PSC 833 induces apoptosis in drug-sensitive human leukemia cell line and modulates resistance to paclitaxel in its multidrug-resistant variant

Background The non-immunosuppressive cyclosporine analog PSC 833 has been s hown to reverse multidrug-resistance of neoplastic cells including the MDR- 1 gene coded P-glycoprotein (P-gp)-mediated cells resistant to paclitaxel. Materials and Methods: Apoptosis was demonstrated in drug-sensitive HL-60 a nd multidrug-resistant human promyelocytic leukemia HL-60/ADR (MRP) and HL- 60/VCR (MDR-1) cells in vitro with the aid of flow cytometry, DNA analysis and western blotting Results: The techniques used herein determined accumul ation of paclitaxel/PSC 833 induced apoptotic cells with sub-G0 (hypodiploi d) DNA content and blocked in the G2/M phase of the cell cycle, internucleo somal DNA fragmentation poly (ADP-ribose) polymerase cleavage, Bcl-2 modula tion and Bax up-regulation, without any significant alterations in. the lev els of Bcl-x(L), CD95/Fas or Fas-L proteins. Conclusion: Drug resistance mo dulator PSC 833 abolished the P-gp- mediated multidrug-resistance to paclit axel and paclitaxel-induced apoptosis in human myeloid leukemia (HL-60/VCR) cells in vitro. Furthermore, PSC 833 alone induced apoptosis in parental d rug-sensitive leukemia cells, but not in both multidrug-resistant sublines studied.