ROS‐Inducible DNA Cross‐Linking Agent as a New Anticancer Prodrug Building Block

Cao, Sheng; Wang, Yibin; Peng, Xiaohua

doi:10.1002/chem.201200075

Cited by 78 publications

(104 citation statements)

References 78 publications

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“…On the other hand, recently studies showed that the cytotoxicity of alkylating reagents can be enhanced by ROS, by formation of ROS-activated prodrugs resulting in higher DNA crosslink activity. Peng's group revealed that the prodrugs of nitrogen mustard coupled with an ROS trigger unit can be triggered by H 2 O 2 to release active anticancer drugs with higher DNA crosslink activities, leading to selective toxicity toward primary leukemic lymphocytes but less toxic to normal lymphocytes [32], [33], [34], [35], [36]. In this study, we found that ROS induced by SC-514 enhanced nitrosoureas-induced DNA crosslink and cytotoxicity (Fig.…”

Section: Discussionmentioning

confidence: 54%

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Sensitization of melanoma cells to alkylating agent-induced DNA damage and cell death via orchestrating oxidative stress and IKKβ inhibition

Tse

Chen

et al. 2017

Redox Biology

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Nitrosourea represents one of the most active classes of chemotherapeutic alkylating agents for metastatic melanoma. Treatment with nitrosoureas caused severe systemic side effects which hamper its clinical use. Here, we provide pharmacological evidence that reactive oxygen species (ROS) induction and IKKβ inhibition cooperatively enhance nitrosourea-induced cytotoxicity in melanoma cells. We identified SC-514 as a ROS-inducing IKKβ inhibitor which enhanced the function of nitrosoureas. Elevated ROS level results in increased DNA crosslink efficiency triggered by nitrosoureas and IKKβ inhibition enhances DNA damage signals and sensitizes nitrosourea-induced cell death. Using xenograft mouse model, we confirm that ROS-inducing IKKβ inhibitor cooperates with nitrosourea to reduce tumor size and malignancy in vivo. Taken together, our results illustrate a new direction in nitrosourea treatment, and reveal that the combination of ROS-inducing IKKβ inhibitors with nitrosoureas can be potentially exploited for melanoma therapy.

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Section: Discussionmentioning

confidence: 54%

“…Recently studies demonstrated that the cytotoxicity of alkylating reagents can be enhanced by ROS with the effects of enhanced DNA crosslink levels and deleterious DNA damages (e.g., ICL formation or alkylation) [32], [33], [34], [35], [36]. Therefore, we further tested whether ROS would alter the DNA crosslink induced by nitrosoureas.…”

Section: Resultsmentioning

confidence: 98%

Sensitization of melanoma cells to alkylating agent-induced DNA damage and cell death via orchestrating oxidative stress and IKKβ inhibition

Tse

Chen

et al. 2017

Redox Biology

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“…Most relevant to the current study was the design of bisfunctional precursors capable of generating two interrelated QM intermediates (bisQM) in series. These derivatives act as a potent crosslinker of DNA with an enviable ratio of crosslinking to monoalkylation 32,[48][49][50] . The reversible nature of reaction additionally prolongs the effective lifetime of the electrophile many-fold and can maintain interstrand crosslinking while still permitting strand exchange (Fig.…”

Section: Resultsmentioning

confidence: 99%

A walk along DNA using bipedal migration of a dynamic and covalent crosslinker

Fakhari

Rokita

2014

Nat Commun

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DNA has previously served as an excellent scaffold for molecular transport based on its noncovalent base pairing to assemble both stationary and mobile elements. Use of DNA can now be extended to transport systems based on reversible covalent chemistry. Autonomous and bipedal-like migration of crosslinking within helical DNA is made possible by tandem exchange of a quinone methide intermediate. In this report, net transport is illustrated to proceed over 10 base pairs. This process is driven towards its equilibrium distribution of crosslinks and consumes neither the walker nor the track irreversibly. Successful migration requires an electron-rich quinone methide to promote its regeneration and a continuous array of nucleophilic sites along its DNA track. Accordingly, net migration can be dramatically influenced by the presence of noncanonical structures within duplex DNA as demonstrated with a backbone nick and extrahelical bulge.

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“…Previously, we reported that 1a – 3a could be activated by H 2 O 2 to form bifunctional QMs that cross-link DNA, 30,31 whereas H 2 O 2 activation of 1b – 3b did not produce ICL products due to the presence of a poor trimethylamine leaving group, thereby prohibiting QM formation. In contrast, UV irradiation of 3a and 1b – 3b induced DNA ICL formation.…”

mentioning

confidence: 97%

Photochemical Generation of Benzyl Cations That Selectively Cross-Link Guanine and Cytosine in DNA

et al. 2016

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UV irradiation of several aryl boronates efficiently produced bifunctional benzyl cations that selectively form guanine-cytosine cross-links in DNA. Photoinduced homolysis of the C–Br bond took place with the aryl boronate bromides 3a and 4a, generating free radicals that were oxidized to benzyl cations via electron transfer. However, photoirradiation of the quaternary ammonium salts 3b and 4b led to heterolysis of C–N bond, directly producing benzyl cations. The electron-donating group in the aromatic ring greatly enhanced cross-linking efficiency.

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ROS‐Inducible DNA Cross‐Linking Agent as a New Anticancer Prodrug Building Block

Cited by 78 publications

References 78 publications

Sensitization of melanoma cells to alkylating agent-induced DNA damage and cell death via orchestrating oxidative stress and IKKβ inhibition

Sensitization of melanoma cells to alkylating agent-induced DNA damage and cell death via orchestrating oxidative stress and IKKβ inhibition

A walk along DNA using bipedal migration of a dynamic and covalent crosslinker

Photochemical Generation of Benzyl Cations That Selectively Cross-Link Guanine and Cytosine in DNA

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