PMID- 31228465
OWN - NLM
STAT- MEDLINE
DCOM- 20200713
LR  - 20231013
IS  - 1873-2968 (Electronic)
IS  - 0006-2952 (Print)
IS  - 0006-2952 (Linking)
VI  - 168
DP  - 2019 Oct
TI  - Enterobactin, an iron chelating bacterial siderophore, arrests cancer cell 
      proliferation.
PG  - 71-81
LID - S0006-2952(19)30236-9 [pii]
LID - 10.1016/j.bcp.2019.06.017 [doi]
AB  - Iron is essential for many biological functions, including being a cofactor for 
      enzymes involved in cell proliferation. In line, it has been shown that cancer 
      cells can perturb their iron metabolism towards retaining an abundant iron supply 
      for growth and survival. Accordingly, it has been suggested that iron deprivation 
      through the use of iron chelators could attenuate cancer progression. While they 
      have exhibited anti-tumor properties in vitro, the current therapeutic iron 
      chelators are inadequate due to their low efficacy. Therefore, we investigated 
      whether the bacterial catecholate-type siderophore, enterobactin (Ent), could be 
      used as a potent anti-cancer agent given its strong iron chelation property. We 
      demonstrated that iron-free Ent can exert cytotoxic effects specifically towards 
      monocyte-related tumor cell lines (RAW264.7 and J774A.1), but not primary cells, 
      i.e. bone marrow-derived macrophages (BMDMs), through two mechanisms. First, we 
      observed that RAW264.7 and J774A.1 cells preserve a bountiful intracellular 
      labile iron pool (LIP), whose homeostasis can be disrupted by Ent. This may be 
      due, in part, to the lower levels of lipocalin 2 (Lcn2; an Ent-binding protein) 
      in these cell lines, whereas the higher levels of Lcn2 in BMDMs could prevent Ent 
      from hindering their LIP. Secondly, we observed that Ent could dose-dependently 
      impede reactive oxygen species (ROS) generation in the mitochondria. Such 
      disruption in LIP balance and mitochondrial function may in turn promote cancer 
      cell apoptosis. Collectively, our study highlights Ent as an anti-cancer 
      siderophore, which can be exploited as an unique agent for cancer therapy.
CI  - Copyright (c) 2019 Elsevier Inc. All rights reserved.
FAU - Saha, Piu
AU  - Saha P
AD  - Department of Physiology & Pharmacology, University of Toledo College of Medicine 
      and Life Sciences, Toledo, OH 43614, USA.
FAU - Yeoh, Beng San
AU  - Yeoh BS
AD  - Graduate Program in Immunology & Infectious Disease, The Pennsylvania State 
      University, University Park, PA 16802, USA.
FAU - Xiao, Xia
AU  - Xiao X
AD  - Division of Nephrology, MGH, Harvard Medical School, Boston, MA 02114, USA.
FAU - Golonka, Rachel M
AU  - Golonka RM
AD  - Department of Physiology & Pharmacology, University of Toledo College of Medicine 
      and Life Sciences, Toledo, OH 43614, USA.
FAU - Kumarasamy, Sivarajan
AU  - Kumarasamy S
AD  - Department of Physiology & Pharmacology, University of Toledo College of Medicine 
      and Life Sciences, Toledo, OH 43614, USA.
FAU - Vijay-Kumar, Matam
AU  - Vijay-Kumar M
AD  - Department of Physiology & Pharmacology, University of Toledo College of Medicine 
      and Life Sciences, Toledo, OH 43614, USA; Department of Medical Microbiology and 
      Immunology, University of Toledo College of Medicine and Life Sciences, Toledo, 
      OH 43614, USA. Electronic address: MatamVijay.Kumar@Utoledo.edu.
LA  - eng
GR  - R01 DK097865/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20190619
PL  - England
TA  - Biochem Pharmacol
JT  - Biochemical pharmacology
JID - 0101032
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Lipocalin-2)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Siderophores)
RN  - 126469-30-5 (Lcn2 protein, mouse)
RN  - 28384-96-5 (Enterobactin)
RN  - E1UOL152H7 (Iron)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/*pharmacology
MH  - Apoptosis/drug effects
MH  - Cell Proliferation/*drug effects
MH  - Cell Survival/drug effects
MH  - Enterobactin/*pharmacology
MH  - Escherichia coli/chemistry
MH  - Homeostasis/drug effects
MH  - Iron/metabolism
MH  - Lipocalin-2/metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mitochondria/drug effects/metabolism
MH  - RAW 264.7 Cells
MH  - Reactive Oxygen Species/metabolism
MH  - Siderophores/*pharmacology
PMC - PMC6733644
MID - NIHMS1532654
OTO - NOTNLM
OT  - Deferoxamine
OT  - Enterochelin
OT  - Labile iron pool
OT  - Lipocalin 2
OT  - Mitochondrial respiration
COIS- Conflicts of interest The authors declare that they have no conflicts of interest 
      with the contents of this article.
EDAT- 2019/06/23 06:00
MHDA- 2020/07/14 06:00
PMCR- 2020/10/01
CRDT- 2019/06/23 06:00
PHST- 2019/04/26 00:00 [received]
PHST- 2019/06/17 00:00 [accepted]
PHST- 2019/06/23 06:00 [pubmed]
PHST- 2020/07/14 06:00 [medline]
PHST- 2019/06/23 06:00 [entrez]
PHST- 2020/10/01 00:00 [pmc-release]
AID - S0006-2952(19)30236-9 [pii]
AID - 10.1016/j.bcp.2019.06.017 [doi]
PST - ppublish
SO  - Biochem Pharmacol. 2019 Oct;168:71-81. doi: 10.1016/j.bcp.2019.06.017. Epub 2019 
      Jun 19.