Anticancer Drug Adriamycin Research Articles

Cytoprotective Role of Autophagy in CDIP1 Expression-Induced Apoptosis in MCF-7 Breast Cancer Cells.

Cell death-inducing p53-target protein 1 (CDIP1) is a proapoptotic protein that is normally expressed at low levels and is upregulated by genotoxic and endoplasmic reticulum stresses. CDIP1 has been reported to be localized to endosomes and to interact with several proteins, including B-cell receptor-associated protein 31 (BAP31) and apoptosis-linked gene 2 (ALG-2). However, the cellular and molecular mechanisms underlying CDIP1 expression-induced apoptosis remain unclear. In this study, we first demonstrated that CDIP1 was upregulated after treatment with the anticancer drug adriamycin in human breast cancer MCF-7 cells but was degraded rapidly in the lysosomal pathway. We also demonstrated that treatment with the cyclin-dependent kinase 5 (CDK5) inhibitor roscovitine led to an increase in the electrophoretic mobility of CDIP1. In addition, a phosphomimetic mutation at Ser-32 in CDIP1 resulted in an increase in CDIP1 expression-induced apoptosis. We also found that CDIP1 expression led to the induction of autophagy prior to apoptosis. Treatment of cells expressing CDIP1 with SAR405, an inhibitor of the class III phosphatidylinositol 3-kinase VPS34, caused a reduction in autophagy and promoted apoptosis. Therefore, autophagy is thought to be a defense mechanism against CDIP1 expression-induced apoptosis.

Synthesis, structure-activity relationship, and biological evaluation of quinolines for development of anticancer agents.

Tetrahydro-β-carbolines (THβCs) are a kind of natural alkaloids with multiple pharmaceutical activities. Herein, a focused compound library derived from THβCs was synthesized and their anticancer activities were studied in several cancer cell lines. Among them, three compounds showed considerable anticancer activities with low micromolar to submicromolar IC50 values. The abilities to induce apoptosis and alter mitochondrial membrane potential levels, which are comparable to those of the commercial anticancer drug adriamycin, were confirmed by one representative compound (21) on the B16/F10 cell line. Our preliminary structure-activity relationship studies indicated that alkylamines with suitable lengths are very important for potency improvement.

New Jatrophane-Type Diterpenoids from Euphorbia kansui as Potential MDR Reversal Agents.

A serial jatrophane-type diterpenoids, comprised with three undescribed compounds kanesulones C-E (1-3) and four known ones (4-7), were obtained from the roots of Euphorbia kansui. The structures of compounds 1-3 were elucidated by detailed interpretation of their spectroscopic data, especially 2D-NMR and HR-ESI-MS, the absolute configuration of 1 was revealed by single crystal X-ray diffraction. These isolates were assayed for their multidrug resistance reversing activities on human breast adenocarcinoma cell line MCF-7/ADR. Compound 1 possessed potential as low toxic MDR modulator that could promote the efficacy of anticancer drug adriamycin ca. 85-fold at 5 μM, as 12 times stronger than the positive drug verapamil.

Evaluation of Antiproliferative Activity of Lac Dye Fractions against MDA-MB-231 and SiHa Cell Lines.

Laccifer lacca (Kerr) produces a mixture of polyhydroxy anthraquinones (laccaic acid) known as lac dye. Literature suggests that these laccaic acids have a structural resemblance with the anticancer drug Adriamycin (ADR). Hence, they may possess potential anticancer activity. This study was designed to explore the in vitro anticancer activity of the three fractions of lac dye, i.e., chloroform (C), methanol (M), and water (W) fractions, and isolation of constituents from bioactive fraction. SRB (Sulforhodamine B) assay method was employed to evaluate the inhibitory action of all three fractions. However, only methanolic showed promising inhibitory action with GI50 <10; this runs in parallel with Adriamycin inhibition (GI50 <10). Two active constituents of the methanolic extract were isolated using column chromatography and were characterized using UV (UV visible spectrophotometer), IR (Infrared spectroscopy), NMR (nuclear magnetic resonance), and mass spectrometry methods. The final structure of the isolated constituents (laccaic acid D and laccaic acid B) was confirmed by 13C and 2D NMR data. Conclusively, only the methanol fraction (M) showed promising anticancer activity against in vitro MDAMB- 231 and SiHa cell lines compared to the standard adriamycin.

Use of benzodiazepines is the risk factor for infection in patients aged 80 years or older with diffuse large B-cell lymphoma: A single-institution retrospective study.

BackgroundThe number of patients aged 80 years or older with diffuse large B-cell lymphoma (DLBCL) is increasing, and the incidence rate of the disease in this population group reaches up to 20%. The risk of infection is higher in older patients than in other patients. Although hypnotic drugs are frequently detected as potentially inappropriate medications, it is unclear whether hypnotic drugs affect the occurrence of infection during chemotherapy. Here, we investigated whether the use of hypnotic drugs is associated with infection during first-line chemotherapy in patients with diffuse large B-cell lymphoma (DLBCL) aged 80 years or older.MethodsJapanese patients aged 80 years or older with diffuse large B-cell lymphoma who had received first-line chemotherapy at Fujita Health University Hospital from January 2005 to March 2020 were enrolled in this retrospective cohort study. The primary study outcome was the identification of the risk factor for infection during first-line chemotherapy.ResultsThis study included 65 patients received first-line chemotherapy. The proportion of patients with National Comprehensive Cancer Network-international prognostic index ≥ 6 was higher in the infection group than in the non-infection group. The relative dose intensity of each anticancer drug (cyclophosphamide, adriamycin, and vincristine) and dose of prednisolone did not significantly differ between the two groups. Multivariate analysis showed that the use of benzodiazepines was a risk factor for infection (odds ratio, 4.131 [95% confidence interval: 1.225–13.94], P = 0.022).ConclusionDLBCL patients using benzodiazepines should be monitored for infection symptoms during chemotherapy.

Chondroitin sulfate modified and adriamycin preloaded hybrid nanoparticles for tumor-targeted chemotherapy of lung cancer.

Promising cancer treatment requires the assistant of drug delivery systems (DDS) with the aim to increase the accumulation of drugs in tumor tissue. Herein, a hybrid DDS was successfully developed to integrate chondroitin sulfate (CS) and calcium carbonate (CC) in to one system. Anticancer drug adriamycin (Adr) was preloaded into CC nanoparticles to obtain Adr-loaded CC nanoparticles (CC/Adr). The resulted CS-CC/Adr nanoparticles as a biocompatible DDS was able to specifically target cancer cells to enhance the chemotherapy of lung cancer due to the surface modification of CS. Intracellular uptake as well as in vivo imaging results revealed the obtained CS-CC/Adr nanoparticles (size of ~100 nm) showed CS mediated tumor specific accumulation into A549 and LLC cells than unmodified CC/Adr, in which the CD44 receptor might be involved, which finally resulted in stronger anticancer capability than Adr or CC/Adr. As a result, CS-CC/Adr nanoparticles could be further extended to clinical administration in our future works.

Euphoresulanes A-M, structurally diverse jatrophane diterpenoids from Euphorbia esula.

Thirteen new jatrophane diterpenoids, euphoresulanes A-M (1-13), and seven known analogues (14-20) were isolated from the whole plants of Euphorbia esula. Their structures were elucidated by extensive spectroscopic analysis, and the absolute configurations of 1, 6, and 10 were confirmed by single crystal X-ray diffraction. Compounds 1-20 were screened for the multidrug resistance (MDR) reversal activity on P-glycoprotein (Pgp)-dependent cancer cell line HepG2/ADR, and 1, 2, 4, 6, and 8 exhibited comparable activity to the positive drugs. Euphoresulane H (8), the most active MDR modulator, could enhance the efficacy of anticancer drug adriamycin to ca. 33 folds at 5μM. The structure-activity relationship (SAR) study revealed that the acyloxy substitution at C-9 is essential to the activity and presence of H-2 was favorable.

Structural basis for stabilization of human telomeric G-quadruplex [d-(TTAGGGT)]4 by anticancer drug adriamycin

Besides inhibiting DNA duplication, DNA dependent RNA synthesis and topoisomerase-II enzyme action, anticancer drug adriamycin is found to cause telomere dysfunction and shows multiple strategies of action on gene functioning. We present evidence of binding of adriamycin to parallel stranded intermolecular [d-(TTAGGGT)]4 G-quadruplex DNA comprising human telomeric DNA by proton and phosphorus-31 nuclear magnetic resonance spectroscopy. Diffusion ordered spectroscopy shows formation of complex between the two molecules. Changes in chemical shift and line broadening of DNA and adriamycin protons suggest participation of specific chemical groups/moieties in interaction. Presence of sequential nuclear Overhauser enhancements at all base quartet steps and absence of large downfield shifts in 31P resonances give clear proof of absence of intercalation of adriamycin chromophore between base quartets. Restrained molecular dynamics simulations using observed 15 short intermolecular inter proton distance contacts depict stacking of ring D of adriamycin with terminal G6 quartet by displacing T7 base and external groove binding close to T1–T2–A3 bases. The disappearance of imino protons monitored as a function of temperature and differential scanning calorimetry experiments yield thermal stabilization of 24 °C, which is likely to come in the way of telomerase association with telomeres. The findings pave the way for design of alternate anthracycline based drugs with specific modifications at ring D to enhance induced thermal stabilization and use alternate mechanism of binding to G-quadruplex DNA for interference in functional pathway of telomere maintenance by telomerase enzyme besides their well known action on duplex DNA. Communicated by Ramaswamy H. Sarma

Ingol diterpenoids as P-glycoprotein-dependent multidrug resistance (MDR) reversal agents from Euphorbia marginata

Twenty new ingol diterpenoids, euphornans A–T (1–20), representing a rare class of C-19-oxidated and H-2, H-3 β-oriented ingols, were isolated from the seeds of Euphorbia marginata. Their structures including absolute configurations were elucidated by extensive spectroscopic analysis, ECD analysis, and single crystal X-ray diffraction. Compounds 1–20 were screened for the multidrug resistance (MDR) reversal activity on P-glycoprotein (Pgp)-dependent MDR cancer cell line HepG2/ADR, and 11, 14, and 18 were identified as potent MDR modulators that could enhance the efficacy of anticancer drug adriamycin to ca. 20 folds at 5 μM. The Pgp inhibition mechanism and brief structure–activity relationships (SARs) of these compounds were also discussed.

Binding of anticancer drug adriamycin to parallel G-quadruplex DNA [d-(TTAGGGT)]4 comprising human telomeric DNA leads to thermal stabilization: A multiple spectroscopy study.

Adriamycin is known to exert its anti cancer action by inhibiting DNA duplication, RNA transcription and topoisomerase-II enzyme action. Recent findings of its binding to G-quadruplex DNA resulting in telomere dysfunction indicated multiple strategies of its action. The interaction of anticancer drug adriamycin with parallel stranded inter molecular G-quadruplex DNA [d-(TTAGGGT)]4 comprising human telomeric DNA sequence TTAGGG was investigated by absorption, fluorescence, circular dichroism and nuclear magnetic resonance spectroscopy to understand mode of their interaction. The adriamycin binds as monomer to G-quadruplex DNA with affinity (Kb1 = 9.8x105 M-1 and Kb2 = 6.7x105 M-1 ) higher than that reported for daunomycin, at two independent sites, mainly in terminal stacking and groove binding modes. The bound complex formed as a result of specific interactions induces thermal stabilization of DNA by 12.5-28.1°C, which is likely to hinder telomere association with telomerase enzyme and contribute significantly to adriamycin-induced apoptosis in cancer cell lines. The findings have therapeutic potential towards drug designing by way of altering substituent groups on anthracyclines to enhance efficacy using additional mechanism of targeting pathway of telomere maintenance by disrupting telomerase association with telomeres.

Evaluation of novel magnetic targeting microspheres loading adriamycin based on carboxymethyl chitosan

Targeted drug delivery system delivers drug to diseased organ, tissue, or cells by utilizing some physical means and biological properties, such as pH gradients in the intestine, differences in capillary diameters, immune system, specific enzymatic degradation, receptor responses, and specific chemical environment at the site of the lesion. Combining two preparation techniques of magnetic microspheres and ion exchange, regarding the anticancer drug adriamycin (ADR) as a model drug, carboxymethyl chitosan (CMC) as carrier, and Fe3O4 ultrafine particles as magnetic material, novel drug-loaded magnetic microspheres-ADR loaded carboxymethyl chitosan magnetic microspheres (ADR-CMC-Mag-MS) were synthesized. In this study, cytotoxicity and in vivo pharmacokinetics of ADR-CMC-Mag-MS were evaluated. The 50% cell inhibiting concentration (IC50) value of ADR-CMC-Mag-MS was (0.051 ± 0.005) μg/mL. And the cytotoxicity against human hepatocellular (Hep3B) cells presented concentration dependence. The area under the curve (AUC) and the peak concentration (Cmax) of ADR-CMC-Mag-MS added magnetic field (mag field) were respectively (1061.68 ± 22.71) μg·min/mL and (6.18 ± 0.13) μg/mL, indicating that the prepared ADR-CMC-Mag-MS had good targeting ability. It was demonstrated that the novel microspheres could deliver the highly toxic anticancer drug to the target site, in order to maximize the drug efficacy and reduce the side effects under the action of the external magnetic field.

Electrochemical Biosensor Hemoglobin Immobilization Determination of the Breast Cancer Drug (Adriamycin)

Electrochemical biosensor is an effective tool for pharmaceutical analysis due to its simplicity, specificity, sensitivity, fast, cost effective and repetitive measurements with miniaturized and portable devices. The paper illustrates the detail methodology for development of an electrochemical biosensor based on hemoglobin (Hb) film modified for anticancer drug adriamycin (ADM). Square wave voltammetry (SWV) studies of the electrodes before and after immobilizing of HB shows the successful formation of a selectivity of the electrode. The proposed Hb based biosensor allows quantitation over the range 1 to 8010-8M, The suggested biosensor method can be successfully applied to the detection and determination of anticancer drug adriamycin in different drug formulations and can be suggested as a suitable sensor for analysis of Adriamycin in biological samples.ً.

Hyaluronan and calcium carbonate hybrid nanoparticles for colorectal cancer chemotherapy

A hybrid drug delivery system (DDS) composed of hyaluronan and calcium carbonate (CC) was developed. By taking advantage of the tumor-targeting ability of hyaluronan and the drug-loading property of CC, the well-formed hyaluronan–CC nanoparticles were able to serve as a DDS targeting colorectal cancer with a decent drug loading content, which is beneficial in the chemotherapy of colorectal cancer. In this study, hyaluronan–CC nanoparticles smaller than 100 nm were successfully developed to load the wide-range anti-cancer drug adriamycin (Adr) to construct hyaluronan–CC/Adr nanoparticles. On the other hand, we also found that hyaluronan–CC/Adr nanoparticles can possibly increase the uptake ratio of Adr into HT29 colorectal cancer cells when compared with hyaluronan-free nanoparticles (CC/Adr) via the CD44 receptor-mediated endocytosis via competitive uptake and in vivo imaging assays. Note that both in vitro (CCK-8 assay on HT29 cells) and in vivo (anti-cancer assay on HT-29 tumor-bearing nude mice model) experiments revealed that hyaluronan–CC/Adr nanoparticles exhibited stronger anti-cancer activity than free Adr or CC/Adr nanoparticles with minimized toxic side effects and preferable cancer-suppression potential.

Thermosensitive polymeric micelles based on the triblock copolymer poly(d,l‐lactide)‐b‐poly(N‐isopropyl acrylamide)‐b‐poly(d,l‐lactide) for controllable drug delivery

ABSTRACTA thermosensitive amphiphilic triblock copolymer, poly(d,l‐lactide) (PLA)‐b‐poly(N‐isopropyl acrylamide) (PNIPAAM)‐b‐PLA, was synthesized by the ring‐opening polymerization of d,l‐lactide; the reaction was initiated from a dihydroxy‐terminated poly(N‐isopropyl acrylamide) homopolymer (HO‐PNIPAAM‐OH) created by radical polymerization. The molecular structure, thermosensitive characteristics, and micellization behavior of the obtained triblock copolymer were characterized with Fourier transform infrared spectroscopy, 1H‐NMR, gel permeation chromatography, dynamic light scattering, and transmission electron microscopy. The obtained results indicate that the composition of PLA‐b‐PNIPAAM‐b‐PLA was in good agreement with what was preconceived. This copolymer could self‐assemble into spherical core–shell micelles (ca. 75–80 nm) in aqueous solution and exhibited a phase‐transition temperature around 26 °C. Furthermore, the drug‐delivery properties of the PLA‐b‐PNIPAAM‐b‐PLA micelles were investigated. The drug‐release test indicated that the synthesized PLA‐b‐PNIPAAM‐b‐PLA micelles could be used as nanocarriers of the anticancer drug adriamycin (ADR) to effectively control the release of the drug. The drug‐delivery properties of PLA‐b‐PNIPAAM‐b‐PLA showed obvious thermosensitive characteristics, and the release time of ADR could be extended to 50 h. This represents a significant improvement from previous PNIPAAM‐based drug‐delivery systems. © 2017 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2017, 134, 45304.

Evaluation of Anticancer and Antimicrobial Activity of Arborinine from Glycosmis pentaphylla

The natural product arborinine, isolated from the plant Glycosmis pentaphylla was evaluated for its anticancer activity against five human cancer cell lines viz. human colon cancer cell line COLO-205, human ovarian cancer cell line OVCAR-3, human cervical cancer cell line SiHa, human breast cancer cell lines T-47D and MDA-MB-435 by SRB assay. The results were compared against a standard anticancer drug Adriamycin. Arborinine shows good activity on COLO-205, OVCAR-3 and T-47D with GI50 value <10 μg/ml in all the three experiments. It also shows mild to moderate antimicrobial activity against Staphylococcus aureus, Klebsiella pneumonia, Bacillus subtilis and Candida albicans strains in Agar well diffusion method.

Biochemical and histological studies on the possible protective impact of the herb basil (Ocimum basilicum) on adriamycin induced toxicity in rats. I. Influence on the liver.

The purpose of this work was to evaluate the effect of basil (Ocimum basilicum) against hepatotoxicity induced in albino rats by the anticancer drug adriamycin (ADR). The biochemical results showed that adriamycin caused significant elevation in serum ALT (Alanine aminotransferase) and AST (Aspartate aminotransferase) enzymes after 4, 6 and 8 weeks of treatment. It also caused an increase in malondialdehyde (lipid peroxidation marker) and decrease in activities of the antioxidant enzymes, superoxide dismutase and catalase. This drug has resulted in various histological changes in the liver. These changes include impairment of the normal structural organization of the hepatic lobules, congestion and dilatation of blood vessels, cytoplasmic vacuolization of the hepatocytes, leucocytic infiltrations and fatty infiltration. Treating animals with ADR and basil (Ocimum basilicum) led to an improvement in both biochemical and histological changes induced by ADR. There are significant decreases in ALT and AST activity. Moreover, Ocimum basilicum reduced the level of malondialdehyde and increased the activity of superoxide dismutase and catalase. In conclusion the results of the present work indicated that Ocimum basilicum had a protective effect against liver damage induced by adriamycin and this is due to antioxidant activities of some substances found in water extract of Ocimum basilicum.

Dinuclear zinc bis(thiosemicarbazone) complexes: Synthesis, in vitro anticancer activity, cellular uptake and DNA interaction study

Four dinucleating bis(thiosemicarbazone) ligands and their zinc complexes have been synthesized and characterized by multinuclear NMR (1H and 13C), IR, UV–Vis, ESI-MS and fluorescence spectroscopic techniques. Their purity was assessed by elemental analysis. Cytotoxicity was tested against five human cancer cell lines using the sulphorhodamine B (SRB) assay, where one of the complexes, 1,3-bis{biacetyl-2′-(4″-N-pyrrolidinylthiosemicarbazone)-3′-(4″-N-pyrrolidinylthiosemicarbazone)zinc(II)}propane (6), was found to be quite cytotoxic against MCF-7 (breast cancer) and HepG2 (hepatoma cancer) cell lines, with a potency similar to that of the well known anticancer drug adriamycin. It is evident from the cellular uptake studies that the uptake is same for the active complex 6 and the inactive complex 8 (1,6-bis{biacetyl-2′-(4″-N-pyrrolidinylthiosemicarbazone)-3′-(4″-N-pyrrolidinylthiosemicarbazone)zinc(II)}hexane) in MCF-7 and HepG2 cell lines. In vitro DNA binding and cleavage studies revealed that all complexes bind with DNA through electrostatic interaction, and cause no significant cleavage of DNA.

Transdermal delivery of adriamycin to transplanted ehrlich ascites tumor in mice.

There is considerable interest in the skin as a site of anti-cancer drug application. Nevertheless, the skin poses a formidable barrier to drug penetration, thereby limiting topical and transdermal bioavailability. However, we previously showed that a thioglycolate-based depilatory agent increases the drug permeability of mouse skin. In the present report, we investigated the skin permeability and efficacy of the anti-cancer drug adriamycin increased when administered transdermally to mice in combination with a thioglycolate-based depilatory agent. Adriamycin in combination with depilatory treatment reduced Ehrlich tumor growth in hairless mice about the weight and size of harvested tumors. In addition, our delivery method for adriamycin increased the therapeutic effectiveness of this agent by decreasing toxicity. Moreover, measurement of adriamycin autofluorescence revealed that topically applied adriamycin penetrate the dermis after depilatory agent treatment. These results indicate that the transdermal delivery of anti-cancer drugs is feasible by handy pretreatment of the skin with a thioglycolate-based depilatory agent.

The force of the spontaneously contracting zebrafish heart, in the assessment of cardiovascular toxicity: Application on adriamycin

The heart of the zebrafish has been used extensively to assess the cardiotoxic effect of compounds, using the frequency of heart contractions as the main index of cardiac response to drugs. In this study, the force and the frequency generated by the spontaneously contracting zebrafish heart, isolated in saline, were found to be 0.87±0.05mN and 1.54±0.03Hz (n=6) respectively within the first hour of recording. Both values of force and frequency remained constant for over 8h. The advantage of prolonged vitality in the assessment of cardiovascular toxicity was shown using the well-known anticancer drug adriamycin, which has severe cardiotoxic side effects. At 10.0μM there was a 21.05±4.42% (p=0.02, n=4) decrease in the force of contraction, while the frequency was not affected after 3h treatment (p>0.05). At 50.0 and 100.0μM there was a 33.24±3.0 and 46.6±4.80% irreversible decrease in force (p<0.05, n=4), while a 18.02±4.07% and 16.16±4.07% reversible increase was observed in the frequency (p=0.02, n=4). These contradictory positive chronotropic and negative inotropic responses indicate the strong inhibitory effect of adriamycin on ventricular cardiomyocytes and its excitatory effects on auto-rhythmical pacemaker cells. If heart frequency was the only parameter used to assess the cardiotoxic effect of adriamycin, at the above range of concentrations, this compound would have been classified as non-cardiotoxic.

The expression and function of Toll-like receptors 3 and 9 in human colon carcinoma

Toll-like receptors (TLRs) are pattern-recognition receptors that are important in immune signaling. TLR recognition of various viral components including double-stranded RNA (TLR3) and unmethylated CpG-DNA (TLR9) plays a crucial role in cell survival. However, TLR expression and function in colon carcinoma cells are not well clarified. We investigated the expression of TLR3 and TLR9 in colon carcinoma cells using immunohistochemical methods. The function of TLR3 and TLR9 signaling in carcinoma cell lines was studied by direct cell stimulation with, or by cell transfection of, polyinosinic-polycytidylic acid (Poly I:C), a synthetic form of dsRNA, and by cell stimulation with CpG-oligodeoxynucleotides (ODNs), respectively. Positive TLR3 and TLR9 immunohistochemical staining was observed in 91 and 86% of human hepatocellular carcinoma (HCC) tissues, respectively. Cell surface stimulation of TLR3 with Poly I:C did not affect cell viability but it did activate NF-κB activity. By contrast, stimulation of intracellular TLRs with transfected Poly I:C significantly induced apoptosis. Cell surface stimulation of TLR9 with CpG-ODNs promoted cell proliferation, and, furthermore, these CpG-ODN TLR9 agonists reduced the cytotoxicity of the anticancer drug adriamycin. Cell surface expression of TLR3 and TLR9 in colon carcinoma cells plays an important role in cell survival. In addition, the proapoptotic activity of intracellularly expressed TLR3 may provide the possibility of using TLR3 agonists as novel clinical cytotoxic agents against colon carcinoma cells.