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ErbB receptor tyrosine kinases contribute to proliferation of malignant melanoma cells: inhibition by gefitinib (ZD1839)
Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Reconstruction Centre, Department of Plastic Surgery, Hand surgery UHL.
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
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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.

Place, publisher, year, edition, pages
2009. Vol. 19, no 3, 156-166 p.
Keyword [en]
antiproliferative, ErbB receptors, gefitinib, melanoma, tyrosine kinase inhibitor
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-19129DOI: 10.1097/CMR.0b013e32832c6339OAI: oai:DiVA.org:liu-19129DiVA: diva2:223383
Available from: 2009-06-12 Created: 2009-06-12 Last updated: 2012-11-27Bibliographically approved
In thesis
1. Studies on the effect of ErbB tyrosine kinase inhibitors on malignant melanoma growth and survival in vitro
Open this publication in new window or tab >>Studies on the effect of ErbB tyrosine kinase inhibitors on malignant melanoma growth and survival in vitro
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:nbn:se:liu:diva-19949 (URN)978-91-7393-610-1 (ISBN)
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
2. Experimental studies on ErbB targeted therapy in malignant melanoma
Open this publication in new window or tab >>Experimental studies on ErbB targeted therapy in malignant melanoma
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Malignant melanoma has one of the fastest increasing incidences among the different types of cancer in the Western world. This raise can partly be ascribed to the change in sun habits that has taken place during the last decades, since the major external risk factor for melanoma is exposure to ultraviolet radiation. In the case of patients with early stages of melanoma, the prognosis is usually good and the disease may be cured by surgery alone. However, with conventional anti-cancer treatments, patients diagnosed with unresectable or metastatic melanoma have a very low 5-year survival rate ranging from less than 10 percent to about 20 percent, depending on the location and extent of metastatic spread. Despite the development of novel promising targeted drugs, such as the immunomodulating antibody ipilimumab and the B-raf inhibitor vemurafenib, that have been shown to significantly extend patient survival, there is still an urgent need for new and improved treatment strategies which can further increase the survival of patients with advanced malignant melanoma.

The aim of this thesis was to investigate the anti-tumor effect of two different tyrosine kinase inhibitors (TKIs), gefitinib and canertinib, on human malignant melanoma cell lines with wild-type BRAF and NRAS. We investigated the effect of these two drugs on cell proliferation, survival and on the ErbB1-4 receptor phosphorylation, as well as the downstream signaling molecules Akt, Erk1/2 and Stat3. We also established a melanoma cell line resistant to gefitinib treatment and studied the resistance mechanisms developed by the cells.

The aim of this thesis was to investigate the anti-tumor effect of two different tyrosine kinase inhibitors (TKIs), gefitinib and canertinib, on human malignant melanoma cell lines with wild-type BRAF and NRAS. We investigated the effect of these two drugs on cell proliferation, survival and on the ErbB1-4 receptor phosphorylation, as well as the downstream signaling molecules Akt, Erk1/2 and Stat3. We also established a melanoma cell line resistant to gefitinib treatment and studied the resistance mechanisms developed by the cells.

In conclusion, gefitinib and canertinib display promising anti-tumor effects on ErbB-expressing malignant melanoma and might be used in future studies in combination with conventional chemotherapy or other targeted therapies in the treatment of malignant melanoma patients not harboring BRAF or NRAS mutations.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2012. 104 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1336
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-85665 (URN)978-91-7519-775-3 (ISBN)
Public defence
2012-12-13, Eken, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2012-11-27 Created: 2012-11-27 Last updated: 2013-03-11Bibliographically approved

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Djerf, EmelieTrinks, CeciliaThunell, LenaHallbeck, Anna-LottaWalz, Thomas M

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