Prodrugs for nitroreductase-based cancer therapy-3: Antitumor activity of the novel dinitroaniline prodrugs/Ssap-NtrB enzyme suicide gene system: Synthesis, in vitro and in silico evaluation in prostate cancer

Tokay, Esra; Güngör, Tuğba; Hacıoğlu, Nelin; Önder, Ferah Cömert; Gülhan, Ünzile Güven; Tok, Tuğba Taşkın; Çelik, Ayhan; Ay, Mehmet Oğuzhan; Köçkar, Feray

doi:10.1016/j.ejmech.2019.111937

Cited by 16 publications

(7 citation statements)

References 29 publications

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“…Moreover, the drug also destroys the surrounding cancer cells, although they are not transduced by the gene product. This phenomenon is known as the bystander effect, where the gene product is able to destroy 1000 times more tumor cells than would be expected through usual gene transduction 40 . Enzyme‐based suicide gene therapy often requires the least in vivo gene transfer, as it results in a large bystander effect in destroying cancer cells.…”

Section: Gene Therapymentioning

confidence: 99%

“…This phenomenon is known as the bystander effect, where the gene product is able to destroy 1000 times more tumor cells than would be expected through usual gene transduction. 40 5-fluorocytosine. The HSV-TK enzyme transforms the inert prodrug into an activated prodrug, which directly terminates the DNA chain and inhibits host cell replication, causing dividing tumor cells to die.…”

Section: Suicide Gene Therapymentioning

confidence: 99%

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Progress in gene therapy treatments for prostate cancer

Xue

Chen

et al. 2021

Biotech and App Biochem

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Prostate cancer is one of the predominant cancers affecting men and has been widely reported. In the past, various therapies and drugs have been proposed to treat prostate cancer. Among these treatments, gene therapy has been considered to be an optimal and widely applicable treatment. Furthermore, due to the increased specificity of gene sequence complementation, the targeted delivery of complementary gene sequences may represent a useful treatment in certain instances. Various gene therapies, including tumor‐suppressor gene therapy, suicide gene therapy, immunomodulation gene therapy and anti‐oncogene therapies, have been established to treat a wide range of diseases, such as cardiac disease, cystic fibrosis, HIV/AIDS, diabetes, hemophilia, and cancers. To this end, several gene therapy clinical trials at various phases are underway. This overview describes the developments and progress in gene therapy, with a special focus being placed on prostate cancer.

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Section: Gene Therapymentioning

confidence: 99%

Section: Suicide Gene Therapymentioning

confidence: 99%

Progress in gene therapy treatments for prostate cancer

Xue

Chen

et al. 2021

Biotech and App Biochem

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“…Nitroreductase (Nit) is an endogenous enzyme that can be overexpressed in hypoxic tumors and is related to the degree of hypoxia. Nit selectively facilitates the transfer of the nitro group in nitroaromatic moieties to the amine group in the presence of NADPH, and these nitroaromatic moieties have been used in the development of hypoxia-sensitive probes and prodrugs . The structure of the lipid will change in the presence of Nit and NADPH to release the drugs and can enable the development of efficient and safe hypoxia delivery systems for tumor treatments.…”

Section: Introductionmentioning

confidence: 99%

Glutathione Consumptive Dual-Sensitive Lipid-Composite Nanoparticles Induce Immunogenic Cell Death for Enhanced Breast Tumor Therapy

Peng,

Yu,

Shen

et al. 2023

Mol. Pharmaceutics

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Although chemotherapy remains the standard therapy for tumor treatment, serious side effects can occur because of nontargeted distribution and damage to healthy tissues. Hollow mesoporous silica nanoparticles (HMSNs) modified with lipids offer potential as delivery systems to improve therapeutic outcomes and reduce adverse effects. Herein, we synthesized HMSNs with integrated disulfide bonds (HMSN) for loading with the chemotherapeutic agent oxaliplatin (OXP) which were then covered with the synthesized hypoxia-sensitive lipid (Lip) on the surface to prepare the dualsensitive lipid-composite nanoparticles (HMSN-OXP-Lip). The empty lipid-composite nanoparticles (HMSN-Lip) would consume glutathione (GSH) in cells because of the reduction of disulfide bonds in HMSN and would also inhibit GSH production because of NADPH depletion driven by Lip cleavage. These actions contribute to increased levels of ROS that induce the immunogenic cell death (ICD) effect. Simultaneously, HMSN-Lip would disintegrate in the presence of high concentrations of GSH. The lipid in HMSN-OXP-Lip could evade payload leakage during blood circulation and accelerate the release of the OXP in the tumor region in the hypoxic microenvironment, which could significantly induce the ICD effect to activate an immune response for an enhanced therapeutic effect. The tumor inhibitory rate of HMSN-OXP-Lip was almost twice that of free OXP, and no apparent side effects were observed. This design provides a dual-sensitive and efficient strategy for tumor therapy by using lipid-composite nanoparticles that can undergo sensitive drug release and biodegradation.

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“…Thus, these prodrugs have been determined as effective candidates in PC3, Hep3B, and HT29 cancer cell lines and in HUVEC normal healthy cell line. [26][27][28][29] Computational approaches such as molecular docking and MD simulation studies have been widely used an important tool for discovery and design of drug candidates and are highly useful for understanding the interactions between ligand and protein. [30][31][32] The latest studies have shown that computational assessments with combined in vitro studies contribute to further studies such as in vivo and clinical translation.…”

Section: Introductionmentioning

confidence: 99%

Nitro Compounds Inhibit Breast Cancer Cell Proliferation, Migration, and Colony Formation: Molecular Docking, Molecular Dynamics Simulations and Pharmacological Properties

Comert Onder,

Sahin,

Davutlar

et al. 2023

ChemistrySelect

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In this study, the concept of combined in vitro and in silico studies were utilized by using some synthesized nitro bearing compounds. The anticancer activities of the studied compounds were performed by using colony formation analysis, cell cytotoxicity, and migration. Nitro group containing two compounds were analyzed using Hoechst staining to indicate the morphological changes on the nuclei of cancer cells under fluorescence microscopy. Scanning electron microscopy (SEM) analysis was performed with N,N‐dibutyl‐nitro‐substituted compound. Nitro containing anticancer agents were shown the inhibition at 1.5 μM and 2 μM concentrations, and nuclear apoptosis was detected. In addition, cell‐to‐cell interaction on MDA‐MB‐231 cells was broken and observed morphologic changes following the treatment with N,N‐dibutyl‐nitro‐substituted compound at the effective doses. In general, the other nitro compounds showed cell cytotoxicity at 5 μM, 10 μM, and 20 μM. Two hits as anticancer agents were determined as potential interleukin‐1 receptor‐associated kinase 1 (IRAK1) and interleukin‐1 receptor‐associated kinase 4 (IRAK4) inhibitor candidates. Molecular docking and molecular dynamics (MD) simulations studies will provide that the binding patterns with specific residues such as Met265, Tyr284 of the IRAK family members, and these will contribute to further in vitro and in vivo studies for targeted breast cancer therapy.

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Prodrugs for nitroreductase-based cancer therapy-3: Antitumor activity of the novel dinitroaniline prodrugs/Ssap-NtrB enzyme suicide gene system: Synthesis, in vitro and in silico evaluation in prostate cancer

Cited by 16 publications

References 29 publications

Progress in gene therapy treatments for prostate cancer

Progress in gene therapy treatments for prostate cancer

Glutathione Consumptive Dual-Sensitive Lipid-Composite Nanoparticles Induce Immunogenic Cell Death for Enhanced Breast Tumor Therapy

Nitro Compounds Inhibit Breast Cancer Cell Proliferation, Migration, and Colony Formation: Molecular Docking, Molecular Dynamics Simulations and Pharmacological Properties

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