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Phase-contrast microscopy studies of early Cisplatin-induced morphological changes of malignant mesothelioma cells and the correspondence to induced apoptosis.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry. Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
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2008 (English)In: Experimental Lung Research, ISSN 0190-2148, E-ISSN 1521-0499, Vol. 34, no 2, 49-67 p.Article in journal (Refereed) Published
Abstract [en]

Cisplatin treatment efficacy of malignant pleural mesothelioma (MPM) is aggravated by resistance and adverse effects. In P31 MPM cells, cisplatin induces morphological changes and apoptosis. To determine if very early (10 minutes) morphological responses corresponded to apoptosis-induction, cisplatin effects on P31 morphology were examined with phase-contrast microscopy (PCM), scanning electron microscopy (SEM), and flow cytometry (fluorescence-activated cell sorting [FACS]), and compared to apoptosis-induction over time. Increased membrane protrusions were identified with PCM and SEM, but these were not consistent with the induction of apoptosis. The authors concluded that very early morphological changes can be determined with PCM in MPM, but they did not convincingly correspond to apoptosis induction.

Place, publisher, year, edition, pages
2008. Vol. 34, no 2, 49-67 p.
Keyword [en]
apoptosis, cisplatin, malignant pleural mesothelioma (MPM), phase-contrast microscopy (PCM), scanning electron microscopy (SEM)
Identifiers
URN: urn:nbn:se:umu:diva-8814DOI: doi:10.1080/01902140701884398PubMedID: 18266129OAI: oai:DiVA.org:umu-8814DiVA: diva2:148485
Available from: 2008-02-14 Created: 2008-02-14 Last updated: 2011-08-25Bibliographically approved
In thesis
1. Cisplatin-resistance and cell death in malignant pleural mesothelioma cells
Open this publication in new window or tab >>Cisplatin-resistance and cell death in malignant pleural mesothelioma cells
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Malignant pleural mesothelioma (MPM) is an aggressive, treatment-resistant tumour. Cisplatin (cis-diamminedichloroplatinum (II)) is the best single-agent chemotherapy for MPM, but platinum-based combination therapies give the best overall response rates. However, cisplatin use is limited by resistance and severe side effects. This thesis has increased the knowledge concerning cisplatin-induced cell death in MPM by describing a novel potential therapeutic target, and three novel phenotypes of cisplatin-resistance in a human MPM cell line (P31) and its cisplatin-resistant sub-line (P31res1.2).

The novel potential therapeutic target, and one of the novel phenotypes, was cisplatin-resistant pro-apoptotic BH3-only proteins. In the P31 cells, cisplatin transiently increased pro-apoptotic BH3-only proteins during 6 h of exposure. This response was almost completely abrogated in the P31res1.2 cells. De-regulated caspase activity and activation was the second novel phenotype identified. The P31res1.2 cells had earlier, possibly mitochondria-independent, caspase-3 activation, increased basal caspase-3 activity and increased basal cleavage of caspase-8 and -9. Despite these differences, 6-h equitoxic cisplatin exposures rendered 50-60% of the cells apoptotic in both cell lines. The third novel phenotype was abrogated Na+K+2Cl--cotransporter (NKCC1) activity. Although NKCC1 activity was dispensable for cisplatin-induced apoptosis, balanced potassium transport activity was essential for P31 cell survival. Finally, the survival signalling protein Protein Kinase B (PKB or Akt) isoforms α and γ were constitutively activated in a PI3K-independent manner in P31 cells. In the P31res1.2 cells, PKBα and γ activities were increased, and there was PI3K-dependent activation of PKBβ. However, this increase in PKB isoform activity was not strongly associated to the cisplatin-resistance of the P31res1.2 cells.

Place, publisher, year, edition, pages
Umeå: Medicinsk biovetenskap, 2008. 104 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1192
Keyword
apoptosis, BH3-only proteins, caspase, cell morphology, potassium transport, protein kinase B (PKB/Akt), signalling pathways, time
National Category
Other Clinical Medicine
Identifiers
urn:nbn:se:umu:diva-1680 (URN)978-91-7264-560-8 (ISBN)
Public defence
2008-08-29, E04, 6E, Norrlands Universitetssjukhus, Umeå, 09:00 (English)
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Available from: 2008-05-28 Created: 2008-05-28 Last updated: 2010-01-18Bibliographically approved

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