Polynuclear platinum anticancer drugs are more potent than cisplatin and induce cell cycle arrest in glioma1

Abstract

We have evaluated the efficacy of the multinuclear platinum chemotherapeutics BBR3464, BBR3571, and BBR3610 against glioma cells in culture and animal models and investigated their mechanism of action at the cellular level. In a clonogenic assay, BBR3610, the most potent compound, had an IC90 dose (achieving 90% colony formation inhibition) that was 250 times lower than that of cisplatin for both LNZ308 and LN443 glioma cells. In subcutaneous xenografts of U87MG glioma cells, BBR3610 approximately doubled the time it took for a tumor to reach a predetermined size and significantly extended survival when these cells were implanted intracranially. Analysis of apoptosis and cell cycle distribution showed that BBR compounds induced G2/M arrest in the absence of cell death, while cisplatin predominantly induced apoptosis. Interestingly, the BBR compounds and cisplatin both induced extracellular signal-regulated kinase 1/2 phosphorylation, and inhibition of this pathway at the level of MEK antagonized the induction of G2/M arrest or apoptosis, respectively. Analysis of Chk1 and Chk2 status did not show any differential effects of the drugs, and it is thus unlikely to underlie the difference in response. Similarly, the drugs did not differentially modulate survivin levels, and knockdown of survivin did not convert the response to BBR3610 to apoptosis. Together, these findings support continued development of BBR3610 for clinical use against glioma and provide a framework for future investigation of mechanism of action.

Apigenin enhances the cisplatin cytotoxic effect through p53-modulated apoptosis

“…Cisplatin is a member of a class of platinum-containing anticancer drugs, which has demonstrated therapeutic properties against a broad range of cancers (19,20). Cisplatin exerts a DNA-binding effect by cross-linking DNA in several different ways, interfering with mitotic cell division.…”

Low-Dose BBR3610 Toxicity in Colon Cancer Cells Is p53-Independent and Enhanced by Inhibition of Epidermal Growth Factor Receptor (ERBB1)-Phosphatidyl Inositol 3 Kinase Signaling

“…Previous studies using mononuclear platinum agents and BBR3464 have correlated platinum agent-induced ERK1/2 activation to a proapoptotic response, with many of these studies using the MEK1/2/5 inhibitors PD98059 and U0126 (Billecke et al, 2006). Using the more specific MEK1/2 inhibitor PD184352 and molecular approaches, we now show that small-molecule inhibition of the RAF-ERK1/2 pathway at the time of platinum-agent exposure enhanced BBR3610 lethality in HCT116 cells in a p53-dependent fashion.…”

“…BBR3610 treatment of glioma cells caused more killing in vitro on a molar basis than BBR3464. Cell killing correlated with a G 2 /M cell cycle arrest, which was in part dependent on enhanced ERK1/2 signaling (Billecke et al, 2006).…”

Polyethylene glycol‐polyethylenimine‐tetrachloroplatinum (IV): A novel conjugate with good abilities of antitumor and gene delivery

“…[3][4][5] Polynuclear platinum anticancer drugs demonstrate high activity in a broad spectrum of human tumors commonly insensitive to chemotherapy, such as nonsmall-cell lung cancer, gastric cancer and glioma. [6][7][8] Polyethylenimine (PEI), one kind of the nonviral gene delivery vectors, has shown high transfection efficiency both in vitro and in vivo. 9,10 However, the transfection efficiency and cytotoxicity of PEI is dependent on its molecular weight.…”