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Cisplatin-resistance and cell death in malignant pleural mesothelioma cells
Umeå University, Faculty of Medicine, Medical Biosciences.
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 [en]
apoptosis, BH3-only proteins, caspase, cell morphology, potassium transport, protein kinase B (PKB/Akt), signalling pathways, time
National Category
Other Clinical Medicine
Identifiers
URN: urn:nbn:se:umu:diva-1680ISBN: 978-91-7264-560-8 (print)OAI: oai:DiVA.org:umu-1680DiVA: diva2:141815
Public defence
2008-08-29, E04, 6E, Norrlands Universitetssjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2008-05-28 Created: 2008-05-28 Last updated: 2010-01-18Bibliographically approved
List of papers
1. Induction of apoptosis by intracellular potassium ion depletion: using the fluorescent dye PBFI in a 96-well plate method in cultured lung cancer cells.
Open this publication in new window or tab >>Induction of apoptosis by intracellular potassium ion depletion: using the fluorescent dye PBFI in a 96-well plate method in cultured lung cancer cells.
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2006 (English)In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 20, no 6, 986-994 p.Article in journal (Refereed) Published
Keyword
Apoptosis, K+-depletion, mesothelioma, PBFI-AM, small-cell lung cancer
Identifiers
urn:nbn:se:umu:diva-13588 (URN)doi:10.1016/J.tiv.2005.12.013 (DOI)16483738 (PubMedID)
Available from: 2008-01-11 Created: 2008-01-11 Last updated: 2011-08-31Bibliographically approved
2. Phase-contrast microscopy studies of early Cisplatin-induced morphological changes of malignant mesothelioma cells and the correspondence to induced apoptosis.
Open this publication in new window or tab >>Phase-contrast microscopy studies of early Cisplatin-induced morphological changes of malignant mesothelioma cells and the correspondence to induced apoptosis.
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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.

Keyword
apoptosis, cisplatin, malignant pleural mesothelioma (MPM), phase-contrast microscopy (PCM), scanning electron microscopy (SEM)
Identifiers
urn:nbn:se:umu:diva-8814 (URN)doi:10.1080/01902140701884398 (DOI)18266129 (PubMedID)
Available from: 2008-02-14 Created: 2008-02-14 Last updated: 2011-08-25Bibliographically approved
3. Acquisition of Cisplatin-resistance in Malignant Mesothelioma Cells Abrogates Na,K(+),2Cl(-;)-cotransport Activity and Cisplatin-induced Early Membrane Blebbing.
Open this publication in new window or tab >>Acquisition of Cisplatin-resistance in Malignant Mesothelioma Cells Abrogates Na,K(+),2Cl(-;)-cotransport Activity and Cisplatin-induced Early Membrane Blebbing.
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2008 (English)In: Cell Physiol Biochem, ISSN 1421-9778, Vol. 22, no 1-4, 45-56 p.Article in journal (Refereed) Published
Abstract [en]

AIMS:

Resistance mechanisms are important limiting factors in the treatment of solid malignancies with cis-diamminedichloroplatinum(II) (cisplatin). To gain further understanding of the effects of acquired cisplatin-resistance, we compared a human malignant pleural mesothelioma cell line (p31) to a sub-line (p31res1.2) with acquired cisplatin-resistance.

METHODS AND RESULTS:

The role of Na(+),K(+),2Cl(-)-cotransport (NKCC1) activity in cisplatin-induced morphological changes and acquired cisplatin-resistance was investigated in a time-resolved manner. Acquisition of cisplatin-resistance resulted in markedly reduced NKCC1 activity, absence of cisplatin-induced early membrane blebbing, and increased basal caspase-3 activity. At equitoxic cisplatin concentrations, P31res1.2 cells had a faster activation of caspase-3 than P31 cells, but the end-stage cytotoxicity and number of cells with DNA fragmentation was similar. Bumetanide inhibition of NKCC1 activity in P31 cells repressed cisplatin-induced early-phase membrane blebbing but did not increase P31 cell resistance to cisplatin.

CONCLUSIONS:

Together, these results suggest that active NKCC1 was necessary for cisplatin-induced early membrane blebbing of P31 cells, but not for cisplatin-resistance. Thus, acquisition of cisplatin-resistance can affect mechanisms that have profound effects on cisplatin-induced morphological changes but are not necessary for the subsequent progression to apoptosis.

Keyword
Apoptosis, Caspase-3, Cisplatin, Malignant mesothelioma, Membrane blebbing, Na+, K+, 2Cl--cotransport
Identifiers
urn:nbn:se:umu:diva-10418 (URN)doi:10.1159/000149782 (DOI)18769031 (PubMedID)
Available from: 2008-09-08 Created: 2008-09-08 Last updated: 2011-08-25Bibliographically approved
4. Brief report: acquisition of cisplatin-resistance in malignant mesothelioma cells deregulates pro-apoptotic BH3-only proteins
Open this publication in new window or tab >>Brief report: acquisition of cisplatin-resistance in malignant mesothelioma cells deregulates pro-apoptotic BH3-only proteins
(English)Manuscript (Other (popular science, discussion, etc.))
Identifiers
urn:nbn:se:umu:diva-3279 (URN)
Available from: 2008-05-28 Created: 2008-05-28 Last updated: 2011-08-31Bibliographically approved
5. Acquired cisplatin-resistance with increased basal caspase-3 activity and suppressed caspase-8 and -9 activation in malignant pleural mesothelioma cells
Open this publication in new window or tab >>Acquired cisplatin-resistance with increased basal caspase-3 activity and suppressed caspase-8 and -9 activation in malignant pleural mesothelioma cells
Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-3280 (URN)
Available from: 2008-05-28 Created: 2008-05-28 Last updated: 2010-01-13Bibliographically approved
6. Phosphoinositide 3-kinase-independent, constitutive activation of protein kinase B isoforms in malignant pleural mesothelioma cells
Open this publication in new window or tab >>Phosphoinositide 3-kinase-independent, constitutive activation of protein kinase B isoforms in malignant pleural mesothelioma cells
Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-3281 (URN)
Available from: 2008-05-28 Created: 2008-05-28 Last updated: 2010-01-13Bibliographically approved

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