Iron (II) Polypyridyl Complexes as Antiglioblastoma Agents to Overcome the Blood-Brain Barrier and Inhibit Cell Proliferation by Regulating p53 and 4E-BP1 Pathways

Background and Purpose: It is urgently required to develop promising candidates to permeate across blood-brain barrier (BBB) efficiently with simultaneous disrupting vasculogenic mimicry capability of gliomas. Previously, a series of iron (II) complexes were synthesized through a modified method. Hence, the aim of this study was to evaluate anticancer activity of Fe(PIP)(3)SO(4) against glioma cancer cells. Methods: Cytotoxic effects were determined via MTT assay, and IC(50) values were utilized to evaluate the cytotoxicity. Cellular uptake of Fe(PIP)(3)SO(4) between U87 and HEB cells was conducted by subtracting content of the complex remaining in the cell culture supernatants. Propidium Iodide (PI)-flow cytometric analysis was used to analyze cell cycle proportion of U87 cells treated with Fe(PIP)(3)SO(4). The reactive oxygen species levels induced by Fe(PIP)(3)SO(4) were measured by 2'-deoxycoformycin (DCF) probe; ABTS assay was utilized to examine the radical scavenge capacity of Fe(PIP)(3)SO(4). To study the bind efficiency to thioredoxin reductase (TrxR), Fe(PIP)(3)SO(4) was introduced into solution containing TrxR. To verify if Fe(PIP)(3)SO(4) could penetrate BBB, HBMEC/U87 coculture as BBB model was established, and penetrating capability of Fe(PIP)(3)SO(4) was tested. In vitro U87 tumor spheroids were formed to test the permeating ability of Fe(PIP)(3)SO(4). Acute toxicity and biodistribution of Fe(PIP)(3)SO(4) were tested on mice for 72 h. Protein profiles associated with U87 cells treated with Fe(PIP)(3)SO(4) were determined by Western blotting analysis. Results: Results showed that Fe(PIP)(3)SO(4) could suppress cell proliferation by inducing G2/M phase cycle retardation and apoptotic pathways, which was related with expression of p53 and initiation factor 4E binding protein 1. In addition, Fe complex could suppress cell proliferation by downregulating reactive oxygen species levels via scavenging free radicals and interaction with TrxR. Furthermore, Fe(PIP)(3)SO(4) could permeate across BBB and simultaneously inhibited the vasculogenic mimicry-channel of U87 cells, suggesting favorable antiglioblastoma efficacy. Acute toxicity manifested lower degree of the complex compared with cisplatin and temozolomide. Conclusion: Fe(PIP)(3)SO(4) exhibited favorable anticancer activity against glioma cells associated with p53 and 4E binding protein 1, accompanied with negligible toxic effects on normal tissues. Herein, Fe(PIP)(3)SO(4) could be developed as a promising metal-based chemotherapeutic agent to overcome BBB and antagonize glioblastomas.