Microtubule inhibitor D-24851 induces p53-independent apoptotic cell death in malignant glioma cells through Bcl-2 phosphorylation and Bax translocation.
D-24851 is a recently developed microtubule inhibitor that induces G2/M cell-cycle arrest and has an antitumor effect in many cancer cell types. It is expected to be a promising chemotherapeutic agent against a broad range of tumors. However, the precise mechanisms underlying its antitumor effect remain to be determined. Here, we investigated the in vitro effect of D-24851 on tumor growth and the apoptosis mechanism in human malignant glioma cells. Because both p53-dependent and -independent pathways of apoptosis have been reported, we used cell lines with wild-type p53 (U87-MG and D54) and cell lines with mutant p53 (U373-MG and T98G) and compared their responses to D-24851. D-24851 substantially inhibited the proliferation of the four glioma cell lines tested in a dose- and time-dependent manner. The inhibitory effect of D-24851 on tumor growth was associated with cell-cycle arrest in G2/M, subsequently inducing apoptosis. D-24851 treatment induced phosphorylated Bcl-2 and translocated Bax from the cytoplasm to the mitochondria, resulting in apoptotic cell death. These events took place regardless of the p53 status of tumor cells. Our results indicated that D-24851 effectively induces apoptosis through Bcl-2 phosphorylation and Bax translocation in human malignant glioma cells in a p53-independent manner. The results of this study make D-24851 even more promising as a therapeutic agent, especially because many malignant gliomas have a heterogeneous p53 status.
Ito
Hideaki
H
Department of Neurosurgery, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Kanzawa
Takao
T
Kondo
Seiji
S
Kondo
Yasuko
Y
D000081:Acetamides / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001932:Brain Neoplasms / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects*; D049109:Cell Proliferation; D004305:Dose-Response Relationship, Drug; D005910:Glioma / Q000473:pathology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein
D000081:Acetamides; C494826:BAX protein, human; D007211:Indoles; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C419187:indibulin