Cellular mechanism of action of 2-nitroimidazoles as hypoxia-selective therapeutic agents

Rashed, Faisal Bin; Diaz‐Dussan, Diana; Mashayekhi, Fatemeh; Macdonald, Dawn; Nation, Patrick N.; Yang, Xiaohong; Sokhi, Sargun; Stoica, Alexandru Cezar; Narain, Ravin; Ismail, Ismail Hassan; Wiebe, Leonard I.; Kumar, Piyush; Weinfeld, Michael

doi:10.1016/j.redox.2022.102300

Cited by 17 publications

(17 citation statements)

References 67 publications

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“…We employed a dual fluorescence approach to monitor the uptake and release of encapsulated drug. Fluorescein isothiocyanate (FITC)-labeled- NG1 was used to evaluate the cellular internalization of the NGs, while azidoazomycin arabinoside (N 3 -AZA, Figure S1), a click chemistry analogue of IAZA in which the iodine is replaced with an azido group, , together with Alexafluor 594 conjugated alkyne, was used to follow the cellular release of drug from NG1 . The cellular uptake of the FITC-labeled NG1 and release profiles of IAZA and N 3 -AZA up to 10 h were evaluated (Figure S5) showing a similar percentage of release at 5 mM (∼65%) between IAZA and N 3 -AZA.…”

Section: Resultsmentioning

confidence: 99%

“…Radiolabeled 2-NIs have shown success as hypoxia-selective radiotracers in clinical settings, and some widely used radiopharmaceuticals for hypoxia imaging include 18 F-fluoromisonidazole ( 18 F-FMISO), ,, 18 F-fluoroazomycin arabinofuranoside ( 18 F-FAZA), − and 123 I-iodoazomycin arabinofuranoside ( 123 I-IAZA). − In addition to its diagnostic capacity, ,, IAZA has shown potential as a hypoxia-directed therapeutic in cell-based assays, either as a radiosensitizer , to enhance therapeutic effects of external X-ray beam radiotherapy or for delivering in situ molecular radiotherapy (MRT) when IAZA is labeled with a therapeutic radionuclide ( 131 I). Most recently Rashed et al examined the effects of IAZA on tumor hypoxia, with a particular emphasis on identifying the cellular phenotype induced by this drug as well as analyzing their effects on target cellular macromolecules. , Cytostasis was observed in a head and neck (FaDu) cancer model, where hypoxic cells displayed higher sensitivity to IAZA exhibiting an altered cell morphology, compromised DNA replication, slower cell cycle progression, and induction of replication stress . Due to its promising anti-tumor properties and no indication of peripheral neurotoxicity at lower doses, a limitation seen with previous 2-NIs in clinical trials, IAZA could offer multifold theranostic potential.…”

Section: Introductionmentioning

confidence: 99%

“…A safe dose was determined for IAZA in a similar toxicity experiment. 30 IAZA was injected once intraperitoneally at 200, 400, or 600 mg per kg body weight. The drug was well tolerated, and no significant weight loss was observed in mice over 7 and 14 days post-injection (Figure 6C,D).…”

Section: ■ Introductionmentioning

confidence: 99%

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Optimized Carbohydrate-Based Nanogel Formulation to Sensitize Hypoxic Tumors

et al. 2023

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Solid tumors are often poorly vascularized, which impairs oxygen supply and drug delivery to the cells. This often leads to genetic and translational adaptations that promote tumor progression, invasion, metastasis, and resistance to conventional chemo-/radiotherapy and immunotherapy. A hypoxia-directed nanosensitizer formulation of a hypoxia-activated prodrug (HAP) was developed by encapsulating iodoazomycin arabinofuranoside (IAZA), a 2-nitroimidazole nucleoside-based HAP, in a functionally modified carbohydrate-based nanogel, facilitating delivery and accrual selectively in the hypoxic head and neck and prostate cancer cells. Although IAZA has been reported as a clinically validated hypoxia diagnostic agent, recent studies have pointed to its promising hypoxia-selective anti-tumor properties, which make IAZA an excellent candidate for further exploration as a multimodal theranostic of hypoxic tumors. The nanogels are composed of a galactose-based shell with an inner core of thermoresponsive (di(ethylene glycol) methyl ethyl methacrylate) (DEGMA). Optimization of the nanogels led to high IAZA-loading capacity (≅80–88%) and a slow time-controlled release over 50 h. Furthermore, nanoIAZA (encapsulated IAZA) displayed superior in vitro hypoxia-selective cytotoxicity and radiosensitization in comparison to free IAZA in the head and neck (FaDu) and prostate (PC3) cancer cell lines. The acute systemic toxicity profile of the nanogel (NG1) was studied in immunocompromised mice, indicating no signs of toxicity. Additionally, growth inhibition of subcutaneous FaDu xenograft tumors was observed with nanoIAZA, demonstrating that this nanoformulation offers a significant improvement in tumor regression and overall survival compared to the control.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Optimized Carbohydrate-Based Nanogel Formulation to Sensitize Hypoxic Tumors

et al. 2023

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“…The potent nanomolar cell-based activity of this series of compounds over the tested prostate carcinoma cell line could be attributed to other possible targets in addition to EGFR and HER2 receptors. The presence of the 2-nitroimidazole moiety in the chemical structure of compounds 9a – h could develop possible covalent bonds between the nitroimidazole moiety and some cellular proteins 28 .…”

Section: Biological Evaluationmentioning

confidence: 99%

Development of new TAK-285 derivatives as potent EGFR/HER2 inhibitors possessing antiproliferative effects against 22RV1 and PC3 prostate carcinoma cell lines

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Elkamhawy

Gul

et al. 2023

Journal of Enzyme Inhibition and Medicinal Chemistry

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Epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) protein tyrosine kinases co-expressed in various cancers such as ovarian, breast, colon, and prostate subtypes. Herein, new TAK-285 derivatives ( 9a – h ) were synthesised, characterised, and biologically evaluated as dual EGFR/HER2 inhibitors. Compound 9f exhibited IC 50 values of 2.3 nM over EGFR and 234 nM over HER2, which is 38-fold of staurosporine and 10-fold of TAK-285 over EGFR. Compound 9f also showed high selectivity profile when tested over a small kinase panel. Compounds 9a – h showed IC 50 values in the range of 1.0–7.3 nM and 0.8–2.8 nM against PC3 and 22RV1 prostate carcinoma cell lines, respectively. Cell cycle analysis, apoptotic induction, molecular docking, dynamics, and MM-GBSA studies confirmed the plausible mechanism(s) of compound 9f as a potent EGFR/HER2 dual inhibitor with an effective antiproliferative action against prostate carcinoma.

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“…Meanwhile, hypoxia is also the specific target for cancer therapy to improve the specificity and safety of treatment. The hypoxia responsive groups, such as 2-nitroimidazole, 68 azo, 69 quinone, 70 etc. can be quickly reduced in the hypoxic TME to alter the state for drug release.…”

Section: Hypoxia Responsive Nanocarriers For Gene Therapymentioning

confidence: 99%