Potentiation of harringtonine cytotoxicity by calcium antagonist diltiazem and biscoclaurine alkaloid cepharanthine in adriamycin-resistant P388 murine leukemia and K562 human leukemia cells.
Harringtonine showed cross resistance in adriamycin-resistant murine leukemia P388 (P388/ADM) and human leukemia K562 (K562/ADM) cells. The relative resistance of the P388/ADM and K562/ADM cells to harringtonine was about 7 and 40, respectively. Calcium influx blockers, diltiazem and the biscoclaurine alkaloid cepharanthine enhanced the cytotoxicity of harringtonine in P388/ADM and K562/ADM cells. The extent of enhancement was different for the two drugs, and up to a 9- to 10-fold increase in harringtonine cytotoxicity occurred in P388/ADM cells, and 14- to 22-fold enhancement in K562/ADM cells with diltiazem or cepharanthine. Harringtonine resistance of P388/ADM was circumvented completely, and the resistance of K562/ADM was circumvented partially, by diltiazem or cepharanthine. The mechanism of enhanced cytotoxicity by diltiazem and cepharanthine is probably inhibition of active efflux of harringtonine in P388/ADM and K562/ADM cells.
Yamamoto
S
S
Department of Pediatrics, Osaka Medical College, Takatsuki, Japan.
Hui
P Z
PZ
Fukuda
Y
Y
Tatsumi
K
K
Mino
M
M
D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D044182:Benzylisoquinolines; D001692:Biological Transport / Q000187:drug effects; D002452:Cell Count; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004110:Diltiazem / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology; D004351:Drug Resistance; D006131:Growth Inhibitors / Q000494:pharmacology; D006248:Harringtonines / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007941:Leukemia P388 / Q000188:drug therapy / Q000473:pathology; D007942:Leukemia, Experimental / Q000473:pathology*; D014750:Vincristine / Q000494:pharmacology; D052117:Benzodioxoles
D000470:Alkaloids; D044182:Benzylisoquinolines; D004110:Diltiazem; D004317:Doxorubicin; D006131:Growth Inhibitors; D006248:Harringtonines; D014750:Vincristine; C006947:cepharanthine; D052117:Benzodioxoles