Chemotherapeutic Application Research Articles

Anticancer Activity of Metallodrugs and Metallizing Host Defense Peptides-Current Developments in Structure-Activity Relationship.

This article provides an overview of the development, structure and activity of various metal complexes with anti-cancer activity. Chemical researchers continue to work on the development and synthesis of new molecules that could act as anti-tumor drugs to achieve more favorable therapies. It is therefore important to have information about the various chemotherapeutic substances and their mode of action. This review focuses on metallodrugs that contain a metal as a key structural fragment, with cisplatin paving the way for their chemotherapeutic application. The text also looks at ruthenium complexes, including the therapeutic applications of phosphorescent ruthenium(II) complexes, emphasizing their dual role in therapy and diagnostics. In addition, the antitumor activities of titanium and gold derivatives, their side effects, and ongoing research to improve their efficacy and reduce adverse effects are discussed. Metallization of host defense peptides (HDPs) with various metal ions is also highlighted as a strategy that significantly enhances their anticancer activity by broadening their mechanisms of action.

Polyacrylic Acid-Coated Selenium-Doped Carbon Dots Inhibit Ferroptosis to Alleviate Chemotherapy-Associated Acute Kidney Injury.

Cisplatin-associated acute kidney injury (AKI) is a severe clinical syndrome that significantly restricts the chemotherapeutic application of cisplatin in cancer patients. Ferroptosis, a newly characterized programmed cell death driven by the lethal accumulation of lipid peroxidation, is widely reported to be involved in the pathogenesis of cisplatin-associated AKI. Targeted inhibition of ferroptosis holds great promise for developing novel therapeutics to alleviate AKI. Unfortunately, current ferroptosis inhibitors possess low bioavailability or perform non-specific accumulation in the body, making them inefficient in alleviating cisplatin-associated AKI or inadvertently reducing the anti-tumor efficacy of cisplatin, thus not suitable for clinical application. In this study, a novel selenium nanomaterial, polyacrylic acid-coated selenium-doped carbon dots (SeCD), is rationally developed. SeCD exhibits high biocompatibility and specifically accumulates in the kidney. Administration of SeCD effectively scavenges broad-spectrum reactive oxygen species and significantly facilitates GPX4 expression by releasing selenium, resulting in strong mitigation of ferroptosis in renal tubular epithelial cells and substantial alleviation of cisplatin-associated AKI, without compromising the chemotherapeutic efficacy of cisplatin. This study highlights a novel and promising therapeutic approach for the clinical prevention of AKI in cancer patients undergoing cisplatin chemotherapy.

Natural alkaloids from Dicranostigma leptopodum (Maxim.) Fedde and their G5. NHAc-PBA dendrimer-alkaloid complexes for targeting chemotherapy in breast cancer MCF-7 cells.

Herein, we isolated five natural alkaloids, iso-corydine (iso-CORY), corydine (CORY), sanguinarine (SAN), chelerythrine (CHE) and magnoflorine (MAG), from traditional medicinal herb Dicranostigma leptopodum (Maxim.) Fedde (whole herb) and elucidated their structures. Then we synthesised G5. NHAc-PBA as targeting dendrimer platform to encapsulate the alkaloids into G5. NHAc-PBA-alkaloid complexes, which demonstrated alkaloid-dependent positive zeta potential and hydrodynamic particle size. G5. NHAc-PBA-alkaloid complexes demonstrated obvious breast cancer MCF-7 cell targeting effect. Among the G5. NHAc-PBA-alkaloid complexes, G5.NHAc-PBA-CHE (IC50=13.66 μM) demonstrated the highest MCF-7 cell inhibition capability and G5.NHAc-PBA-MAG (IC50=24.63 μM) had equivalent inhibitory effects on cell proliferation that comparable to the level of free MAG (IC50=23.74 μM), which made them the potential breast cancer targeting formulation for chemotherapeutic application. This work successfully demonstrated a pharmaceutical research model of 'natural bioactive product isolation-drug formulation preparation-breast cancer cell targeting inhibition'.

Zeolitic Imidazolate Framework (ZIF-8) Decorated Iron Oxide Nanoparticles Loaded Doxorubicin Hydrochloride for Osteosarcoma Treatment - in vitro and in vivo Preclinical Studies.

As a broad-spectrum antitumorigenic agent, doxorubicin (DOX) is commonly used as a chemotherapeutic drug for treating osteosarcoma (OS). Still, it is associated with significant cell toxicity and ineffective drug delivery, whereas the zeolite imidazolate framework is extensively applied in the biomedical field as a carrier owing to its favorable biocompatibility, high porosity, and pH-responsiveness. Therefore, we need to develop a drug delivery platform that can effectively increase the antitumorigenic effect of the loaded drug and concurrently minimize drug toxicity. In this study, a Fe3O4@ZIF-8 nanocomposite carrier was prepared with ZIF-8 as the shell and encapsulated with Fe3O4 by loading DOX to form DOX- Fe3O4@ZIF-8 (DFZ) drug-loaded magnetic nanoparticles. Then, we characterized and analyzed the morphology, particle size, and characteristics of Fe3O4@ZIF-8 and DFZ by TEM, SEM, and Malvern. Moreover, we examined the inhibitory effects of DFZ in vitro and in vivo. Meanwhile, we established a tumor-bearing mouse model, evaluating its tumor-targeting by external magnetic field guidance. DFZ nanoparticles possessed have a size of ~110 nm, with an encapsulation rate of 21% and pH responsiveness. DFZ exerted a superior cytostatic effect and apoptosis rate on K7M2 cells in vitro compared to DOX(p<0.01). In animal experiments, DFZ offers up to 67% tumor inhibition and has shown a superior ability to induce apoptosis than DOX alone in TUNEL results(p<0.01). Tumor-targeting experiments have validated that DFZ can be effectively accumulated in the tumor tissue and enhance anticancer performance. In summary, the DFZ nano-delivery system exhibited a more substantial anti-tumorigenic effect as well as superior active tumor targeting of DOX- Fe3O4@ZIF-8 compared to that of DOX alone in terms of biocompatibility, drug loading capacity, pH-responsiveness, tumor-targeting, and anti-tumorigenic effect, indicating its chemotherapeutic application potential.

3-Heptylidene-4,6-Dimethoxy-3H-Isobenzofuran-1-One Is Genotoxic, Increases the Frequency of Cell Death, and Potentiates the Effects of Cyclophosphamide and Cisplatin.

3-heptylidene-4,6-dimethoxy-3H-isobenzofuran-1-one (Phthalide 1) is the precursor of three resorcinol lipids that have been described as potential chemotherapeutic agents and capable of potentiating the effects of cyclophosphamide. In this study, we evaluated the genotoxic potential, cell-killing potential, and interactions with cyclophosphamide and cisplatin of phthalide 1. Twelve groups were created from 120 mice: Negative Control, cyclophosphamide (100 mg/kg), cisplatin (6 mg/kg), Phthalide 1 (5, 10 and 20 mg/kg), and associations of 1 with cyclophosphamide and 1 with cisplatin. The results demonstrate that 1 increases (p < 0.05) the frequency of chromosomal damage, liver and kidney cell death, and splenic phagocytosis. The association of 1 with cyclophosphamide and cisplatin demonstrated a chemopreventive effect and, therefore, a reduction (p < 0.05) in the frequency of chromosomal damage. However, cell death and splenic phagocytosis did not suffer significant variations. As a result of the above, 1 has potential chemotherapeutic application and may be a candidate for developing a new generation of chemotherapeutics. In addition, it has characteristics to be used as a chemotherapy adjuvant in association with cyclophosphamide and cisplatin since it increases the frequency of cell death induced by chemotherapy. We also reported that the chemopreventive effect of 1, in association with cyclophosphamide and cisplatin, can prevent adverse effects (induction of DNA damage in non-tumor cells) without interfering with the mode of action of chemotherapy drugs and, therefore, without reducing the induction of cell death.

Ultrasound responsive Gd-DOTA/doxorubicin-loaded nanodroplet as a theranostic agent for magnetic resonance image-guided controlled release drug delivery of melanoma cancer

Theranostic agents use simultaneous for diagnostic and therapeutic procedures. In the present study, the effect of Gd-DOTA/doxorubicin-loaded perfluorohexane nanodroplets as a theranostic nanoparticle for control released drug delivery and ultrasound/MR imaging was investigated on B16F10 melanoma cancer cells. The intracellular uptake was performed by inductively coupled plasma optical emission spectrometry (ICP-OES) that indicated sonicated Gd-DOTA/DOX@PFH NDs uptake by cancer cells was approximately 1.5 times more than the non-sonicated nanodroplets after 12 h. In vitro and in vivo toxicity assays revealed that synthesized NDs are biocompatible and do not have organ toxicity. Ultrasound exposure significantly enhanced the release of doxorubicin from NDs (P-value< 0.05). Ultrasound echogenicity and T1-MRI relaxometry indicated that synthesized NDs have strong ultrasound signal intensity and high r1 relaxivity (6.34 mM−1 S−1). The concentration of DOX in mice vital organs for Gd-DOTA/DOX NDs was significantly lower than that of free DOX. Doxorubicin concentration after 150 min in the tumor region for the DOX-loaded Gd-NDs+US group reached 14.8 μg/g followed by sonication, which was 2.3 fold higher than that of the non-sonicated group. According to the obtained results, the synthesized nanodroplets, with excellent diagnostic (ultrasound/MRI) and therapeutic properties, could be promising theranostic agents in cancer imaging and drug delivery for chemotherapeutic application.

Induction of apoptosis in human hormone‐refractory prostate cancer cell lines by using resveratrol in combination with AT‐101

The aim of this study was to determine the appropriate doses of AT-101 and resveratrol combination in the in vitro hormone-refractory prostate cancer (PC) cell lines, in order to evaluate the cytotoxic and genotoxic effects of this combination on the proliferation of cancer cells, namely PC-3, DU-145 and LNCAP. Cytotoxicity in PC cell lines was analysed by using the XTT Cell Proliferation Assay. DNA damage was performed with the cell death assay. Apoptotic protein levels were performed by Roche Human Apoptosis Array. IC50 values were determined by XTT analysis. The strongest combined doses (100µM resveratrol+5µM AT-101) were found to have the strongest synergistic apoptotic and cytotoxic effects on DU-145 cells at 72hr. While the combined use of resveratrol and AT-101 increased the expression of markers in apoptotic cell pathways on cells, a decrease in the expression of anti-apoptotic markers was detected (p˂0.05). Combined applications of these compounds showed an important synergism in the hormone-refractory PC cell lines, and it was determined that after the post-translational modification, they were significantly effective on the apoptotic pathway. These results have revealed that the combination of resveratrol and AT-101 holds great expectation as a new chemotherapeutic application in the treatment of human prostate cancer.

Anticancer Activity of Some Ruthenium(III) Complexes with Quinolone Antibiotics: In Vitro Cytotoxicity, Cell Cycle Modulation, and Apoptosis-Inducing Properties in LoVo Colon Cancer Cell Line

Cisplatin is one of the most effective anticancer agents used to treat colon cancer, which is the third malignancy between the most common human cancers in the world, but the resistance developed represents an obstacle against the full success of chemotherapy. An emerging interest appeared in finding other metallic compounds, such as ruthenium(III) complexes, for chemotherapeutic application in cancer. Our study focused on the anticancer activity of several ruthenium (Ru) complexes with quinolone antibiotics in colon tumor cell cultures. Real-time cell analysis and drug-mediated cytotoxicity tests monitored the inhibitory effects in the drug-treated LoVo colon cancer cells. Flow cytometry assays were performed to evaluate cell cycle phases distribution and apoptotic events. The obtained results showed dose-dependent increased levels of cell lysis and induction of apoptosis in LoVo cancer cells treated with the Ru(III) complexes. In addition, data showed a major decrease in cell proliferation, since the percentages of cells distributed in the S cell cycle phase diminished, and a G0/G1 cell arrest was observed. Therefore, our results strongly suggest that the newly synthesized Ru(III) complexes might play an important role in future chemotherapeutic approaches, since their activity is based on diminishing cell proliferation, induction of apoptosis, and modulation of cell cycle phases.

Network pharmacology-based evaluation of natural compounds with paclitaxel for the treatment of metastatic breast cancer

Metastatic breast cancer is a prevalent life-threatening disease. Paclitaxel (PTX) is widely used in metastatic breast cancer therapy, but the side effects limit its chemotherapeutic application. Multidrug strategies have recently been used to maximize potency and decrease the toxicity of a particular drug by reducing its dosage. Therefore, we have evaluated the combined anti-cancerous effect of PTX with tested natural compounds (andrographolide (AND), silibinin (SIL), mimosine (MIM) and trans-anethole (TA)) using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, trypan blue dye exclusion assay, proliferating cell nuclear antigen (PCNA) staining, network pharmacology, molecular docking, molecular dynamics (MD) and in vivo chick chorioallantoic membrane (CAM) angiogenesis assay. We observed a reduction in the IC50 value of PTX with tested natural compounds. Further, the network pharmacology-based analysis of compound-disease-target (C-D-T) network showed that PTX, AND, SIL, MIM and TA targeted 55, 61, 56, 31 and 18 proteins of metastatic breast cancer, respectively. Molecular docking results indicated that AND and SIL inhibited the C-D-T network's core target kinase insert domain receptor (KDR) protein more effectively than others. While MD showed that the binding of AND with KDR was stronger and more stable than others. In trypan blue dye exclusion assay and PCNA staining, AND and SIL along with PTX were found to be more effective than PTX alone. CAM assay results suggested that AND, SIL and TA increase the anti-angiogenic potential of PTX. Thus, natural compounds can be used to improve the anti-cancer potential of PTX.

Influence of Clerodendrum volubile leaf extract on doxorubicin-induced toxicity and inhibition of carbonyl reductase mediated metabolism.

Doxorubicin (DOX) is a commonly used chemotherapeutic drug. However, its non-target organ toxicities pose a serious problem. This study is to assess the protective role of Clerodendrum volubile leaf extract (CVE) against DOX-induced toxicities in rats. In addition, the inhibitory activities of three phytochemical compounds (Rutin, Gallic acid and Rosmarinic acid) from CVE against Carbonyl reductase 1 (CBR1) were examined. Rats were randomly divided into 5 groups: (a) Control group rats were given 0.9% NaCl as vehicle, (b) DOX group: A single dose of DOX (25mg/kg; i.p.) was administered and rats were sacrificed 4days after DOX injection, while groups (c-e) CVE-treated DOX rat groups were given 125, 250 and 500mg/kg body weight of extracts orally for 12 consecutive days; 8days before, and 4days after the DOX administration. Computational techniques were used to determine the inhibitory activities of the compounds against CBR1. DOX intoxication caused a significant increase (p<0.05) in serum marker enzymes: ALT, AST, ALP, LDH, CK activities. The levels of liver and heart tissues antioxidant parameters: GPx, SOD, CAT, and GSH were significantly (p<0.05) decreased in DOX-intoxicated rats with concomitant elevation of malondialdehyde levels. Pretreatment with CVE reversed the above trends. From the structural analysis, Rutin and RSA exhibited the highest binding free energies against CBR1, and also exhibited structural stability when bound with CBR1. Our study indicates the protective effect of CVE when used in combination with doxorubicin thus improving its chemotherapeutic application via inhibition of CBR-mediated metabolism.

Analysis of a hybrid impulsive tumor-immune model with immunotherapy and chemotherapy

Abstract In this paper, a tumour-immune model with pulsed treatment of different frequency is proposed. The globally attractive conditions of the tumour-free periodic solution are presented in views of the comparison theorem for impulsive differential equations. Furthermore, the effect of period, dosage and times of drug delivery on the critical threshold is addressed by means of computer simulation, which indicates that there exists an optimal frequency of chemotherapeutic application. In addition, a tumour-immune model with fixed-time pulsed of immunotherapy and state feedback impulsive chemotherapy is given to keep the normal cells above and toxicity below the acceptable levels. Some numerical results are also provided to investigate the effect of the initial densities, predetermined threshold, drug dose and impulsive period on the dynamical behavior of hybrid impulsive system.

Comprehensive Set of Tertiary Complex Structures and Palmitic Acid Binding Provide Molecular Insights into Ligand Design for RXR Isoforms.

The retinoid X receptor (RXR) is a ligand-sensing transcription factor acting mainly as a universal heterodimer partner for other nuclear receptors. Despite presenting as a potential therapeutic target for cancer and neurodegeneration, adverse effects typically observed for RXR agonists, likely due to the lack of isoform selectivity, limit chemotherapeutic application of currently available RXR ligands. The three human RXR isoforms exhibit different expression patterns; however, they share high sequence similarity, presenting a major obstacle toward the development of subtype-selective ligands. Here, we report the discovery of the saturated fatty acid, palmitic acid, as an RXR ligand and disclose a uniform set of crystal structures of all three RXR isoforms in an active conformation induced by palmitic acid. A structural comparison revealed subtle differences among the RXR subtypes. We also observed an ability of palmitic acid as well as myristic acid and stearic acid to induce recruitment of steroid receptor co-activator 1 to the RXR ligand-binding domain with low micromolar potencies. With the high, millimolar endogenous concentrations of these highly abundant lipids, our results suggest their potential involvement in RXR signaling.

An actin depolymerizing agent 19,20-epoxycytochalasin Q of Xylaria sp. BCC 1067 enhanced antifungal action of azole drugs through ROS-mediated cell death in yeast

Multidrug resistance is a highly conserved phenomenon among all living organisms and a major veritable public health problem worldwide. Repetitive uses of antibiotics lead to antimicrobial drug resistance. Here, 19,20-epoxycytochalasin Q (ECQ) was isolated from endophytic fungus Xylaria sp. BCC 1067 and, its chemical structure was determined via chromatographic and spectral methods. ECQ displayed an antifungal activity with low MIC50 of 410 and 55 mg/l in the model yeast Saccharomyces cerevisiae wild-type and ScΔpdr5 strains, respectively. ECQ was a new inducer and potential substrate of key multi-drug efflux pumps S. cerevisiae ScPdr5 and Candida albicans CaCdr1. ECQ targeted actin filament, disrupting actin dynamics of yeast cells. ECQ also sensitized the ScΔsrv2 mutant, lacking suppressor of RasVal19. Overexpression of ScPDR5 or CaCDR1 genes prevented aggregation of actin and alleviated antifungal effect of ECQ. Additionally, ECQ induced high accumulation of reactive oxygen species, caused plasma membrane leakage and decreased yeast cell survival. Importantly, a discovery of ECQ implied a cellular connection between multi-drug resistance and actin stability, an important determinant of transporter mediated-drug resistance mechanism. Combination of ECQ and antifungal azoles displayed promising drug synergy against S. cerevisiae strains expressing multi-drug transporters, thereby providing potential solution for antifungal therapy and chemotherapeutic application.

HPLC Isolate from the Leaves of Kaffir Lime (Citrus hystrix DC) Exhibits Selective Cytotoxicity Against Human Breast Adenocarcinoma Cell Line, MCF-7

The increasing mortality and morbidity rate caused by breast cancer warrants the need to screen for compounds ideal for chemotherapeutic application. This study evaluated the cytotoxicity of Citrus hystrix leaves utilizing a bioactivity-guided fractionation scheme. Using various chromatographic techniques, the fractions were subjected to MTT [3-(4, 5-dimethylthiazol-2- yl)-2, diphenyltetrazo-lium bromide] assay to determine cytotoxicity and bioassays to confirm apoptosis as the mode of cell death. The results revealed that the crude extract was moderately cytotoxic against human breast adenocarcinoma (MCF-7) but not to other cancer cell lines tested. Solvent partitioning of the crude extract revealed that hexane partition exhibited the highest cytotoxicity (IC50: 23 μg/mL) to MCF-7. Sequentially, vacuum liquid chromatography (VLC) of the hexane partition separated VLC 7 (IC50: 17.2 μg/mL) with the highest percent yield. Hence, VLC 7 was subjected to gravity column chromatography (GCC), where GCC 7.4 exhibited promising cytotoxicity to MCF-7 (IC50: 14.6 μg/mL). Selectivity index (SI) indicated that GCC 7.4 was highly selective against MCF-7 (SI &gt; 2), relative to non-cancer cell lines NIH3T3, HDFn, and AA8. Interestingly, GCC 7.4 induced apoptosis as confirmed by several markers including phosphatidylserine (PS) membrane translocation, mitochondrial membrane depolarization, nuclear condensation, and DNA fragmentation. To further purify the components present in GCC 7.4, high-performance liquid chromatography (HPLC) was performed. HPLC 7.4.5 was active against MCF-7 (IC50: 5.5 μg/mL) without being cytotoxic against the non-cancer cell line NIH3T3. Overall, the results demonstrated that C. hystrix leaves possess promising compounds that are highly selective and cytotoxic against MCF-7 by inducing apoptosis.

Peptide-guided resiquimod-loaded lignin nanoparticles convert tumor-associated macrophages from M2 to M1 phenotype for enhanced chemotherapy

Nanomedicines represent innovative and promising alternative technologies to improve the therapeutic effects of different drugs for cancer ablation. Targeting M2-like tumor-associated macrophages (TAMs) has emerged as a favorable therapeutic approach to fight against cancer through the modulation of the tumor microenvironment. However, the immunomodulatory molecules used for this purpose present side effects upon systemic administration, which limits their clinical translation. Here, the biocompatible lignin polymer is used to prepare lignin nanoparticles (LNPs) that carry a dual agonist of the toll-like receptors TLR7/8 (resiquimod, R848). These LNPs are targeted to the CD206-positive M2-like TAMs using the “mUNO” peptide, in order to revert their pro-tumor phenotype into anti-tumor M1-like macrophages in the tumor microenvironment of an aggressive triple-negative in vivo model of breast cancer. Overall, we show that targeting the resiquimod (R848)-loaded LNPs to the M2-like macrophages, using very low doses of R848, induces a profound shift in the immune cells in the tumor microenvironment towards an anti-tumor immune state, by increasing the representation of M1-like macrophages, cytotoxic T cells, and activated dendritic cells. This effect consequently enhances the anticancer effect of the vinblastine (Vin) when co-administered with R848-loaded LNPs. Statement of significanceLignin-based nanoparticles (LNPs) were successfully developed to target a potent TLR7/8 agonist (R848) of the tumor microenvironment (TME). This was achieved by targeting the mannose receptor (CD206) on the tumor supportive (M2-like) macrophages with the “mUNO” peptide, to reprogram them into an anti-tumor (M1-like) phenotype for enhanced chemotherapy. LNPs modified the biodistribution of the R848, and enhanced its accumulation and efficacy in shifting the immunological profile of the cells in the TME, which was not achieved by systemic administration of free R848. Moreover, a reduction in the tumor volumes was observed at lower equivalent doses of R848 compared with other studies. Therefore, the co-administration of R848@LNPs is a promising chemotherapeutic application in aggressive tumors, such as the triple-negative breast cancer.

Chemotherapeutic efficacy of cucurmosin for pancreatic cancer as an alternative of gemcitabine: a comparative metabolomic study.

As the preferred drug for single chemotherapeutic application in pancreatic cancer, gemcitabine often demonstrated low sensitivity and strong chemotherapy resistance in patients. Therefore, the search for other drugs with high efficiency and low side effects has become of high importance. The aim of this study was to assess the therapeutic effects of cucurmosin on pancreatic cancer as an alternative of gemcitabine and explore its underlying biochemical mechanism. The subcutaneous xenograft mice with pancreatic cancer were treated by high- and low-dose cucurmosin and gemcitabine, respectively. A comparative metabolomic analysis was performed on the serum samples from the different groups by 1H nuclear magnetic resonance (NMR) techniques and then subjected to univariate and multivariate statistical analysis. Cucurmosin demonstrated a dose-dependent inhibition to the pancreatic tumors. High-dose cucurmosin provided similar chemotherapeutic efficacy with gemcitabine by positively regulating pyruvate metabolism, glycolysis or gluconeogenesis, and cysteine and methionine metabolism. Inactivating GFR signaling pathway and further inducing apoptosis of tumor cells are the important mechanism of anti-tumor function of cucurmosin. Cucurmosin is a promising chemotherapeutic drug for pancreatic cancer. However, the dose selection and surface modification should be optimized according to the stage of pancreatic cancer, and an expanded study in both laboratory and clinical regimes needs to be performed.

The protective effects of umbilical cord-derived endothelial colony forming cells on hepatic veno-occlusive disease.

Hepatic veno-occlusive disease (HVOD) characterized by endothelial cell dysfunction is one of the serious complications after hematopoietic stem-cell transplantation or chemotherapeutic drug application. The mortality of HVOD patients with multiorgan dysfunction is as high as 80%. The primary aim of this study was to evaluate whether the infusion of human umbilical cord-derived endothelial colony forming cells (hUC-ECFCs) could mitigate HVOD injury and investigate the underlying mechanism. We found that the expression of chemokine C-X-C chemokine ligand 12 (CXCL12) was markedly increased in the livers of HVOD mice. Meanwhile, hUC-ECFCs infusion could significantly ameliorate liver injury in HVOD mice, which was accompanied by hUC-ECFCs recruitment in the liver, reduced liver pathological alterations, and decreased serum alanine aminotransferase and aspartate aminotransferase activity. Besides, CXCL12-induced migration in hUC-ECFCs was partly impeded by chemokine receptor type 7 (CXCR7) silence or CXCR4 blockage. In conclusion, our results demonstrated that hUC-ECFCs could mitigate HVOD through homing to the injured liver via the CXCL12-CXCR4/CXCR7 signaling pathway.

Cathepsin B-Responsive Liposomes for Controlled Anticancer Drug Delivery in Hep G2 Cells.

In recent decades, several types of anticancer drugs that inhibit cancer cell growth and cause cell death have been developed for chemotherapeutic application. However, these agents are usually associated with side effects resulting from nonspecific delivery, which may induce cytotoxicity in healthy cells. To reduce the nonspecific delivery issue, nanoparticles have been successfully used for the delivery of anticancer drugs to specific target sites. In this study, a functional polymeric lipid, PEG-GLFG-K(C16)2 (PEG-GLFG, polyethylene glycol-Gly-Leu-Phe-Gly-Lys(C16)2), was synthesized to enable controlled anticancer drug delivery using cathepsin B enzyme-responsive liposomes. The liposomes composed of PEG-GLFG/DOTAP (1,2-dioleoyl-3-trimethylammonium-propane (chloride salt))/DPPC (dipalmitoylphosphatidylcholine)/cholesterol were prepared and characterized at various ratios. The GLFG liposomes formed were stable liposomes and were degraded when acted upon by cathepsin B enzyme. Doxorubicin (Dox) loaded GLFG liposomes (GLFG/Dox) were observed to exert an effective anticancer effect on Hep G2 cells in vitro and inhibit cancer cell proliferation in a zebrafish model.

New superior bioactive metal complexes of ligand with N, O donor atoms bearing sulfadiazine moiety: Physicochemical study and thermal behavior for chemotherapeutic application

Sulfadiazine is a drug famous for its anti-inflammatory, antimicrobial, and antitumor effects. Remarkably, its biological activity can be further enhanced upon incorporating a suitable metal ion. However, these metal-comprising complexes are not widely available. In the current study, a sulfadiazine Schiff base derivative was exploited as a ligand for synthesizing new complexes utilizing Cu(II), Co(II), Ni(II), Fe(III), and Cr(III) metals. The structural and analytical characteristics of the ligand and the newly prepared complexes were elucidated using various spectral and thermal investigations. Also, the biological activity of the ligand and the metal complexes, including the cytotoxic effect on normal cells and on liver malignant cells and the antimicrobial activity, was examined. The infrared spectra demonstrated that the ligand coordinated to all the added metal ions in a neutral form. It behaved in a bidentate manner in all mononuclear complexes. The new complexes exhibited octahedral geometry. Evaluating the biological activities revealed that the ligand and its novel metal-containing complexes had moderate antimicrobial activity, while the metal complexes, especially those comprising of Cr(III), Fe(III), and Cu(II), displayed a superior chemotherapeutic effect on HepG2 cell line in comparison to the ligand with very week or rare cytotoxic effects on normal human cells. Efficiently, new sulfadiazine Schiff base derivative-containing metal complexes with enhanced therapeutic potential were manufactured and could be applied on experimental models for the treatment of various types of infections and malignancies.

Selenium Anticancer Properties and Impact on Cellular Redox Status

(1) Background: In this review, we provide information published in recent years on the chemical forms, main biological functions and especially on antioxidant and prooxidant activities of selenium. The main focus is put on the impact of selenoproteins on maintaining cellular redox balance and anticancerogenic function. Moreover, we summarize data on chemotherapeutic application of redox active selenium compounds. (2) Methods: In the first section, main aspects of metabolism and redox activity of selenium compounds is reviewed. The second outlines multiple biological functions, asserted when selenium is incorporated into the structure of selenoproteins. The final section focuses on anticancer activity of selenium and chemotherapeutic application of redox active selenium compounds as well. (3) Results: optimal dietary level of selenium ensures its proper antioxidant and anticancer activity. We pay special attention to antioxidant activities of selenium compounds, especially selenoproteins, and their importance in antioxidant defence. It is worth noting, that data on selenium anticancer properties is still contraversive. Moreover, selenium compounds as chemotherapeutic agents usually are used at supranutritional doses. (4) Conclusions: Selenium play a vital role for many organism systems due to its incorporation into selenoproteins structure. Selenium possesses antioxidant activity at optimal doses, while at supranutritional doses, it displays prooxidant activity. Redox active selenium compounds can be used for cancer treatment; recently special attention is put to selenium containing nanoparticles.