Amrubicin induces apoptosis in human tumor cells mediated by the activation of caspase-3/7 preceding a loss of mitochondrial membrane potential.
Amrubicin, a completely synthetic 9-aminoanthracycline derivative, inhibits cell growth by stabilizing a topoisomerase II-DNA complex. This study was designed to examine the apoptosis induced in human leukemia U937 cells by amrubicin and its active metabolite amrubicinol. Amrubicin, amrubicinol and other antitumor agents, such as daunorubicin and etoposide, induced typical apoptosis with characteristic nuclear morphological change and DNA fragmentation. Measuring the population of sub-G(1) phase cells, it was found that under conditions where cell growth was inhibited by either amrubicin or amrubicinol, U937 cells underwent apoptotic cell death in a dose-dependent manner accompanied by an arrest of the cell cycle at G(2)/M. Furthermore, amrubicin- and amrubicinol-induced apoptosis was mediated by the activation of caspase-3/7, but not caspase-1, preceding a loss of mitochondrial membrane potential. These results indicate that both a reduction in mitochondrial membrane potential and the activation of caspase-3/7 are key events in the apoptosis induced by amrubicin and amrubicinol as well as the other antitumor agents. In addition, studies with oligomycin suggested that the apoptosis induced by amrubicin and amrubicinol involved substantially different pathways from that triggered by daunorubicin and etoposide. Oligomycin blocked the etoposide-induced increase in the number of sub-G(1) phase cells without preventing the activation of caspase-3/7, and had no inhibitory effect on the expansion of the sub-G(1) population in daunorubicin-treated cells, whereas apoptosis-related changes caused by amrubicin and amrubicinol were suppressed in the presence of oligomycin.
Hanada
Mitsuharu
M
Pharmacology Research Laboratories, Drug Research Division, Dainippon Sumitomo Pharma, 3-1-98 Kasugadenaka, Konohana-ku, Osaka 554-0022, Japan. mitsuharu-hanada@ds-pharma.co.jp
Noguchi
Toshihiro
T
Yamaoka
Takashi
T
D018943:Anthracyclines / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism*; D053179:Caspase 7 / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D003630:Daunorubicin / Q000494:pharmacology; D004359:Drug Therapy, Combination; D004789:Enzyme Activation / Q000187:drug effects*; D005047:Etoposide / Q000494:pharmacology; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects; D020298:U937 Cells
D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; C116173:amrubicinol; D005047:Etoposide; C055866:amrubicin; D053148:Caspase 3; D053179:Caspase 7; D003630:Daunorubicin