Iron chelation cancer therapy using hydrophilic block copolymers conjugated with deferoxamine

Komoto, Kana; Nomoto, Takahiro; Muttaqien, Sjaikhurrizal El; Takemoto, Hiroyuki; Matsui, Makoto; Miura, Yutaka; Nishiyama, Nobuhiro

doi:10.1111/cas.14607

Cited by 41 publications

(57 citation statements)

References 57 publications

(117 reference statements)

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“…In another recent study, Komoto et al [ 154 ] revealed the first success of the design of polymeric DFO for the enhancement of iron chelation cancer therapy. They developed polymeric DFO by the covalent conjugation of DFO to poly(ethylene glycol)poly(aspartic acid) (PEGPAsp) block copolymers.…”

Section: Combined Therapy With More Than One Chelatormentioning

confidence: 99%

Iron Chelators in Treatment of Iron Overload

Entezari

Haghi

Norouzkhani

et al. 2022

Journal of Toxicology

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Patients suffering from iron overload can experience serious complications. In such patients, various organs, such as endocrine glands and liver, can be damaged. Although iron is a crucial element for life, iron overload can be potentially toxic for human cells due to its role in generating free radicals. In the past few decades, there has been a major improvement in the survival of patients who suffer from iron overload due to the application of iron chelation therapy in clinical practice. In clinical use, deferoxamine, deferiprone, and deferasirox are the three United States Food and Drug Administration-approved iron chelators. Each of these iron chelators is well known for the treatment of iron overload in various clinical conditions. Based on several up-to-date studies, this study explained iron overload and its clinical symptoms, introduced each of the above-mentioned iron chelators, and evaluated their advantages and disadvantages with an emphasis on combination therapy, which in recent studies seems a promising approach. In numerous clinical conditions, due to the lack of accurate indicators, choosing a standard approach for iron chelation therapy can be difficult; therefore, further studies on the issue are still required. This study aimed to introduce each of these iron chelators, combination therapy, usage doses, specific clinical applications, and their advantages, toxicity, and side effects.

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Section: Combined Therapy With More Than One Chelatormentioning

confidence: 99%

Iron Chelators in Treatment of Iron Overload

Entezari

Haghi

Norouzkhani

et al. 2022

Journal of Toxicology

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“…DFO is also capable of inhibiting hRR activity by chelating Fe III , forming a 1:1 ligand–metal complex [ 218 ]. While DFO does not directly affect the hRRM2 subunit, sequestration of intracellular iron prevents the activation and regeneration of the tyrosyl radical center, thus inhibiting hRR activity [ 219 , 220 , 221 ]. This inhibition is reversible with the addition of iron and appears to affect p53R2 more potently than hRRM2.…”

Section: Non-nucleoside Inhibitors Of Hrrm2mentioning

confidence: 99%

Inhibitors of the Cancer Target Ribonucleotide Reductase, Past and Present

2022

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Ribonucleotide reductase (RR) is an essential multi-subunit enzyme found in all living organisms; it catalyzes the rate-limiting step in dNTP synthesis, namely, the conversion of ribonucleoside diphosphates to deoxyribonucleoside diphosphates. As expression levels of human RR (hRR) are high during cell replication, hRR has long been considered an attractive drug target for a range of proliferative diseases, including cancer. While there are many excellent reviews regarding the structure, function, and clinical importance of hRR, recent years have seen an increase in novel approaches to inhibiting hRR that merit an updated discussion of the existing inhibitors and strategies to target this enzyme. In this review, we discuss the mechanisms and clinical applications of classic nucleoside analog inhibitors of hRRM1 (large catalytic subunit), including gemcitabine and clofarabine, as well as inhibitors of the hRRM2 (free radical housing small subunit), including triapine and hydroxyurea. Additionally, we discuss novel approaches to targeting RR and the discovery of new classes of hRR inhibitors.

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“…DFO binds Fe 3+ within cells or free plasma Fe 3+ , creating a complex (ferrioxamine) that is redox and metabolically inert [ 36 ]. Once DFO binds intracellular iron [ 49 ], it is then released from cells and excreted primarily in the urine, with a small component entering the bile and feces, resulting in whole-body iron depletion [ 50 ]. While DFO has been demonstrated to inhibit neuroblastoma cell lines in vitro [ 36 , 47 ], it is less effective in vivo due to its rapid metabolism and poor lipophilicity, which limits its ability to enter cells [ 36 ].…”

Section: Cancer Therapy Using the Metal-binding Ligands Dfo And Thiosemicarbazones Dp44mt And Dpcmentioning

confidence: 99%

The Oncogenic Signaling Disruptor, NDRG1: Molecular and Cellular Mechanisms of Activity

Chekmarev

Azad

Richardson

2021

Cells

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NDRG1 is an oncogenic signaling disruptor that plays a key role in multiple cancers, including aggressive pancreatic tumors. Recent studies have indicated a role for NDRG1 in the inhibition of multiple tyrosine kinases, including EGFR, c-Met, HER2 and HER3, etc. The mechanism of activity of NDRG1 remains unclear, but to impart some of its functions, NDRG1 binds directly to key effector molecules that play roles in tumor suppression, e.g., MIG6. More recent studies indicate that NDRG1s-inducing drugs, such as novel di-2-pyridylketone thiosemicarbazones, not only inhibit tumor growth and metastasis but also fibrous desmoplasia, which leads to chemotherapeutic resistance. The Casitas B-lineage lymphoma (c-Cbl) protein may be regulated by NDRG1, and is a crucial E3 ligase that regulates various protein tyrosine and receptor tyrosine kinases, primarily via ubiquitination. The c-Cbl protein can act as a tumor suppressor by promoting the degradation of receptor tyrosine kinases. In contrast, c-Cbl can also promote tumor development by acting as a docking protein to mediate the oncogenic c-Met/Crk/JNK and PI3K/AKT pathways. This review hypothesizes that NDRG1 could inhibit the oncogenic function of c-Cbl, which may be another mechanism of its tumor-suppressive effects.

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Iron chelation cancer therapy using hydrophilic block copolymers conjugated with deferoxamine

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Cited by 41 publications

References 57 publications

Iron Chelators in Treatment of Iron Overload

Iron Chelators in Treatment of Iron Overload

Inhibitors of the Cancer Target Ribonucleotide Reductase, Past and Present

The Oncogenic Signaling Disruptor, NDRG1: Molecular and Cellular Mechanisms of Activity

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