Acquisition of Cisplatin-resistance in Malignant Mesothelioma Cells Abrogates Na,K(+),2Cl(-;)-cotransport Activity and Cisplatin-induced Early Membrane Blebbing.
2008 (English)In: Cell Physiol Biochem, ISSN 1421-9778, Vol. 22, no 1-4, 45-56 p.Article in journal (Refereed) Published
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.
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.
Place, publisher, year, edition, pages
2008. Vol. 22, no 1-4, 45-56 p.
Apoptosis, Caspase-3, Cisplatin, Malignant mesothelioma, Membrane blebbing, Na+, K+, 2Cl--cotransport
IdentifiersURN: urn:nbn:se:umu:diva-10418DOI: doi:10.1159/000149782PubMedID: 18769031OAI: oai:DiVA.org:umu-10418DiVA: diva2:150089