Recent Development of Prodrugs of Gemcitabine

Pandit, Bhoomika; Royzen, Maksim

doi:10.3390/genes13030466

Cited by 42 publications

(32 citation statements)

References 31 publications

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“…Additionally, two nucleoside analogs, namely gemcitabine and 6-thioguanine, have a weak HDP-inducing activity as well. Both compounds work mainly by incorporating into DNA and RNA as fraudulent bases to cause termination of cellular synthesis of DNA/RNA and have been approved for treatment of cancers and inflammatory bowel diseases [ 44 , 45 ].…”

Section: Discussionmentioning

confidence: 99%

High-Throughput Identification of Epigenetic Compounds to Enhance Chicken Host Defense Peptide Gene Expression

2022

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Enhancing the synthesis of endogenous host defense peptides (HDPs) has emerged as a novel antibiotic-free approach to infectious disease control and prevention. A number of epigenetic compounds have been identified as HDP inducers and several have proved beneficial in antimicrobial therapy. However, species-specific regulation of HDP synthesis is evident. In attempt to identify epigenetic compounds with potent HDP-inducing activity for poultry-specific application, we developed a stable luciferase reporter cell line, known as HTC/AvBD10-luc, following our earlier construction of HTC/AvBD9-luc. HTC/AvBD10-luc was developed through permanent integration of a chicken macrophage cell line, HTC, with a lentiviral luciferase reporter vector driven by a 4-Kb AvBD10 gene promoter. Using a high throughput screening assay based on the two stable cell lines, we identified 33 hits, mostly being histone deacetylase (HDAC) inhibitors, from a library of 148 epigenetic compounds. Among them, entinostat and its structural analog, tucidinostat, were particularly effective in promoting multiple HDP gene expression in chicken macrophages and jejunal explants. Desirably, neither compounds triggered an inflammatory response. Moreover, oral gavage of entinostat significantly enhanced HDP gene expression in the chicken intestinal tract. Collectively, the high throughput assay proves to be effective in identifying HDP inducers, and both entinostat and tucidinostat could be potentially useful as alternatives to antibiotics to enhance intestinal immunity and disease resistance.

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Section: Discussionmentioning

confidence: 99%

High-Throughput Identification of Epigenetic Compounds to Enhance Chicken Host Defense Peptide Gene Expression

2022

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“…The stepwise phosphorylation of dFdCMP leads to the formation of triphosphate of gemcitabine (dFdCTP), which exhibited the anti-tumor activity (Figure ). Enzymatic deamination by cytidine deaminase (CDA) can lead to the inactivation of gemcitabine via the formation of 2′-deoxy-2′,2′-difluorouridine (dFdU) (Figure ). Although gemcitabine is successfully used, the rapid metabolic inactivation, poor oral bioavailability, and innate or acquired drug resistance limit its widely clinical application. − …”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Anti-Cancer Evaluation of Novel Cyclic Phosphate Prodrug of Gemcitabine

Zhang

et al. 2023

J. Med. Chem.

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ProTide and cyclic phosphate ester are two successful prodrug technologies to overcome the limitations of nucleoside drugs, among which the cyclic phosphate ester strategy has not been widely used in the optimization of gemcitabine. Herein, we designed a series of novel ProTide and cyclic phosphate ester prodrugs of gemcitabine. Cyclic phosphate ester derivative 18c exhibits much higher anti-proliferative activity than positive control NUC-1031 with IC50s of 3.6–19.2 nM on multiple cancer cells. The metabolic pathway of 18c demonstrates that 18c’s bioactive metabolites prolong its anti-tumor activity. More importantly, we separated the two P chiral diastereomers of gemcitabine cyclic phosphate ester prodrugs for the first time, revealing their similar cytotoxic potency and metabolic profile. 18c displays significant in vivo anti-tumor activity in both 22Rv1 and BxPC-3 xenograft tumor models. These results suggest that compound 18c is a promising anti-tumor candidate for treating human castration-resistant prostate and pancreatic cancer.

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“…administration of GEM, the enzyme deoxycytidine deaminase, which is present in the liver and plasma, metabolizes the drug into inactive 2 , 2 -difluorodeoxyuridine (dFdU). This process presents a short plasma half-life (t 1 2 ) of 15-20 min [5,6]. Therefore, to order to achieve the required therapeutic concentration, a higher dose of GEM is administered with continuous i.v.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Gemcitabine (GEM) is a chemotherapeutic drug approved by clinicians and used for treating a broad range of cancers, including ovarian, bladder, breast, liver, pancreatic, and nonsmall-cell lung cancers [ 1 ]. The anticancer effects of GEM result from the fact that it acts as a deoxycytidine nucleoside analog [ 1 ]. It exerts its effect through inhibition of the activity of ribonucleotide reductase, thereby reducing the synthesis of DNA, and preventing the continuation of the cell cycle at the G1/S stage [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

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Gemcitabine-Loaded Nanocarrier of Essential Oil from Pulicaria crispa: Preparation, Optimization, and In Vitro Evaluation of Anticancer Activity

AlMotwaa

Al-Otaibi

2022

Pharmaceutics

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The limitations of gemcitabine (GEM) in cancer therapy are due to its poor pharmacokinetics, which cause undesired adverse effects. The current study was aimed at investigating the anticancer effect and apoptotic mechanism of synthesized nanoemulsion (NE) containing Pulicaria crispa essential oil (PC-EO) and GEM (PC-NE:GEM) on MCF-7 and Hep-G2 cancer cell lines. An optimized NE formulation was selected based on the Box–Behnken method. The droplet size of the optimized PC-NE was 9.93 ± 0.53 nm, but after GEM loading, it was increased to 11.36 ± 0.0.21 nm. Results from FTIR revealed that GEM was successfully loaded onto PC-NE. The antineoplastic effect of PC-NE:GEM on MCF-7 and Hep-G2 cancer cells was increased more than 100-fold relative to that of GEM. A combination index and isobologram based on CompuSyn software revealed the synergistic effect of the formulation produced by a 1:1 ratio combination of PC-NE and GEM. These findings were confirmed by examination of cellular morphologies. The combination formulation strongly induced about 4.48-fold and 2.95-fold increases in apoptosis in MCF-7 and Hep-G2 cells, respectively, when compared with GEM. Moreover, PC-NE:GEM produced a synergistic increase in ROS production in MCF-7 cells (15.23%) and Hep-G2 cells (31.69%), when compared with GEM. In addition, PC-NE:GEM enhanced the activation of the intrinsic apoptosis pathway through upregulation of expressions of p53 and Caspase-3, and downregulation of Bcl-2 expression in MCF-7 cells, while the expressions of Caspase-3, Bax, and p53 were upregulated in HepG2 cells. These results indicate that the GEM-loaded NE containing PC-EO may reduce the dose of GEM and eliminate the associated side effects.

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Recent Development of Prodrugs of Gemcitabine

Cited by 42 publications

References 31 publications

High-Throughput Identification of Epigenetic Compounds to Enhance Chicken Host Defense Peptide Gene Expression

High-Throughput Identification of Epigenetic Compounds to Enhance Chicken Host Defense Peptide Gene Expression

Design, Synthesis, and Anti-Cancer Evaluation of Novel Cyclic Phosphate Prodrug of Gemcitabine

Gemcitabine-Loaded Nanocarrier of Essential Oil from Pulicaria crispa: Preparation, Optimization, and In Vitro Evaluation of Anticancer Activity

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