Novel ROS-activated agents utilize a tethered amine to selectively target acute myeloid leukemia

Bell-Horwath, Tiffany R.; Vadukoot, Anish K.; Thowfeik, Fathima Shazna; Li, Guorui; Wunderlich, Mark; Mulloy, James C.; Merino, Edward J.

doi:10.1016/j.bmcl.2013.03.048

Cited by 14 publications

(11 citation statements)

References 27 publications

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“…Cytotoxicity analysis was carried out as previously described. [6] All R values were greater than 0.98, and standard errors of the three biological replicates were less than 20%. Unless otherwise stated, all RAC1 incubations occurred at 2 µ m for 24 h.…”

Section: Methodsmentioning

confidence: 99%

“…[5] We used an alternative and complementary approach based on selective activation by reactive oxygen species (ROS) to design next-generation smart DNA modifiers, termed ROS-activated cytotoxic agents (RACs). [6, 7] In this manuscript, we investigate the role and mechanism of DNA repair in treated cells to better understand the DNA modifying action of these novel RAC agents (Figure 1). …”

Section: Introductionmentioning

confidence: 99%

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A ROS‐Activatable Agent Elicits Homologous Recombination DNA Repair and Synergizes with Pathway Compounds

et al. 2015

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We designed ROS-activated cytotoxic agents (RACs) that are active against AML cancer cells. In this study, the mechanism of action and synergistic effects against cells coexpressing the AML oncogenes MLL-AF9 fusion and FLT3-ITD were investigated. One RAC (RAC1) had an IC50 value of 1.8 ± 0.3 µm, with ninefold greater selectivity for transformed cells compared to untransformed cells. Treatment induced DNA strand breaks, apoptosis, and cell cycle arrest. Proteomics and transcriptomics revealed enhanced expression of the pentose phosphate pathway, DNA repair, and pathways common to cell stress. Western blotting confirmed repair by homologous recombination. Importantly, RAC1 treatment was synergistic in combination with multiple pathway-targeting therapies in AML cells but less so in untransformed cells. Together, these results demonstrate that RAC1 can selectively target poor prognosis AML and that it does so by creating DNA double-strand breaks that require homologous recombination.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A ROS‐Activatable Agent Elicits Homologous Recombination DNA Repair and Synergizes with Pathway Compounds

et al. 2015

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“…135,136 We have shown that one agent is highly active and selective toward leukemia cells. Biochemical evaluation of these leukemia cells showed that levels of the catalase antioxidant enzyme are reduced compared to those of untransformed cells.…”

Section: Ros-targeted Anticancer Agentsmentioning

confidence: 99%

Excessive Reactive Oxygen Species and Exotic DNA Lesions as an Exploitable Liability

2016

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Although the terms “excessive reactive oxygen species (ROS)” and “oxidative stress” are widely used, the implications of oxidative stress are often misunderstood. ROS are not a single species but a variety of compounds, each with unique biochemical properties and abilities to react with biomolecules. ROS cause activation of growth signals through thiol oxidation and may lead to DNA damage at elevated levels. In this review, we first discuss a conceptual framework for the interplay of ROS and antioxidants. This review then describes ROS signaling using FLT3-mediated growth signaling as an example. We then focus on ROS-mediated DNA damage. High concentrations of ROS result in various DNA lesions, including 8-oxo-7,8-dihydro-guanine, oxazolone, DNA–protein cross-links, and hydantoins, that have unique biological impacts. Here we delve into the biochemistry of nine well-characterized DNA lesions. Within each lesion, the types of repair mechanisms, the mutations induced, and their effects on transcription and replication are discussed. Finally, this review will discuss biochemically inspired implications for cancer therapy. Several teams have put forward designs to harness the excessive ROS and the burdened DNA repair systems of tumor cells for treating cancer. We discuss inhibition of the antioxidant system, the targeting of DNA repair, and ROS-activated prodrugs.

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“…In this manuscript we have designed novel pro-drugs that are unreactive until oxidized by hydrogen peroxide. Once oxidized, the molecules, like the two natural products, are capable of a conjugate addition reaction 9,19 .…”

Section: Introductionmentioning

confidence: 99%

“…A recent manuscript shows that induction of novel adducts changes anti-cancer activity and targets cancers 22 . The previous agents we designed possess mid-nanomolar activity against some tumor cells and up to 10-fold selectivity for AML cells 8,9 . Upon oxidation, the compound reacts by 1,2-addition with an amine identified as essential.…”

Section: Introductionmentioning

confidence: 99%

Design of a hydrogen peroxide-activatable agent that specifically targets cancer cells

Vadukoot

AbdulSalam

Wunderlich

et al. 2014

Bioorganic & Medicinal Chemistry

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Some cancers, like acute myeloid leukemia (AML), use reactive oxygen species to endogenously activate cell proliferation and angiogenic signaling cascades. Thus many cancers display increases in reactive oxygen like hydrogen peroxide concentrations. To translate this finding into a therapeutic strategy we designed new hydrogen peroxide-activated agents with two key molecular pharmacophores. The first pharmacophore is a peroxide-acceptor and the second is a pendant amine. The acceptor is an N-(2,5-dihydroxyphenyl)acetamide susceptible to hydrogen peroxide oxidation. We hypothesized that selectivity between AML and normal cells could be achieved by tuning the pendant amine. Synthesis and testing of fourteen compounds that differed at the pendent amine led to the identification of an agent (14) with 2 μM activity against AML cancer cells and an eleven fold-lower activity in healthy CD34+ blood stem cells. Interestingly, analysis shows that upon oxidation the pendant amine cyclizes, ejecting water, with the acceptor to give a bicyclic compound capable of reacting with nucleophiles. Preliminary mechanistic investigations show that AML cells made from addition of two oncogenes (NrasG12D and MLL-AF9) increase the ROS-status, is initially an anti-oxidant as hydrogen peroxide is consumed to activate the pro-drug, and cells respond by upregulating electrophilic defense as visualized by western blotting of KEAP1. Thus, using this chemical approach we have obtained a simple, potent, and selective ROS-activated anti-AML agent.

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Novel ROS-activated agents utilize a tethered amine to selectively target acute myeloid leukemia

Cited by 14 publications

References 27 publications

A ROS‐Activatable Agent Elicits Homologous Recombination DNA Repair and Synergizes with Pathway Compounds

A ROS‐Activatable Agent Elicits Homologous Recombination DNA Repair and Synergizes with Pathway Compounds

Excessive Reactive Oxygen Species and Exotic DNA Lesions as an Exploitable Liability

Design of a hydrogen peroxide-activatable agent that specifically targets cancer cells

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