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Research Article

Deregulation of Apoptotic Volume Decrease and Ionic Movements in Multidrug Resistant Tumor Cells: Role of chloride channels

¹University of Copenhagen ²NeuroSearch

Submitted 22 December 2008 ; revised 21 September 2009 ; accepted in final form 13 October 2009

Changes in cell volume and ion gradients across the plasma membrane play a pivotal role in the initiation of apoptosis. Here we explore the kinetics of apoptotic volume decrease (AVD) and ion content dynamics in wildtype (wt) and Multidrug Resistant (MDR) Ehrlich Ascites Tumor Cells (EATC). In wt EATC, induction of apoptosis with cisplatin (5 µM) leads to three distinctive AVD stages; an early AVD₁ (4-12 h), associated with a 30% cell water loss, a transition stage AVD_T ( 12 to 32 h) where cell volume is partly recovered, and a secondary AVD₂ (past 32 h) where cell volume was further reduced. AVD₁ and AVD₂ were coupled to net loss of Cl^-, K⁺, Na⁺ and amino acids (ninhydrin positive substances)whereas during AVD_T Na⁺ and Cl^- was accumulated. MDR EATC was resistant to cisplatin showing increased viability and less caspase 3 activation. Compared to wt EATC, MDR EATC underwent a less pronounced AVD₁, an augmented AVD_T and a delay in induction of AVD₂. Changes in AVD were associated with inhibition of Cl^- loss during AVD₁, augmented NaCl uptake during AVD_T, and a delay of Cl^- loss during AVD₂. Application of the anion channel inhibitor NS3728 inhibited AVD and completely abolished the differences in AVD, ionic movements and caspase-3 activation between wt and MDR EATC. Finally, the maximal capacity of VRAC was found to be strongly repressed in MDR EATC. Together, these data suggest that impairment of AVD, primarily via modulation of NaCl movements, contribute to protection against apoptosis in MDR EATC.

Apoptotic Volume Decrease; caspase-3; chloride channel; VRAC