Disulfide-masked iron prochelators: Effects on cell death, proliferation, and hemoglobin production

E. A. Akam, R. D. Utterback, J. R. Marcero, H. A. Dailey, Elisa Tomat

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

The iron metabolism of malignant cells, which is altered to ensure higher acquisition and utilization, motivates the investigation of iron chelation strategies in cancer treatment. In a prochelation approach aimed at increasing intracellular specificity, disulfide reduction/activation switches are incorporated on iron-binding scaffolds resulting in intracellularly activated scavengers. Herein, this strategy is applied to several tridentate donor sets including thiosemicarbazones, aroylhydrazones and semicarbazones. The novel prochelator systems are antiproliferative in breast adenocarcinoma cell lines (MCF-7 and metastatic MDA-MB-231) and do not result in the intracellular generation of oxidative stress. Consistent with iron deprivation, the tested prochelators lead to cell-cycle arrest at the G1/S interface and induction of apoptosis. Notably, although hemoglobin-synthesizing blood cells have the highest iron need in the human body, no significant impact on hemoglobin production was observed in the MEL (murine erythroleukemia) model of differentiating erythroid cells. This study provides new information on the intracellular effects of disulfide-based prochelators and indicates aroylhydrazone (AH1-S)2 as a promising prototype of a new class of antiproliferative prochelator systems.

Original languageEnglish (US)
Pages (from-to)186-193
Number of pages8
JournalJournal of Inorganic Biochemistry
Volume180
DOIs
StatePublished - Mar 1 2018

Fingerprint

Cell death
Disulfides
Hemoglobins
Cell Death
Iron
Cell Proliferation
Cells
Semicarbazones
Thiosemicarbazones
G1 Phase Cell Cycle Checkpoints
Leukemia, Erythroblastic, Acute
Erythroid Cells
Oxidative stress
Oncology
Chelation
Human Body
Metabolism
Scaffolds
Blood Cells
Adenocarcinoma

Keywords

  • Anticancer
  • Cell-cycle arrest
  • Hemoglobin production
  • Iron
  • Prochelator

ASJC Scopus subject areas

  • Biochemistry
  • Inorganic Chemistry

Cite this

Disulfide-masked iron prochelators : Effects on cell death, proliferation, and hemoglobin production. / Akam, E. A.; Utterback, R. D.; Marcero, J. R.; Dailey, H. A.; Tomat, Elisa.

In: Journal of Inorganic Biochemistry, Vol. 180, 01.03.2018, p. 186-193.

Research output: Contribution to journalArticle

Akam, E. A. ; Utterback, R. D. ; Marcero, J. R. ; Dailey, H. A. ; Tomat, Elisa. / Disulfide-masked iron prochelators : Effects on cell death, proliferation, and hemoglobin production. In: Journal of Inorganic Biochemistry. 2018 ; Vol. 180. pp. 186-193.
@article{cd23ebb880bf48f5b64927364029c3f8,
title = "Disulfide-masked iron prochelators: Effects on cell death, proliferation, and hemoglobin production",
abstract = "The iron metabolism of malignant cells, which is altered to ensure higher acquisition and utilization, motivates the investigation of iron chelation strategies in cancer treatment. In a prochelation approach aimed at increasing intracellular specificity, disulfide reduction/activation switches are incorporated on iron-binding scaffolds resulting in intracellularly activated scavengers. Herein, this strategy is applied to several tridentate donor sets including thiosemicarbazones, aroylhydrazones and semicarbazones. The novel prochelator systems are antiproliferative in breast adenocarcinoma cell lines (MCF-7 and metastatic MDA-MB-231) and do not result in the intracellular generation of oxidative stress. Consistent with iron deprivation, the tested prochelators lead to cell-cycle arrest at the G1/S interface and induction of apoptosis. Notably, although hemoglobin-synthesizing blood cells have the highest iron need in the human body, no significant impact on hemoglobin production was observed in the MEL (murine erythroleukemia) model of differentiating erythroid cells. This study provides new information on the intracellular effects of disulfide-based prochelators and indicates aroylhydrazone (AH1-S)2 as a promising prototype of a new class of antiproliferative prochelator systems.",
keywords = "Anticancer, Cell-cycle arrest, Hemoglobin production, Iron, Prochelator",
author = "Akam, {E. A.} and Utterback, {R. D.} and Marcero, {J. R.} and Dailey, {H. A.} and Elisa Tomat",
year = "2018",
month = "3",
day = "1",
doi = "10.1016/j.jinorgbio.2017.12.016",
language = "English (US)",
volume = "180",
pages = "186--193",
journal = "Journal of Inorganic Biochemistry",
issn = "0162-0134",
publisher = "Elsevier Inc.",

}

TY - JOUR

T1 - Disulfide-masked iron prochelators

T2 - Effects on cell death, proliferation, and hemoglobin production

AU - Akam, E. A.

AU - Utterback, R. D.

AU - Marcero, J. R.

AU - Dailey, H. A.

AU - Tomat, Elisa

PY - 2018/3/1

Y1 - 2018/3/1

N2 - The iron metabolism of malignant cells, which is altered to ensure higher acquisition and utilization, motivates the investigation of iron chelation strategies in cancer treatment. In a prochelation approach aimed at increasing intracellular specificity, disulfide reduction/activation switches are incorporated on iron-binding scaffolds resulting in intracellularly activated scavengers. Herein, this strategy is applied to several tridentate donor sets including thiosemicarbazones, aroylhydrazones and semicarbazones. The novel prochelator systems are antiproliferative in breast adenocarcinoma cell lines (MCF-7 and metastatic MDA-MB-231) and do not result in the intracellular generation of oxidative stress. Consistent with iron deprivation, the tested prochelators lead to cell-cycle arrest at the G1/S interface and induction of apoptosis. Notably, although hemoglobin-synthesizing blood cells have the highest iron need in the human body, no significant impact on hemoglobin production was observed in the MEL (murine erythroleukemia) model of differentiating erythroid cells. This study provides new information on the intracellular effects of disulfide-based prochelators and indicates aroylhydrazone (AH1-S)2 as a promising prototype of a new class of antiproliferative prochelator systems.

AB - The iron metabolism of malignant cells, which is altered to ensure higher acquisition and utilization, motivates the investigation of iron chelation strategies in cancer treatment. In a prochelation approach aimed at increasing intracellular specificity, disulfide reduction/activation switches are incorporated on iron-binding scaffolds resulting in intracellularly activated scavengers. Herein, this strategy is applied to several tridentate donor sets including thiosemicarbazones, aroylhydrazones and semicarbazones. The novel prochelator systems are antiproliferative in breast adenocarcinoma cell lines (MCF-7 and metastatic MDA-MB-231) and do not result in the intracellular generation of oxidative stress. Consistent with iron deprivation, the tested prochelators lead to cell-cycle arrest at the G1/S interface and induction of apoptosis. Notably, although hemoglobin-synthesizing blood cells have the highest iron need in the human body, no significant impact on hemoglobin production was observed in the MEL (murine erythroleukemia) model of differentiating erythroid cells. This study provides new information on the intracellular effects of disulfide-based prochelators and indicates aroylhydrazone (AH1-S)2 as a promising prototype of a new class of antiproliferative prochelator systems.

KW - Anticancer

KW - Cell-cycle arrest

KW - Hemoglobin production

KW - Iron

KW - Prochelator

UR - http://www.scopus.com/inward/record.url?scp=85040372203&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85040372203&partnerID=8YFLogxK

U2 - 10.1016/j.jinorgbio.2017.12.016

DO - 10.1016/j.jinorgbio.2017.12.016

M3 - Article

C2 - 29324291

AN - SCOPUS:85040372203

VL - 180

SP - 186

EP - 193

JO - Journal of Inorganic Biochemistry

JF - Journal of Inorganic Biochemistry

SN - 0162-0134

ER -