,Erk1/2 and Stat3 activity.

Our results showed that phosphorylation of ErbB1, ErbB2 and ErbB3 decreased followingtreatment with both gefitinib and canertinib and that the subsequent downstream signaling via Akt,Erk1/2 and Stat3 was inhibited after TKI treatment. However, it was noted that the gefitinibinducedinhibition of Akt, and particularly Erk1/2, was transient and only a weak inhibition of Stat3phosphorylation was seen. Gefitinib treatment of the RaH3 and RaH5 cells resulted in anaccumulation of the cells in the G1 phase of the cell cycle without any induction of apoptosis.Canertinib caused a more pronounced inhibition of Akt, Erk1/2, and Stat3 phosphorylation thangefitinib. This might be one explanation to why canertinib induced apoptosis in RaH3 and RaH5cells whereas gefitinib only caused cell cycle arrest. In conclusion, gefitinib and canertinib displaypromising anti-tumor effects on ErbB expressing malignant melanoma and might be used in futurestudies in combination with conventional chemotherapy or other targeted therapies in the treatmentof malignant melanoma.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press , 2009. , 56 p.
Series
Linköping Studies in Health Sciences. Thesis, ISSN 1100-6013 ; 100
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-19949ISBN: 978-91-7393-610-1 (print)OAI: oai:DiVA.org:liu-19949DiVA: diva2:232018
Presentation
2009-08-28, Karl-Johan salen, Onkologen, Campus US, Linköpings universitet, Linköping, 10:00 (Swedish)
Opponent
Supervisors
Available from: 2009-09-21 Created: 2009-08-19 Last updated: 2012-10-30Bibliographically approved
List of papers
1. ErbB receptor tyrosine kinases contribute to proliferation of malignant melanoma cells: inhibition by gefitinib (ZD1839)
Open this publication in new window or tab >>ErbB receptor tyrosine kinases contribute to proliferation of malignant melanoma cells: inhibition by gefitinib (ZD1839)
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2009 (English)In: Melanoma research, ISSN 0960-8931, E-ISSN 1473-5636, ISSN 0960-8931, Vol. 19, no 3, 156-166 p.Article in journal (Refereed) Published
Abstract [en]

Members of the epidermal growth factor (EGF) family of structurally related tyrosine kinase receptors, known as the ErbB receptors (EGFR/ErbB1/HER1, ErbB2/HER2/neu, ErbB3/HER3 and ErbB4/HER4) and their respective ligands, have been suggested to be involved in the development and progression of malignant melanoma. Here we investigate the effects of the ErbB1 tyrosine kinase inhibitor gefitinib (ZD1839, Iressa) on human malignant melanoma cells (RaH3 and RaH5) in vitro. ZD1839 inhibited proliferation of exponentially growing RaH3 and RaH5 cells in a dose-dependent manner with a half-maximally effective dose of 3.5 and 2.0 mu mol/l, respectively. Cell growth was inhibited at 0.1 mu mol/l ZD1839 in both cell lines. Maximal inhibition was accomplished at 10 mu mol/l ZD1839; however, the effect was not complete as both cell lines showed a continuous slow growth during the treatment period. Flow cytometry analysis of cell-cycle distribution showed that ZD1839 treatment caused accumulation of RaH3 and RaH5 cells in the G, phase. The growth arrest induced by ZD1839 coincided with upregulation of the cyclin-dependent kinase inhibitor p27(KIP1). There was no increase in apoptosis as determined by analysis of plasma phosphatidyl serine redistribution. Western blot analysis revealed that ZD1839 substantially reduced tyrosine phosphorylation of ErbB1 as well as ErbB2 and ErbB3. This was accompanied by a concomitant decrease in Akt-phosphorylation, Erk1/2-phosphorylation, and Stat3-phosphorylation. Our results show that ZD1839 interferes with the growth of human malignant melanoma cells by cytostatic effects. These findings indicate the possible use of ErbB receptor kinase inhibitors as a novel treatment strategy in malignant melanoma.

Keyword
antiproliferative, ErbB receptors, gefitinib, melanoma, tyrosine kinase inhibitor
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-19129 (URN)10.1097/CMR.0b013e32832c6339 (DOI)
Available from: 2009-06-12 Created: 2009-06-12 Last updated: 2012-11-27Bibliographically approved
2. The pan-ErbB receptor tyrosine kinase inhibitor canertinib promotes apoptosis of malignant melanoma in vitro and displays anti-tumor activity in vivo
Open this publication in new window or tab >>The pan-ErbB receptor tyrosine kinase inhibitor canertinib promotes apoptosis of malignant melanoma in vitro and displays anti-tumor activity in vivo
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2011 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 414, no 3, 563-568 p.Article in journal (Refereed) Published
Abstract [en]

The ErbB receptor family has been suggested to constitute a therapeutic target for tumor-specific treatment of malignant melanoma. Here we investigate the effect of the pan-ErbB tyrosine kinase inhibitor canertinib on cell growth and survival in human melanoma cells in vitro and in vivo. Canertinib significantly inhibited growth of cultured melanoma cells, RaH3 and RaH5, in a dose-dependent manner as determined by cell counting. Half-maximum growth inhibitory dose (IC(50)) was approximately 0.8 mu M and by 5 mu M both cell lines were completely growth-arrested within 72 h of treatment. Incubation of exponentially growing RaH3 and RaH5 with 1 mu M canertinib accumulated the cells in the G(1)-phase of the cell cycle within 24 h of treatment without induction of apoptosis as determined by flow cytometry. Immunoblot analysis showed that 1 mu M canertinib inhibited ErbB1-3 receptor phosphorylation with a concomitant decrease of Akt-, Erk1/2- and Stat3 activity in both cell lines. In contrast to the cytostatic effect observed at doses less than= 5 mu M canertinib, higher concentrations induced apoptosis as demonstrated by the Annexin V method and Western blot analysis of PARP cleavage. Furthermore, canertinib significantly inhibited growth of RaH3 and RaH5 melanoma xenografts in nude mice. Pharmacological targeting of the ErbB receptors may prove successful in the treatment of patients with metastatic melanoma.

Place, publisher, year, edition, pages
Elsevier, 2011
Keyword
Malignant melanoma; Tyrosine kinase inhibitor; Canertinib; ErbB-receptor; Apoptosis
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-73740 (URN)10.1016/j.bbrc.2011.09.118 (DOI)000298519500021 ()
Note

On the day of the defence date the status of this article was Manuscript and the title "The pan-ErbB receptor tyrosine kinase inhibitor Canertinib (CI-1033)promotes cell cycle arrest and apoptosis of human malignantmelanoma in vitro".

Available from: 2012-01-12 Created: 2012-01-12 Last updated: 2017-12-08

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Djerf, Emelie

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