Experimental Study On The Anti-leukemic Effects Of GP-7 In K562 And K562/ADM Cells

Objective: To investigate the anti-leukemic effects of 4-[4"-(2", 2", 6", 6"-tetramethyl-1"-pipeddinyloxy) amino]-4'-demethylepipodophyllotoxin (GP-7) on human chronic myelogenous leukemia K562 and its multidrug-resistant K562/ADM cells.Methods: Under the control of etoposide, K562 or K562/ADM cells were treated with GP-7, its cell proliferation was detected by MTT assay, cell cycle and apoptosis ratio were detected by flow cytometry, apoptotic morphology was observed by light microscopy, and apoptotic DNA fragmentation was detected by agarose gel electrophoresis.Results: When treated with 8～128/μmol·L^-1 of GP-7 for 48 h or 64μmol·L^-1 GP-7 for 24～72 h, the proliferation of K562 and K562/ADM cells was inhibited in a dose-or time-dependent manner (r_K562=0.978, P <0.01; r_K562/ADM = 0.947, P < 0.05 or r_K562 = 0.964, P < 0.05; r_K562/ADM = 0.999, P<0.01) , and the inhibition effects of GP-7 on K562 and K562/ADM cells were 2.03 fold (P < 0.01) and 1.50 (P < 0.01) fold higher than those of etoposide, while the inhibition effects of GP-7 and etoposide on K562 cells were 2.49 fold (P < 0.01) and 1.83 fold (P < 0.01) higher than those on K562/ADM cells. When treated with 64μmol·L^-1 of GP-7 for 48 h, both K562 and K562/ADM cells were arrested at G₂/M phase whereas etoposide caused S phase aggregation of the cells. GP-7 could induce apoptosis of both K562 and K562/ADM cell lines, but there was no significant difference between GP-7- and etoposide-induced apoptotic ratio. GP-7 could also induce typical apoptotic morphological changes and DNA fragmentation of K562 and K562/ADM cells, but DNA fragmentation induced by GP-7 in K562/ADM cells was weaker than that in K562 cells. When treated with GP-7 or etoposide for 48 h, 128 and 256 GP-7 induced more DNA fragmentation than that of etoposide did, but 32 and 64μmol·L^-1 GP-7 induced less DNA fragmentation than that of etoposide did. Conclusions: GP-7 may exert its anti-leukemic effects on K562 and its multidrug-resistant K562/ADM cells via the inhibition of cell proliferation and the induction of apoptosis, and GP-7 is prior to etoposide in antagonizing leukemic K562 and K562/ADM cells.