Expression of P-170 glycoprotein sensitizes lymphoblastoid CEM cells to mitochondria-mediated apoptosis

Multidrug resistance caused by P-glycoprotein (P-170) is a phenomenon by wh ich cells exposed to a single drug acquire resistance to other structurally and functionally unrelated drugs. This is a widespread phenomenon describe d in vivo in the management of infectious as well as non-infectious disease s. Several in vitro models have been developed in order to evaluate physiop athological properties of P-170. Among these are P-170-expressing variants of the human T-lymphoblastoid CEM cell line called VBL100. As a general rul e, drug resistance normally results in resistance to apoptosis induction. B y contrast, a paradoxical activity is exerted in this cell model by the cyt okine tumour necrosis factor-alpha (TNF-alpha), which is capable of inducin g apoptosis in P-170-expressing variants better than in wild-type (wt) cell s. In the present study, we partially address the mechanisms underlying thi s activity. In fact, the susceptibility of VBL100 cells to TNF-alpha appear s to be specifically due to the depolarization of their mitochondrial membr ane, a key factor for apoptotic induction. The same was observed with staur osporine, a specific mitochondrion-mediated proapoptotic chemical probe. Co nversely, other proapoptotic stimuli, such as Fas/CD95 or the anti-cancer d rug etoposide, did induce significant cell death in wild type cells only. T hus, schematically, mitochondrially dependent stimuli appeared to be more e ffective in VBL100-cell killing, while 'physiological' stimuli showed the o pposite behaviour. Importantly, under steady-state conditions, VBL100 cells displayed per se a mitochondrial membrane hyperpolarization that appeared strictly related to their high susceptibility to specific apoptotic stimuli . In conclusion, the study of a well-established cell model such as that re presented by the wt/VBL CEM lymphoid cell line seems to suggest that the mu ltidrug resistance phenotype can specifically sensitize cells towards 'unph ysiological', mitochondria-associated cell death cascade or, in the same fa shion, it could shift cells from type I (mainly plasma membrane-associated) towards type II (mainly mitochondrial membrane-associated) phenotype.