Effects of an irinotecan derivative, ZBH-1208, on the immune system in a mouse model of brain tumor and its antitumor mechanism
MOLECULAR MEDICINE REPORTS
Authors: Hui, Yuzuo; Gao, Zhiyu; Ren, Songtao; Wang, Yunhua; Ma, Xiaoping
Abstract
The present study aimed to evaluate the inhibitory effects of an irinotecan derivative, ZBH-1208, on brain tumors, and to explore the underlying molecular mechanisms. To determine the effects of ZBH-1208, a brain tumor mouse model was established by transplanting B22 cells. Subsequently, the visceral indices of immune organs and white blood cell counts were determined, and the effects of ZBH-1208 on the expression levels of cell cycle-related proteins were assessed by western blotting. The tumor inhibition rates of 20 and 40 mg/kg ZBH-1208 were 11.7 and 54.1%, respectively. Compared with the negative control group, ZBH-1208 barely affected visceral indices or white blood cell count. Furthermore, the expression levels of p53, p21, cyclin-dependent kinase 7 (CDK7), Wee1, phosphorylated (p)-cell division cycle 2 (CDC2) (Tyr15), p-CDC2 (Thr161) and cyclin B1 proteins were upregulated, whereas the expression levels of cyclin E were downregulated, and those of CDC2, CDK2 and CDC25C were barely altered. In conclusion, the present study demonstrated that ZBH-1208 suppressed the growth of B22 mouse brain tumor xenografts, but did not affect their visceral indices or white blood cell counts. It was suggested that ZBH-1208 exerted its effects by regulating the expression of p53, p21, Wee1, p-CDC2 (Tyr15) and cyclin E proteins.
Investigation of the cytotoxic effect of flavopiridol in canine lymphoma cell lines
VETERINARY AND COMPARATIVE ONCOLOGY
Authors: Ema, Y.; Igase, M.; Takeda, Y.; Yanase, T.; Umeki, S.; Hiraoka, H.; Okuda, M.; Mizuno, T.
Abstract
The cyclin-dependent kinase (CDK) inhibitor, flavopiridol, was tested as a potential new cancer therapeutic agent to treat canine lymphoma by examining its effect on cell growth of canine lymphoma cell lines in vitro. Flavopiridol induced profound cell death in all eight lymphoma cell lines at 400 nM, and in all cases cell death was due to apoptosis. Apoptosis was inhibited by caspase inhibitor, despite the variable sensitivities between cell lines. Analysis of the mechanism of flavopiridol-induced apoptosis showed that Rb phosphorylation was inhibited, possibly due to CDK4 or CDK6 inhibition. There was also decreased expression of Rb protein and anti-apoptotic proteins, Mcl-1 and XIAP, possibly through transcriptional regulation by inhibition of CDK7 or CDK9 activation. Canine lymphoma cell line-xenotransplanted mice were then treated with flavopiridol and profound tumour shrinkage was observed. This study describes a new therapeutic approach using flavopiridol for canine lymphoma treatment.