AUTHOR=Zhu Huili , Dai Chengli , He Lizhen , Xu Anding , Chen Tianfeng TITLE=Iron (II) Polypyridyl Complexes as Antiglioblastoma Agents to Overcome the Blood-Brain Barrier and Inhibit Cell Proliferation by Regulating p53 and 4E-BP1 Pathways JOURNAL=Frontiers in Pharmacology VOLUME=10 YEAR=2019 URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2019.00946 DOI=10.3389/fphar.2019.00946 ISSN=1663-9812 ABSTRACT=

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)₃SO₄ against glioma cancer cells.

Methods: Cytotoxic effects were determined via MTT assay, and IC₅₀ values were utilized to evaluate the cytotoxicity. Cellular uptake of Fe(PIP)₃SO₄ 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)₃SO₄. The reactive oxygen species levels induced by Fe(PIP)₃SO₄ were measured by 2'-deoxycoformycin (DCF) probe; ABTS assay was utilized to examine the radical scavenge capacity of Fe(PIP)₃SO₄. To study the bind efficiency to thioredoxin reductase (TrxR), Fe(PIP)₃SO₄ was introduced into solution containing TrxR. To verify if Fe(PIP)₃SO₄ could penetrate BBB, HBMEC/U87 coculture as BBB model was established, and penetrating capability of Fe(PIP)₃SO₄ was tested. In vitro U87 tumor spheroids were formed to test the permeating ability of Fe(PIP)₃SO₄. Acute toxicity and biodistribution of Fe(PIP)₃SO₄ were tested on mice for 72 h. Protein profiles associated with U87 cells treated with Fe(PIP)₃SO₄ were determined by Western blotting analysis.

Results: Results showed that Fe(PIP)₃SO₄ 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)₃SO₄ 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)₃SO₄ 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)₃SO₄ could be developed as a promising metal-based chemotherapeutic agent to overcome BBB and antagonize glioblastomas.