title: Expression of P-170 glycoprotein sensitizes lymphoblastoid CEM cells to mitochondria-mediated apoptosis.
abstract: Multidrug resistance caused by P-glycoprotein (P-170) is a phenomenon by which cells exposed to a single drug acquire resistance to other structurally and functionally unrelated drugs. This is a widespread phenomenon described in vivo in the management of infectious as well as non-infectious diseases. Several in vitro models have been developed in order to evaluate physiopathological properties of P-170. Among these are P-170-expressing variants of the human T-lymphoblastoid CEM cell line called VBL100. As a general rule, drug resistance normally results in resistance to apoptosis induction. By contrast, a paradoxical activity is exerted in this cell model by the cytokine tumour necrosis factor-alpha (TNF-alpha), which is capable of inducing apoptosis in P-170-expressing variants better than in wild-type (wt) cells. In the present study we partially address the mechanisms underlying this activity. In fact, the susceptibility of VBL100 cells to TNF-alpha appears to be specifically due to the depolarization of their mitochondrial membrane, a key factor for apoptotic induction. The same was observed with staurosporine, a specific mitochondrion-mediated proapoptotic chemical probe. Conversely, other proapoptotic stimuli, such as Fas/CD95 or the anti-cancer drug etoposide, did induce significant cell death in wild type cells only. Thus, schematically, mitochondrially dependent stimuli appeared to be more effective in VBL100-cell killing, while 'physiological' stimuli showed the opposite 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 represented by the wt/VBL CEM lymphoid cell line seems to suggest that the multidrug resistance phenotype can specifically sensitize cells towards 'unphysiological', mitochondria-associated cell death cascade or, in the same fashion, it could shift cells from type I (mainly plasma membrane-associated) towards type II (mainly mitochondrial membrane-associated) phenotype.
authors: Department of Ultrastructures, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.
authors: P
authors: P
authors: Matarrese
authors: U
authors: U
authors: Testa
authors: R
authors: R
authors: Cauda
authors: S
authors: S
authors: Vella
authors: L
authors: L
authors: Gambardella
authors: W
authors: W
authors: Malorni
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D017209:Apoptosis / Q000502:physiology*; D005434:Flow Cytometry; D006801:Humans; D007425:Intracellular Membranes / Q000502:physiology; D008564:Membrane Potentials; D008928:Mitochondria / Q000502:physiology*; D010539:Permeability; D014407:Tumor Cells, Cultured
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1