title: Retaining cytotoxic activity of anthrapyridone CO1 against multidrug resistant cells is related to the ability to induce concomitantly apoptosis and lysosomal death of leukaemia HL60/VINC and HL60/DOX cells.
abstract: OBJECTIVE
  The effect of anthrapyridone compound CO1 retaining cytotoxic activity against multidrug resistant (MDR) tumour cells on inducing cell death of the sensitive leukaemia HL60 cell line and its MDR sublines (HL60/VINC and HL60/DOX) was examined.
  
  
  METHODS
  The effects of CO1 and the reference compound doxorubicin (DOX) on examined cells were analysed by studying their cytotoxicity, drug intracellular accumulation, cell cycle distribution, caspase-3 and caspase-8 activity, Fas expression and lysosomal integrity.
  
  
  RESULTS
  CO1 was much less effective at influencing the cell cycle of examined cells than DOX a well-known antitumour drug targeting cellular DNA and causing G2/M checkpoint arrest. CO1 caused much less pronounced appearance of the sub-G1 population and oligonucleosomal DNA fragmentation, characteristic of apoptosis, compared with DOX. Significantly lower caspase-3 and caspase-8 activity was also observed in the response of these cells to CO1 compared with DOX treatment. CO1 did not change the expression of the Fas death receptor, characteristic of apoptotic pathways, on the surface of studied cells. Interestingly, the results showed that CO1 caused lysosomal membrane permeability (LMP) of the cells, whereas DOX did not perturb the lysosomal integrity of the studied cells.
  
  
  CONCLUSIONS
  The results suggest that CO1 could induce LMP-mediated cell death as a main lethal effect in a caspase-independent fashion.
authors: Department of Biochemistry, University of Szczecin, Szczecin, Poland.
authors: Robert
authors: R
authors: Nowak
authors: Jolanta
authors: J
authors: Tarasiuk
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D016193:G1 Phase / Q000187:drug effects; D018922:HL-60 Cells; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D006801:Humans; D007938:Leukemia / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C491901:FAS protein, human; D006576:Heterocyclic Compounds, 4 or More Rings; C573508:anthrapyridone CO1; D019014:fas Receptor; D004317:Doxorubicin; D053148:Caspase 3; D053181:Caspase 8