Anti-leukemia effects of the novel synthetic 1-benzylindole derivative 21-900 in vitro and in vivo.
Cancers are the major cause of death worldwide. Chemotherapy using cytotoxic drugs and targeted therapy is required when surgery is difficult, ineffective, or impossible. We previously synthesized the novel synthetic 1-benzylindole derivative 21-900 and found that it inhibits histone deacetylase (HDAC) activities and tubulin assembly. Here we tested its effects on the human leukaemia cell lines HL-60 and MOLT-4 in vitro and in vivo. We found that its potent cytotoxic effects were mediated through cell cycle arrest at the G2/M phase, which increased the population of sub-G1 cells, leading to apoptosis. Further, tubulin was depolymerized by 21-900 in a manner similar to that of vincristine, leading to disruption of microtubule dynamics and increased levels of the mitotic marker MPM-2. Further, 21-900 increased the expression of cleavage form of poly (ADP-ribose) polymerase (PARP), caspase 3, 7 (cleavage form), and pro-apoptotic protein BAK and decreased the expression of pro-survival BCL-2-family proteins BCL-2, MCL-1, and BID pro-form, leading to the induction of apoptosis. The growth of tumours in nude mice formed by xenografts of HL-60 and MOLT-4 cells was significantly inhibited by 21-900 without causing the mice to lose body weight. These findings indicate that 21-900 may serve as a potent anti-leukaemia drug.
The Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
Wei-Chun
WC
HuangFu
The Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
Min-Wu
MW
Chao
The Ph.D. Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
Chun-Chun
CC
Cheng
Graduate Institute of Medical Sciences, School of Medicine, Taipei Medical University, Taipei, Taiwan.
Yu-Chieh
YC
Wei
School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan.
Yi-Wen
YW
Wu
School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan.
Jing-Ping
JP
Liou
Graduate Institute of Medical Sciences, School of Medicine, Taipei Medical University, Taipei, Taiwan.|Department of Pharmacology, School of Medicine, Taipei Medical University, Taipei, Taiwan.
George
G
Hsiao
The Center of Translational Medicine, Taipei Medical University, Taipei, Taiwan.|The Ph.D. Program for Medical Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
Yu-Ching
YC
Lee
School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan.
Chia-Ron
CR
Yang
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D016195:G2 Phase / Q000187:drug effects; D006655:Histone Deacetylases / Q000378:metabolism; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007938:Leukemia / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D016513:Mice, SCID; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000378:metabolism; D058105:Polymerization; D016019:Survival Analysis; D014404:Tubulin / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D007211:Indoles; D014404:Tubulin; C000164:1-benzylindole; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D048031:JNK Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D006655:Histone Deacetylases