Induction of G2/M phase arrest and apoptosis of human leukemia cells by potent antitumor triazoloacridinone C-1305.
In this study, we show that triazoloacridinone derivative C-1305, a potent antitumor compound, in human lymphoblastic (MOLT4) and promyelocytic (HL60) leukemia cells induces G2/M arrest followed by apoptosis. In both type of cells, C-1305 at biological relevant concentrations corresponding to EC(90) value, induced a significant increase in the fraction of G2/M cells. The cell cycle perturbations were accompanied by the appearance of sub-G1 fraction, which can be considered as the apoptotic cells population. In both human leukemia cells apoptosis was additionally proved by appearance of DNA fragmentation, activation of caspase-3, PARP cleavage, externalization of phosphatydilserine as well as decrease of the mitochondrial transmembrane potential DeltaPsi(m) and ATP depletion. Treatment of lymphoblastic MOLT4 cells with the C-1305 at EC(90) concentration, caused massive death by apoptosis. Compared to MOLT4 cells, the capacity of HL60 cells to execute apoptosis after C-1305 treatment at equitoxic dose was significantly weaker, but very effective at high concentration (4x EC(90)). These differences could originate from different sensitivity of both cell types to cytotoxic action of C-1305 (EC(50) value for MOLT4 cells was 8 times lower than for HL60 cells and the EC(90) value was 14 times lower, respectively). Collectively, these results show that C-1305 is a novel and potent compound which induces G2/M arrest and subsequent apoptosis of human leukemia cells. This strong ability to induce apoptosis of tumor cells support the view that C-1305 could be consider as a new potent and promising antitumor agent.
Augustin
Ewa
E
Gdańsk University of Technology, Department of Pharmaceutical Technology and Biochemistry, Narutowicza St. 11/12, 80-952 Gdańsk, Poland. augustin@chem.pg.gda.pl
Moś-Rompa
Anna
A
Skwarska
Anna
A
Witkowski
Jacek M
JM
Konopa
Jerzy
J
D000166:Acridines / Q000737:chemistry / Q000494:pharmacology*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004587:Electrophoresis, Agar Gel; D005434:Flow Cytometry; D016195:G2 Phase / Q000187:drug effects*; D018922:HL-60 Cells; D006801:Humans; D020287:In Situ Nick-End Labeling; D007425:Intracellular Membranes / Q000187:drug effects; D007938:Leukemia; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology*
D000166:Acridines; D000970:Antineoplastic Agents; C488734:C 1305; D014230:Triazoles; D000255:Adenosine Triphosphate; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3