Acquisition of Cisplatin-resistance in Malignant Mesothelioma Cells Abrogates Na,K(+),2Cl(-;)-cotransport Activity and Cisplatin-induced Early Membrane Blebbing

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.

Andersson, BrittaUmeå universitet,Klinisk kemi (author)
Behnam-Motlagh, ParvizUmeå universitet,Klinisk kemi(Swepub:umu)pabe0001 (author)
Engström, Karl-GunnarUmeå universitet,Kirurgi(Swepub:umu)kaen0006 (author)
Henriksson, RogerUmeå universitet,Onkologi(Swepub:umu)rohe0003 (author)
Grankvist, KjellUmeå universitet,Klinisk kemi(Swepub:umu)kjgr0002 (author)
Umeå universitetKlinisk kemi (creator_code:org_t)

In:Cellular Physiology and Biochemistry: S. Karger22:1-4, s. 45-561015-89871421-9778

By the author/editor: Janson, Veronica; Andersson, Britt ...; Behnam-Motlagh, ...; Engström, Karl-G ...; Henriksson, Roge ...; Grankvist, Kjell

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Cell and Molecul ...

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