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Anticancer effect of SN-38 on colon cancer cell lines with different metastatic potential
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, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
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2008 (English)In: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 19, no 6, 1493-1498 p.Article in journal (Refereed) Published
Abstract [en]

SN-38 is an active metabolite of the topoisomerase I inhibitor irinotecan. The mechanism behind its antitumor effect in colorectal cancer is not fully understood. In this study, we examined the response of colon cancer cell lines with different metastatic potential to SN-38. The parental human colon cancer cell line KM12C and its two highly metastatic derivatives KM12SM and KM12L4a were cultivated in 5% CO2 at 37°C for 24 h and then exposed to SN-38 (2.5 µg/ml) at 37°C for 4, 24 and 48 h, respectively. The cell cycle was measured by flow cytometry, apoptotic activity was determined by flow cytometry and immunocytochemistry and the expression of topoisomerase I, Bax and survivin proteins were examined by Western blot. The exposure of the cells to SN-38 induced S-phase and G2 arrest (P<0.0001) and the KM12L4a cells had the highest response in a time-dependent manner (P<0.0001). The rates of apoptosis in the KM12SM (P=0.001) and KM12L4a cell lines (P=0.01) were increased time-dependently, though there was no such change in the KM12C cells. The expression of topoisomerase I protein was decreased in each cell line tested and the expression of Bax protein was increased, especially in KM12L4a. In conclusion, the effect of SN-38 on the colon cancer cell lines was mediated via conducting S-phase and G2 arrest and apoptosis. This effect was found in the cell lines with higher metastatic potentials, indicating that SN-38 can be used to treat advanced colon cancers.

Place, publisher, year, edition, pages
2008. Vol. 19, no 6, 1493-1498 p.
Keyword [en]
Colon cancer cell lines, SN-38, apoptosis
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:liu:diva-14787DOI: 10.3892/or.19.6.1493OAI: oai:DiVA.org:liu-14787DiVA: diva2:25266
Available from: 2008-09-24 Created: 2008-09-24 Last updated: 2017-12-13
In thesis
1. Molecular Studies of Irradiation and SN-38 on Colorectal Cancer
Open this publication in new window or tab >>Molecular Studies of Irradiation and SN-38 on Colorectal Cancer
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Colorectal cancer (CRC) is one of most common cancer diseases worldwide. In Swedenapproximately 5,000 new cases of CRC are generated each year, which makes it the thirdmost common cancer disease among both men and women. The past decades ofimproved treatment strategies have considerably increased the five-year survival for CRCpatients. However more could be achieved in this area, in particular for metastatic CRC,which is the cause of most CRC-related deaths. Therefore it is important to study thebiological response to certain treatments induced in CRC to find valuable predictiveand/or prognostic factors to select patients for better suited treatments.

The aim of this thesis was to gain insight into the molecular changes that occurfollowing irradiation or treatment with SN-38 in rectal cancer patients or colon cancercell lines by studying the RNA expression, protein expression, DNA cell cycledistribution and apoptotic response. The expression of phosphatase of regenerating liver(PRL) proteins was investigated in rectal cancers from 125 patients included in arandomized clinical trial of preoperative radiotherapy (RT). Increased expression of PRLswas seen at the invasive margin of primary and metastatic cancers compared with theinner area of the tumors. Moreover, strong PRL staining at the invasive margin correlatedto distant recurrence and worse survival of patients in the RT group but not in non-RTgroup (Paper I). Radiosensitivity was studied by treating KM12C, KM12SM andKM12L4a colon cancer cell lines with radiation. KM12C is of low metastatic naturecompared with the highly metastatic KM12SM and KM12L4a. Upregulation of ΔNp73and PRL-3 might contribute to the radioresistant phenotype in KM12C. In contrast,KM12L4a shows a high frequency of apoptosis and lack of upregulation of ΔNp73, PRL-3 and survivin, which might explain its radiosensitive phenotype (Paper II). KM12C,KM12SM and KM12L4a were treated with SN-38 which inhibits topoisomerase 1 (topo-1). The results show that SN-38 induces G2/S arrest and possess the capacity to triggerapoptosis in the three cell lines (Paper III). To further elucidate SN-38 effect on these celllines, the gene expression profile following SN-38 treatment was studied. Oligonucleotidearrays consisting of ~27,000 spots were hybridized with sample and reference cDNA.Both unsupervised and supervised hierarchical clustering analysis, and functional analysiswere performed. Supervised hierarchical clustering gives a strong signal of 1453discriminated genes, the vast majority being upregulated. Both upregulated anddownregulated genes point toward a favorable impact of SN-38 regarding the apoptoticpathways. For example RhoB and Bax are upregulated together with downregulation ofKras and survivin, which promotes apoptosis (Paper IV).

In conclusion, PRLs may be valuable biomarkers for RT resistance, predicting apoor prognosis in rectal cancer patients. Targeting radio-resistance factors, such asΔNp73 and survivin may contribute to an increased sensitivity to RT. SN-38 affects cellproliferation and apoptosis.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2008. 60 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1070
Keyword
Colorectal cancer (CRC), molecular changes, SN-38
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-14789 (URN)978-91-7393-838-9 (ISBN)
Public defence
2008-09-29, Eken, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 09:00 (Swedish)
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Available from: 2008-09-24 Created: 2008-09-24 Last updated: 2009-08-22Bibliographically approved

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Wallin, ÅsaSvanvik, JoarHolmlund, BirgittaSun, Xiao-Feng

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Wallin, ÅsaSvanvik, JoarHolmlund, BirgittaSun, Xiao-Feng
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OncologyFaculty of Health SciencesSurgeryDepartment of Surgery in ÖstergötlandDepartment of Clinical and Experimental MedicineDepartment of Oncology UHL
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Oncology Reports
Cancer and Oncology

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