Mechanisms of Resistance to Antineoplastic Drugs
Robert I. Glazer in Developments in Cancer Chemotherapy, 2019
Cells also possess a complex array of drug-metabolizing enzymes which have a relatively broad substrate specificity and can therefore deactivate a wide range of drugs. These enzymes are traditionally classified into two general classes. Phase I drug-metabolizing enzymes, the majority of which are cytochrome P-450-dependent enzymes, in general catalyze the oxidation of substrates to more chemically reactive metabolites. These intermediates are often more toxic forms of these chemicals. While these enzyme activities convert carcinogens such as benzo(a)pyrene to more toxic intermediates, their role in the metabolism of anticancer drugs is less clear. However, the cytotoxic drug ellipticine is converted to a more toxic 9-hydroxy species by the phase I enzyme aryl hydrocarbon hydroxylase. Changes in the expression of this enzyme can result in resistance to ellipticine.20
Intelligent Nanomaterials for Medicine: Carrier Platforms and Targeting Strategies—State of the Art
Lajos P. Balogh in Nano-Enabled Medical Applications, 2020
Peptides can have lipophilic or hydrophilic properties based on their amino acid composition and can therefore be used to construct amphiphilic molecules that form nanostructures by self-assembly [132–134]. Design considerations of these biopolymers for drug carriers are similar to other biocompatible polymers, but should take into account that peptides may act as strong immunogens and that the body already contains several lines of defense against foreign proteins and peptidic structures like virus capsids. In addition, a variety of peptidases exist in the body; if a system is preclinically developed for later clinical use in man, species differences in peptidase expression needs to be carefully considered. Virus self-assembly can act as an inspiration to build hollow or solid peptidic nanostructures [135, 136]. Bawa et al. showed enhanced cellular delivery and activity of the anticancer drug ellipticine to human lung carcinoma A549 cells using self-assembling peptide-based nanoparticles [137]. Naskar et al. presented the formation of multivesicular structures from self-assembling peptides, depicting sensitivity upon exposure to calcium ions leading to vesicular disruption. This intelligent sensing/switching functionality, allows cargo release suited for medically relevant payloads [138]. However, a natural extension of peptide-based systems is the exploitation of biologic peptide functions like their use as receptor ligands or enzymatic activity, naturally leading to nanomaterials with complex or switchable functionalities. Clinically, peptidic systems have entered clinical trials dominantly as nanoplatforms for vaccines offering multivalency as a potent immune system stimulant.
Nucleic Acids as Therapeutic Targets and Agents
David E. Thurston, Ilona Pysz in Chemistry and Pharmacology of Anticancer Drugs, 2021
In in vitro cytotoxicity studies, ellipticine has significant activity in nasopharyngeal carcinoma cell lines. A number of ellipticine analogues have been synthesized and studied in the clinic through the years. However, although some have been observed to induce remission of tumor growth, as a class they produce a high level of toxicity (e.g., nausea, vomiting, hypertension, cramp, severe fatigue, mouth dryness and mycosis of the tongue, and esophagus), and so none have progressed to the approval stage.
In vitro cytotoxicity of polyphenols from Datura innoxia aqueous leaf-extract on human leukemia K562 cells: DNA and nuclear proteins as targets
Published in Drug and Chemical Toxicology, 2020
Elham Chamani, Roshanak Ebrahimi, Khatereh Khorsandi, Azadeh Meshkini, Asghar Zarban, Gholamreza Sharifzadeh
Potent natural antioxidants change chromatin either by directly affecting the DNA backbone or by targeting the proteins related to it (Russo et al. 2017). It has been reported that dietary polyphenols such as curcumin, resveratrol, and catechin can influence transcription through posttranslational modifications of histones which change the structure of chromatin (Russo et al. 2017). Banerjee et al. (2017) investigated the effect of ellipticine, a plant alkaloid, on chromatin and nucleosomal DNA. Their results revealed that ellipticine interacted with chromatin components, especially core histone proteins. Recent studies have reported on the toxic effect of D. stromonium on breast (MDA-MB-231), head, neck (FaDu), and lung (A549) cancer cell lines (Maheshwari et al. 2013). They showed that its lectin and agglutinin contents had inhibitory effects on head, neck, lungs, and breast cancer cells and reduced the proliferation of C6 glioma cells (Sasaki et al. 2002).
Stimulus-responsive peptide hydrogels: a safe and least invasive administration approach for tumor treatment
Published in Journal of Drug Targeting, 2023
Yuchen Hu, Ying Fan, Ban Chen, Hong Li, Gang Zhang, Jiangtao Su
The peptide concentration can not only affect the self-assembly behaviour as mentioned above but also influence the encapsulated drugs. For example, P4 (Ac-NH-LDLKLELKLDLKLELK-CONH2), which is capable of forming a scaffold hydrogel consisting of >99% water, was used to stabilise the hydrophobic anticancer agent ellipticine. Peptide-ellipticine (P4-EPT) complexes were obtained, and ellipticine was stabilised in different forms depending on the concentration of the peptide. Neutral, protonated and crystalline ellipticine were obtained with 0.5 mg/mL P4, while neutral and crystalline ellipticine were obtained in complexes with lower concentrations of peptide. Scanning electron microscopy (SEM) experiments confirmed that 0.5 mg/mL P4 led to a smaller complex and a thicker coating on ellipticine with complex dimensions of approximately 50 - 100 nm. When the peptide concentration decreased to 0.2 mg/mL and 0.04 mg/mL, the size of the complex increased to 150 - 200 nm and 1 mm, respectively [55].
Cytotoxic compounds from the leaves and stems of the endemic Thai plant Mitrephora sirikitiae
Published in Pharmaceutical Biology, 2020
Natthinee Anantachoke, Duangporn Lovacharaporn, Vichai Reutrakul, Sylvie Michel, Thomas Gaslonde, Pawinee Piyachaturawat, Kanoknetr Suksen, Samran Prabpai, Narong Nuntasaen
The methanol extracts and the isolated compounds were evaluated for their cytotoxic activities against several cell lines, including murine lymphocytic leukaemia (P-388), human oral epidermoid carcinoma (KB), human colon carcinoma (Col-2 and HT-29), human breast cancer (MCF-7), human lung carcinoma (Lu-1 and A549), rat glioma (ASK), and noncancerous human embryonic kidney cell (HEK-293) by sulforhodamine B (SRB) assay in 96-well microtiter plates (Skehan et al. 1990). This method measures the cellular protein content of cultures in 96-well microtiter plates. The cell lines were seeded into 96-well microtiter plates and treated with the test compounds at concentrations of 0.16–20 µg/mL for 72 h, except for the P-388 cells, which were treated for 48 h. Then the cell cultures were fixed with 20% trichloroacetic acid (Merck) and stained with 0.4% SRB (Sigma-Aldrich) dissolved in 1% acetic acid (Merck) for 1 h. The cellular-protein-bound dye was extracted with 10 mM unbuffered Trisbase solution (pH 10.5) (Sigma-Aldrich) for the determination of optical density at 510 nm with a microtiter plate reader (Thermo Scientific™ Multiskan™ GO Microplate Spectrophotometer). The cytotoxic potency was expressed as median inhibition concentrations (IC50), the concentration that inhibits 50% of cell viability (µg/mL and µM). The IC50 values were determined from the nonlinear regression curve fit in GraphPad Prism software (version 5). Ellipticine (Sigma-Aldrich), a cytotoxic plant alkaloid causing topoisomerase II inhibition and DNA intercalation, was used as a positive control.
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