PMID- 31551768
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20200930
IS  - 1663-9812 (Print)
IS  - 1663-9812 (Electronic)
IS  - 1663-9812 (Linking)
VI  - 10
DP  - 2019
TI  - Iron (II) Polypyridyl Complexes as Antiglioblastoma Agents to Overcome the 
      Blood-Brain Barrier and Inhibit Cell Proliferation by Regulating p53 and 4E-BP1 
      Pathways.
PG  - 946
LID - 10.3389/fphar.2019.00946 [doi]
LID - 946
AB  - 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.
FAU - Zhu, Huili
AU  - Zhu H
AD  - Department of Neurology and Stroke Center, The First Affiliated Hospital, Jinan 
      University, Guangzhou, China.
FAU - Dai, Chengli
AU  - Dai C
AD  - The First Affiliated Hospital and the Department of Chemistry, Jinan University, 
      Guangzhou, China.
FAU - He, Lizhen
AU  - He L
AD  - The First Affiliated Hospital and the Department of Chemistry, Jinan University, 
      Guangzhou, China.
FAU - Xu, Anding
AU  - Xu A
AD  - Department of Neurology and Stroke Center, The First Affiliated Hospital, Jinan 
      University, Guangzhou, China.
FAU - Chen, Tianfeng
AU  - Chen T
AD  - The First Affiliated Hospital and the Department of Chemistry, Jinan University, 
      Guangzhou, China.
LA  - eng
PT  - Journal Article
DEP - 20190903
PL  - Switzerland
TA  - Front Pharmacol
JT  - Frontiers in pharmacology
JID - 101548923
PMC - PMC6733960
OTO - NOTNLM
OT  - 4E-BP1
OT  - blood-brain barrier
OT  - glioblastomas
OT  - iron (II) polypyridyl complex
OT  - metal complex
EDAT- 2019/09/26 06:00
MHDA- 2019/09/26 06:01
PMCR- 2019/09/03
CRDT- 2019/09/26 06:00
PHST- 2019/01/08 00:00 [received]
PHST- 2019/07/24 00:00 [accepted]
PHST- 2019/09/26 06:00 [entrez]
PHST- 2019/09/26 06:00 [pubmed]
PHST- 2019/09/26 06:01 [medline]
PHST- 2019/09/03 00:00 [pmc-release]
AID - 10.3389/fphar.2019.00946 [doi]
PST - epublish
SO  - Front Pharmacol. 2019 Sep 3;10:946. doi: 10.3389/fphar.2019.00946. eCollection 
      2019.