The polynuclear platinum BBR3610 induces G2/M arrest and autophagy early and apoptosis late in glioma cells.
BBR3610 is a polynuclear platinum compound, in which two platinums are linked by a spermine-like linker, and studies in a variety of cancers, including glioma, have shown that it is more potent than conventional platinums and works by different means. Identifying the mechanism of action of BBR3610 would help in developing the drug further for clinical use. Previous work showed that BBR3610 does not induce immediate apoptosis but results in an early G2/M arrest. Here, we report that BBR3610 induces early autophagy in glioma cells. Increased autophagy was also seen in intracranial xenografts treated with BBR3610. Interestingly, upon attenuation of autophagy by RNAi-mediated knockdown of ATG5 or ATG6/BECN1, no change in cell viability was observed, suggesting that the autophagy is neither an effective protection against BBR3610 nor an important part of the mechanism by which BBR3610 reduces glioma cell viability. This prompted a multimodal analysis of 4 cell lines over 2 weeks posttreatment with BBR3610, which showed that the G2/M arrest occurred early and apoptosis occurred later in all cell lines. The cells that survived entered a senescent state associated with mitotic catastrophe in 2 of the cell lines. Together, our data show that the response to treatment with a single agent is complex and changes over time.
Shingu
Takashi
T
Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030-4009, USA.
Chumbalkar
Vaibhav C
VC
Gwak
Ho-Shin
HS
Fujiwara
Keishi
K
Kondo
Seiji
S
Farrell
Nicholas P
NP
Bogler
Oliver
O
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D016195:G2 Phase / Q000187:drug effects*; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000627:therapeutic use*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
C502778:ATG5 protein, human; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D000071187:Autophagy-Related Protein 5; C523470:BBR3610; C491997:BECN1 protein, human; D000071186:Beclin-1; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D009944:Organoplatinum Compounds; D034741:RNA, Small Interfering; D002945:Cisplatin