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While drug therapy plays a crucial role in cancer treatment, many anticancer drugs, particularly cytotoxic and molecular-targeted drugs, cause severe side effects, which often limit the dosage of these drugs. Efforts have been made to alleviate these side effects by developing derivatives, analogues, and liposome formulations of existing anticancer drugs and by combining anticancer drugs with substances that reduce side effects. However, these approaches have not been sufficiently effective in reducing side effects. Molecular hydrogen (H2) has shown promise in this regard. It directly reduces reactive oxygen species, which have very strong oxidative capacity, and indirectly exerts antioxidant, anti-inflammatory, and anti-apoptotic effects by regulating gene expression. Its clinical application in various diseases has been expanded worldwide. Although H2 has been reported to reduce the side effects of anticancer drugs in animal studies and clinical trials, the underlying molecular mechanisms remain unclear. Our comprehensive literature review revealed that H2 protects against tissue injuries induced by cisplatin, oxaliplatin, doxorubicin, bleomycin, and gefitinib. The underlying mechanisms involve reductions in oxidative stress and inflammation. H2 itself exhibits anticancer activity. Therefore, the combination of H2 and anticancer drugs has the potential to reduce the side effects of anticancer drugs and enhance their anticancer activities. This is an exciting prospect for future cancer treatments. [ABSTRACT FROM AUTHOR]

Cuproptosis, a newly discovered form of programmed cell death, relies on mitochondrial respiration, the chain of which has been found to be altered in ovarian cancer (OC). The current work probed into the effects of Cuproptosis on the prognosis, immune microenvironment and therapeutic response of OC based on Cuproptosis-related lncRNAs. Data on OC gene expression and clinical characteristics were collected from TCGA, ICGC and GEO databases, and mRNA and lncRNA were distinguished. Cuproptosis-related lncRNAs were screened for consensus clustering analysis. Differentially expressed lncRNAs (DElncRNAs) were identified between clusters, and least absolute shrinkage and selection operator (LASSO) and Cox regression analysis were performed to establish a prognostic signature. Its potential value in OC was evaluated by Gene Set Enrichment Analysis (GSEA), tumor cell mutation and immune microenvironment analysis, and response to immunotherapy and antineoplastic drugs. According to the classification scheme of Cuproptosis-related lncRNAs, OC was divided into four molecular subtypes, which were different in survival time, immune characteristics and somatic mutation. The prognostic signature between subtypes included 10 lncRNAs, which were significantly correlated with the prognosis, immune microenvironment related indexes, the expression of immune checkpoint molecules and the sensitivity of antineoplastic drug Paclitaxel and Gefitinib of OC. We examined the expression of ten LncRNAs in OC cell lines and found that LINC00189, ZFHX4-AS1, RPS6KA2-IT1 and C9orf106 were expressed elevated in OC cell lines, and LINC00861, LINC00582, DEPDC1-AS1, LINC01556, LEMD1-AS1, TYMSOS expression was decreased in OC cell lines. The results of CCK8 showed that the cell viability of OC cells decreased after inhibition of C9orf106, whereas the cell viability of OC cells increased after inhibition of LEMD1-AS1. This work revealed new Cuproptosis-related lncRNA molecular subtypes exhibiting tumor microenvironment (TME) heterogeneity for OC and proposed a prognostic signature that may have benefits in understanding the prognosis, pathological features and immune microenvironment of OC patients. [ABSTRACT FROM AUTHOR]

Peptidergic systems show promise as targets for fighting tumors. While some peptides encourage the growth and spread of tumor cells and angiogenic mechanisms, others display antitumor properties. As such, peptide ligands and receptor antagonists could be used as antitumor agents alone or in conjunction with chemotherapy or radiotherapy. Peptide receptor antagonists can counteract the oncogenic effects of specific peptides by inducing apoptosis in various types of tumor cells, hindering cancer cell migration and inhibiting angiogenesis. Peptides and peptide receptor antagonists are not currently used in clinical practice as antitumor agents. Still, aprepitant, a neurokinin 1 receptor antagonist, is a promising candidate due to its ability to promote apoptosis in many cancer cells. However, to utilize aprepitant as an anticancer agent, the dosage must be increased and administered for a more extended period. Moving beyond current protocols for aprepitant’s use as an antiemetic is essential. Additionally, a common anticancer strategy with aprepitant is possible regardless of cancer cell type. Finally, combining aprepitant with chemotherapy or radiotherapy is encouraged.

Definition: Peptidergic systems show promise as targets for fighting tumors. While some peptides encourage the growth and spread of tumor cells and angiogenic mechanisms, others display antitumor properties. As such, peptide ligands and receptor antagonists could be used as antitumor agents alone or in conjunction with chemotherapy or radiotherapy. Peptide receptor antagonists can counteract the oncogenic effects of specific peptides by inducing apoptosis in various types of tumor cells, hindering cancer cell migration and inhibiting angiogenesis. Peptides and peptide receptor antagonists are not currently used in clinical practice as antitumor agents. Still, aprepitant, a neurokinin 1 receptor antagonist, is a promising candidate due to its ability to promote apoptosis in many cancer cells. However, to utilize aprepitant as an anticancer agent, the dosage must be increased and administered for a more extended period. Moving beyond current protocols for aprepitant's use as an antiemetic is essential. Additionally, a common anticancer strategy with aprepitant is possible regardless of cancer cell type. Finally, combining aprepitant with chemotherapy or radiotherapy is encouraged. [ABSTRACT FROM AUTHOR]

In this study, 14 structurally novel gefitinib-1,2,3-triazole derivatives were synthesized using a click chemistry approach and characterized by 1H NMR, 13C NMR and high-resolution mass spectrometry (HRMS). Preliminary cell counting kit-8 results showed that most of the compounds exhibit excellent antitumor activity against epidermal growth factor receptor wild-type lung cancer cells NCI-H1299, A549 and NCI-H1437. Among them, 4b and 4c showed the most prominent inhibitory effects. The half maximal inhibitory concentration (IC50) values of 4b were 4.42 ± 0.24 μM (NCI-H1299), 3.94 ± 0.01 μM (A549) and 1.56 ± 0.06 μM (NCI-1437). The IC50 values of 4c were 4.60 ± 0.18 µM (NCI-H1299), 4.00 ± 0.08 μM (A549) and 3.51 ± 0.05 μM (NCI-H1437). Furthermore, our results showed that 4b and 4c could effectively inhibit proliferation, colony formation and cell migration in a concentration-dependent manner, as well as induce apoptosis in H1299 cells. In addition, 4b and 4c exerted its anti-tumor effects by inducing cell apoptosis, upregulating the expression of cleaved-caspase 3 and cleaved-PARP and downregulating the protein levels of Bcl-2. Based on these results, it is suggested that 4b and 4c be developed as potential new drugs for lung cancer treatment. [ABSTRACT FROM AUTHOR]

Cell cycle-dependent kinase 2 (CDK2) is located downstream of CDK4/6 in the cell cycle and regulates cell entry into S-phase by binding to Cyclin E and hyper-phosphorylating Rb. Proto-oncogene murine double minute 2 (MDM2) is a key negative regulator of p53, which is highly expressed in tumors and plays an important role in tumorigenesis and progression. In this study, we identified a dual inhibitor of CDK2 and MDM2, III-13, which had good selectivity for inhibiting CDK2 activity and significantly reduced MDM2 expression. In vitro results showed that III-13 inhibited proliferation of a wide range of tumor cells, regardless of whether Cyclin E1 (CCNE1) was overexpressed or not. The results of in vivo experiments showed that III-13 significantly inhibited proliferation of tumor cells and did not affect body weight of mice. The results of the druggability evaluation showed that III-13 was characterized by low bioavailability and poor membrane permeability when orally administered, suggesting the necessity of further structural modifications. Therefore, this study provided a lead compound for antitumor drugs, especially those against CCNE1-amplified tumor proliferation. [ABSTRACT FROM AUTHOR]

While drug therapy plays a crucial role in cancer treatment, many anticancer drugs, particularly cytotoxic and molecular-targeted drugs, cause severe side effects, which often limit the dosage of these drugs. Efforts have been made to alleviate these side effects by developing derivatives, analogues, and liposome formulations of existing anticancer drugs and by combining anticancer drugs with substances that reduce side effects. However, these approaches have not been sufficiently effective in reducing side effects. Molecular hydrogen (H2) has shown promise in this regard. It directly reduces reactive oxygen species, which have very strong oxidative capacity, and indirectly exerts antioxidant, anti-inflammatory, and anti-apoptotic effects by regulating gene expression. Its clinical application in various diseases has been expanded worldwide. Although H2 has been reported to reduce the side effects of anticancer drugs in animal studies and clinical trials, the underlying molecular mechanisms remain unclear. Our comprehensive literature review revealed that H2 protects against tissue injuries induced by cisplatin, oxaliplatin, doxorubicin, bleomycin, and gefitinib. The underlying mechanisms involve reductions in oxidative stress and inflammation. H2 itself exhibits anticancer activity. Therefore, the combination of H2 and anticancer drugs has the potential to reduce the side effects of anticancer drugs and enhance their anticancer activities. This is an exciting prospect for future cancer treatments.

Cabozantinib malate (CBZM), a new anticancer medication, has been studied for its solubility and thermodynamic properties in a variety of {dimethyl sulfoxide (DMSO) + water (H2O)} mixtures at 298.2–318.2 K and 101.1 kPa. Using the shake flask technique, the solubility of CBZM was assessed and the results were correlated to the van't Hoff, Apelblat, Buchowski–Ksiazczak λh, Yalkowsky–Roseman, Jouyban–Acree, and Jouyban–Acree-van't Hoff models. There was a significant correlation between the experimental CBZM solubility data and all computational models, as evidenced by the error values for all computational models being less than 5.0%. Temperature and DMSO mass percentage improved the CBZM mole fraction solubility in the cosolvent solutions of {DMSO + H2O}. At 318.2 K, pure DMSO had the highest mole fraction solubility of CBZM (4.38 × 10−2), whereas pure H2O had the lowest mole fraction solubility (2.24 × 10−7 at 298.2 K). The positive values of computed thermodynamic parameters indicated that the dissolution of CBZM was endothermic and entropy-driven in all of the {DMSO + H2O} solutions investigated. It was found that the CBZM solvation in {DMSO + H2O} solutions is governed by enthalpy. When compared to CBZM-H2O, CBZM-DMSO showed the highest molecular interactions. The findings of this investigation demonstrated that DMSO has a great deal of potential for CBZM solubilization in H2O. [ABSTRACT FROM AUTHOR]

The DNA origami method has revolutionized the field of DNA nanotechnology since its introduction. These nanostructures, with their customizable shape and size, addressability, nontoxicity, and capacity to carry bioactive molecules, are promising vehicles for therapeutic delivery. Different approaches have been developed for manipulating and folding DNA origami, resulting in compact lattice-based and wireframe designs. Platinum-based complexes, such as cisplatin and phenanthriplatin, have gained attention for their potential in cancer and antiviral treatments. Phenanthriplatin, in particular, has shown significant antitumor properties by binding to DNA at a single site and inhibiting transcription. The present work aims to study wireframe DNA origami nanostructures as possible carriers for platinum compounds in cancer therapy, employing both cisplatin and phenanthriplatin as model compounds. This research explores the assembly, platinum loading capacity, stability, and modulation of cytotoxicity in cancer cell lines. The findings indicate that nanomolar quantities of the ball-like origami nanostructure, obtained in the presence of phenanthriplatin and therefore loaded with that specific drug, reduced cell viability in MCF-7 (cisplatin-resistant breast adenocarcinoma cell line) to 33%, while being ineffective on the other tested cancer cell lines. The overall results provide valuable insights into using wireframe DNA origami as a highly stable possible carrier of Pt species for very long time-release purposes. [ABSTRACT FROM AUTHOR]

Background: Ferroptosis is an emerging type of regulated cell death and associated with antitumoral therapy, while some microRNAs have been shown to regulate the tumorigenesis and cancer progression. Meanwhile, polyphyllin I (PPI) has exhibited antitumoral effects by promoting cancer cell apoptosis and ferroptosis. However, it is unclear whether PPI induces cancer cell ferroptosis by regulating microRNAs. Methods: We used two gastric cancer cell lines (AGS and MKN-45) to set up a tumor model of the nude mice, which were then treated daily with PPI to measure the cancer growth in vitro and in vivo. Ferroptosis was measured using immunofluorescence staining and flow cytometric analysis according to levels of intracellular ROS, lipid ROS and ferrous ions. Moreover, NRF2 expression was measured by Western blotting. In some experiments, the mimics or inhibitors of miR-124-3p were used to further confirm its involvement in PPI-induced cancer cell ferroptosis. Results: Here we found that miR-124-3p mediated cancer ferroptosis and tumor repression induced by PPI since PPI increased miR-124-3p expression in gastric cancer cells and promoted their ferroptosis, whereas inhibition of miR-124-3p mostly abolished the effects of PPI on tumor growth, ferroptosis and NRF2 expression. Moreover, miR-124-3p mimics promoted cancer cell ferroptosis by downregulating NRF2 through directly targeting 3′-UTR region of NRF2, confirming a role for miR-124-3p in regulating PPI-induced ferroptosis. Conclusion: PPI exerts its antitumoral effects on the gastric cancer by promoting cell ferroptosis via regulating miR-124-3p. Our findings have clinical implications for cancer chemotherapy. [ABSTRACT FROM AUTHOR]

A novel superatom-assembled Zr12O12 nanocage has been theoretically designed and characterized to investigate its potential application as a novel delivery carrier for 5-fluorouracil (5-Fu), mercaptopurine (MP), and thioguanine (TG) via density functional theory calculations in this work. The designed Zr12O12 nanocage possesses high stability in view of its large binding energy (E b), atomic cohesion energy (E col), and highest occupied molecular orbital-lowest unoccupied molecular orbital gap. Our results reveal that Zr12O12 tends to bind with 5-Fu via a single Zr–O bond and combine with MP and TG through multidentate chelate modes with the adsorption energies of −22.27 to −55.19 kcal mol−1. The Wiberg bond index, atoms in molecules theory, and localized molecular orbitals analyses demonstrate that all the newly formed linkage bonds between Zr12O12 and drugs are polar covalent bonds. In particular, among these studied drugs, the recovery time for the near-infrared light-triggered release of TG drug from Zr12O12 surface is the shortest, indicating that Zr12O12 can serve as an excellent candidate for the delivery of TG. This study not only offers a new member to enrich the inorganic nanocage family but also provides a potential carrier for the delivery of anticancer drugs. [ABSTRACT FROM AUTHOR]

Traditional chemotherapy drugs have definite antitumor mechanisms and good therapeutic efficacy; however, their poor water solubility, serious side effects and drug resistance limit their clinical application. To the best of our knowledge, the present study reported for the first time the in vivo and in vitro anticancer effects of procyanidin B1 (PCB1), a compound that is isolated from natural sources such as grape seeds, apples, peanut skin and cranberries. Cell Counting Kit-8 assay showed that PCB1 effectively decreased the number of viable HCT-116 cells compared with cells treated with the small molecule cytotoxic drug doxorubicin. Quantitative PCR and apoptosis analysis, Cell cycle analysis, and WB analysis) of the molecular mechanism showed that PCB1 induced cell apoptosis and cell cycle arrest in S phase by increasing expression of pro-apoptosis protein caspase-3 and BAX and decreasing expression of anti-apoptosis protein Bcl-2. The efficient antitumor activity of PCB1 was demonstrated through in vivo experiments on a xenograft mouse model, demonstrating that PCB1 significantly suppressed tumor growth. The present study suggested that PCB1 represents a novel class of plant-based compounds isolated from natural sources that can be applied as an anticancer drug. [ABSTRACT FROM AUTHOR]

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The antitumor efficacy of Chinese herbal medicines has been widely recognized. Leading compounds such as sterols, glycosides, flavonoids, alkaloids, terpenoids, phenylpropanoids, and polyketides constitute their complex active components. The antitumor monomers derived from Chinese medicine possess an attractive anticancer activity. However, their use was limited by low bioavailability, significant toxicity, and side effects, hindering their clinical applications. Recently, new chemical entities have been designed and synthesized by combining natural drugs with other small drug molecules or active moieties to improve the antitumor activity and selectivity, and reduce side effects. Such a novel conjugated drug that can interact with several vital biological targets in cells may have a more significant or synergistic anticancer activity than a single‐molecule drug. In addition, antitumor conjugates could be obtained by combining pharmacophores containing two or more known drugs or leading compounds. Based on these studies, the new drug research and development could be greatly shortened. This study reviews the research progress of conjugates with antitumor activity based on Chinese herbal medicine. It is expected to serve as a valuable reference to antitumor drug research and clinical application of traditional Chinese medicine. [ABSTRACT FROM AUTHOR]

Context Lung cancer, the most common type of cancer, has a high mortality rate. Cucurbitacin B (CuB), a natural compound extracted from Cucurbitaceae plants, has antitumor effects. Objective We investigated the role of CuB on lung cancer and its potential mechanisms. Materials and methods A549 cells were treated with 0.1, 0.3, 0.6, and 0.9 μM CuB for 12, 24, and 48 h or untreated. Gene and protein levels were evaluated by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting. Enzyme-linked immunosorbent assay (ELISA) detected inflammatory factors levels (TNF-α and IL-10). 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), flow cytometry, and colony formation assays measured cell viability, apoptosis, and proliferation. The interaction between miR-let-7c and long non-coding RNA X inactive-specific transcript (XIST) or interleukin-6 (IL-6) was verified by dual-luciferase reporter assays. Results CuB treatment inhibited the proliferation of lung cancer cells and promoted cell apoptosis, and increased the expression of Bax and cleaved caspase3, decreased cyclin B1 and Bcl-2 expression. CuB suppressed XIST and IL-6 expression, and enhanced miR-let-7c expression. XIST silencing enhanced the inhibitory effect of CuB on cell proliferation and the promotion effect on apoptosis via upregulating miR-let-7c. Moreover, XIST targeted miR-let-7c to activate the IL-6/STAT axis. MiR-let-7c overexpression enhanced the regulatory effect of CuB on proliferation and apoptosis via suppressing the IL-6/STAT3 pathway. Discussion and conclusion CuB regulated cell proliferation and apoptosis by inhibiting the XIST/miR-let-7c/IL-6/STAT3 axis in lung cancer. These findings indicate CuB may have the possibility of clinical application in lung cancer treatment.

In this study, 14 structurally novel gefitinib-1,2,3-triazole derivatives were synthesized using a click chemistry approach and characterized by 1H NMR, 13C NMR and high-resolution mass spectrometry (HRMS). Preliminary cell counting kit-8 results showed that most of the compounds exhibit excellent antitumor activity against epidermal growth factor receptor wild-type lung cancer cells NCI-H1299, A549 and NCI-H1437. Among them, 4b and 4c showed the most prominent inhibitory effects. The half maximal inhibitory concentration (IC50) values of 4b were 4.42 ± 0.24 μM (NCI-H1299), 3.94 ± 0.01 μM (A549) and 1.56 ± 0.06 μM (NCI-1437). The IC50 values of 4c were 4.60 ± 0.18 µM (NCI-H1299), 4.00 ± 0.08 μM (A549) and 3.51 ± 0.05 μM (NCI-H1437). Furthermore, our results showed that 4b and 4c could effectively inhibit proliferation, colony formation and cell migration in a concentration-dependent manner, as well as induce apoptosis in H1299 cells. In addition, 4b and 4c exerted its anti-tumor effects by inducing cell apoptosis, upregulating the expression of cleaved-caspase 3 and cleaved-PARP and downregulating the protein levels of Bcl-2. Based on these results, it is suggested that 4b and 4c be developed as potential new drugs for lung cancer treatment.

Cell cycle-dependent kinase 2 (CDK2) is located downstream of CDK4/6 in the cell cycle and regulates cell entry into S-phase by binding to Cyclin E and hyper-phosphorylating Rb. Proto-oncogene murine double minute 2 (MDM2) is a key negative regulator of p53, which is highly expressed in tumors and plays an important role in tumorigenesis and progression. In this study, we identified a dual inhibitor of CDK2 and MDM2, III-13, which had good selectivity for inhibiting CDK2 activity and significantly reduced MDM2 expression. In vitro results showed that III-13 inhibited proliferation of a wide range of tumor cells, regardless of whether Cyclin E1 (CCNE1) was overexpressed or not. The results of in vivo experiments showed that III-13 significantly inhibited proliferation of tumor cells and did not affect body weight of mice. The results of the druggability evaluation showed that III-13 was characterized by low bioavailability and poor membrane permeability when orally administered, suggesting the necessity of further structural modifications. Therefore, this study provided a lead compound for antitumor drugs, especially those against CCNE1-amplified tumor proliferation.

Metal-organic frameworks (MOFs) are mixed porous materials which are composed of metal clusters or ions and organic pillars. Given their channel tunability, high porosity, large specific surface area, and good biocompatibility, MOFs can be combined with various biological macromolecules. In recent years, they have been widely studied in the field of biomedicine, especially in the loading of anti-tumor drugs, showing great application prospects. Multifunctional anti-tumor MOF combined with different therapeutic methods provides a new idea and method for tumor treatment. On the basis of the structure of MOF, this paper introduces the advantages of using MOF to load anti-tumor drugs and reviews the application of MOF in tumor therapy.

Abnormal angiogenesis plays a key role in cancer progression. In recent years, anti-angiogenic therapy has attracted increasing attention. Berberine (BBR), the main component extracted from Coptis (Ranunculaceae) rhizome, has an anti-angiogenic effect. However, the underlying mechanisms remain to be elucidated. Endothelial cell proliferation is a pivotal process in angiogenesis. In our research, we observed that BBR specifically downregulated the expression of the extracellular signal-regulated kinase 1/2 (ERK1/2) protein in human umbilical vein endothelial cells (HUVECs). The role of BBR in HUVEC proliferation was then assessed using methylthiazolyldiphenyl-tetrazolium bromide and cell counting Kit-8 (CCK-8) assays. The effect of BBR on the ERK1/2 signaling pathway was evaluated using Western blotting. BBR decreased HUVEC proliferation in a dose-dependent manner and inhibited the expression of phospho-ERK1/2 in HUVECs. PD98059, a specific inhibitor of ERK1/2 signaling, attenuated the BBR-induced decrease in the proliferation of HUVECs. Phorbol 12-myristate 13-acetate, a natural activator of ERK1/2 signaling, did not alter BBR-induced proliferation. In conclusion, BBR inhibited endothelial cell proliferation by suppressing ERK1/2 signaling. These findings may provide a potential therapeutic strategy for suppressing tumor growth. [ABSTRACT FROM AUTHOR]

Cisplatin (CDDP) is a potent antitumor drug used in first-line chemotherapy against several solid tumors, including breast cancer. However, toxicities and drug resistance limit its clinical application. Thermosensitive liposome (TSL) functionalized with hyaluronic acid (HA) containing cisplatin (TSL-CDDP-HA) was developed by our research group aiming to promote the release of CDDP in the tumor region under hyperthermia conditions, as well as to decrease toxicity. Thus, this study aimed to evaluate this new formulation (HA-coated TSL-CDDP) concerning in vitro behavior and in vivo toxicity compared to non-coated TSL-CDDP and free CDDP. Cytotoxicity assays and nuclear morphology were carried out against triple-negative breast cancer cells (MDA-MB-231), while an in vivo toxicity study was performed using healthy Swiss mice. The results showed an increase (around 3-fold) in cytotoxicity of the cationic formulation (non-coated TSL-CDDP) compared to free CDDP. On the other hand, TSL-CDDP treatment induced the appearance of 2.5-fold more senescent cells with alteration of nuclear morphology than the free drug after hyperthermia condition. Furthermore, the association of liposomal formulations treatment with hyperthermia increased the percentage of apoptotic cells compared to those without heating. The percentage of apoptotic cells was 1.7-fold higher for TSL-CDDP-HA than for TSL-CDDP. For the in vivo toxicity data, the TSL-CDDP treatment was also toxic to healthy cells, inducing nephrotoxicity with a significant increase in urea levels compared to the saline control group (73.1 ± 2.4 vs. 49.2 ± 2.8 mg/mL). On the other hand, the HA-coated TSL-CDDP eliminated the damages related to the use of CDDP since the animals did not show changes in hematological and biochemical examinations and histological analyses. Thus, data suggest that this new formulation is a potential candidate for the intravenous therapy of solid tumors. [ABSTRACT FROM AUTHOR]

Although the clinical application of nanoparticles is still limited by biological barriers and distribution, with the deepening of our understanding of nanoparticles over the past decades, people are gradually breaking through the previous limitations in the diagnosis and treatment of tumors, providing novel strategies for clinical decision makers. The transition of nanoparticles from passive targeting to active tumor-targeting by abundant surface-modified nanoparticles is also a development process of precision cancer treatment. Different particles can be used as targeted delivery tools of antitumor drugs. The mechanism of gold nanoparticles inducing apoptosis and cycle arrest of tumor cells has been discovered. Moreover, the unique photothermal effect of gold nanoparticles may be widely used in tumor therapy in the future, with less side effects on surrounding tissues. Lipid-based nanoparticles are expected to overcome the blood–brain barrier due to their special characteristics, while polymer-based nanoparticles show better biocompatibility and lower toxicity. In this paper, we discuss the development of nanoparticles in tumor therapy and the challenges that need to be addressed. [ABSTRACT FROM AUTHOR]

• Five new cocrystals of TMZ with aromatic acids, aromatic amide, and TMZ monohydrate were synthesized. • The cocrystal formations are stabilized by N–H···O, O–H···O, O–H···N hydrogen bonds and π⋅⋅⋅π interactions. • The cocrystals demonstrated better stability and dissolution properties compared to pure TMZ. • TMZ-4NO 2 BA⋅H 2 O cocrystal hydrate showed improved cytotoxicity than the pure drug on LN229 Glioblastoma cells. Temozolomide (TMZ), the first-line anti-glioblastoma prodrug, hydrolyses at physiological pH (pH>7) in the aqueous medium. With a short elimination half-life (T1/2) of ∼1.8 h, TMZ hydrolytically metabolizes to its metabolites 5-(3-monomethyl-1-triazeno)imidazole-4-carboxamide (MTIC) and then further into 5-aminoimidazole-4-carboxamide (AIC). The objective of current work is to develop novel stable cocrystals of TMZ with safe coformers such as isonicotinic acid (INA), 4-nitrobenzoic acid (4NO 2 BA), 3-aminobenzoic acid (3ABA), salicylic acid (2-hydroxybenzoic acid, 2HBA) and aromatic amide 4-hydroxybenzamide (4HBz) to stabilize the drug in a cocrystal form. All the cocrystals were characterized by single crystal X-ray diffraction (SCXRD), powder XRD (PXRD), and thermogravimetry-differential scanning calorimetry (TG-DSC) analyses. Dissolution profiling in phosphate buffer saline pH 6.8 revealed that the drug release rate from TMZ–2HBA Form II cocrystals and TMZ–4NO 2 BA⋅H 2 O cocrystal hydrate were significantly higher than pure TMZ. The hydrolytic stability of all the cocrystals and hydrates in pH 6.8 buffer was longer than that of TMZ while showing three-fold hydrolytic stability in case of TMZ–4NO 2 BA⋅H 2 O and TMZ-2HBA cocrystals. Their lattice arrangements in SCXRD explain the improved hydrolytic stability in these two cases. In vitro studies on human glioblastoma cell lines showed a significant improvement in the cytotoxicity and possibly improved bioavailability of TMZ–4NO 2 BA⋅H 2 O cocrystal hydrate. [Display omitted] [ABSTRACT FROM AUTHOR]

Cabozantinib malate (CBZM), a new anticancer medication, has been studied for its solubility and thermodynamic properties in a variety of {dimethyl sulfoxide (DMSO) + water (H2O)} mixtures at 298.2–318.2 K and 101.1 kPa. Using the shake flask technique, the solubility of CBZM was assessed and the results were correlated to the van’t Hoff, Apelblat, Buchowski–Ksiazczak λh, Yalkowsky–Roseman, Jouyban–Acree, and Jouyban–Acree-van’t Hoff models. There was a significant correlation between the experimental CBZM solubility data and all computational models, as evidenced by the error values for all computational models being less than 5.0%. Temperature and DMSO mass percentage improved the CBZM mole fraction solubility in the cosolvent solutions of {DMSO + H2O}. At 318.2 K, pure DMSO had the highest mole fraction solubility of CBZM (4.38 × 10−2), whereas pure H2O had the lowest mole fraction solubility (2.24 × 10−7 at 298.2 K). The positive values of computed thermodynamic parameters indicated that the dissolution of CBZM was endothermic and entropy-driven in all of the {DMSO + H2O} solutions investigated. It was found that the CBZM solvation in {DMSO + H2O} solutions is governed by enthalpy. When compared to CBZM-H2O, CBZM-DMSO showed the highest molecular interactions. The findings of this investigation demonstrated that DMSO has a great deal of potential for CBZM solubilization in H2O.

Using genetic engineering technology, the green fluorescent protein (GFP) reporter gene plasmid was constructed, which is convenient for live-cell imaging, Western blot (WB), cell flow analysis and live-cell tracing, so as to realize the screening of anti-tumor drugs. The promoter sequence of NF-κB gene and GFP gene fragment were amplified by polymerase chain reaction (PCR), cloned into the pGL6-Enhancer vector, and the plasmid construction was proved by colony PCR, digestion identification and sequencing. The successful plasmid is then transfected into HEK-293T cells, and the reported plasmid is normally expressed within the cell based on live-cell fluorescence imaging, WB and flow cytometry. Finally, the anti-tumor drugs rapamycin, paclitaxel, gemcitabine, and the peptide anti-tumor drugs M1-20 and M1-21, which were being developed in our laboratory, were selected to verify that the gene system can respond to the effects of the drug on cells. The establishment of this drug screening platform provides a useful tool for studying the effects of anti-tumor drugs on cells, and also provides materials for building a live cell tracer system. [ABSTRACT FROM AUTHOR]

Metal-organic frameworks (MOFs) are mixed porous materials which are composed of metal clusters or ions and organic pillars. Given their channel tunability, high porosity, large specific surface area, and good biocompatibility, MOFs can be combined with various biological macromolecules. In recent years, they have been widely studied in the field of biomedicine, especially in the loading of anti-tumor drugs, showing great application prospects. Multifunctional anti-tumor MOF combined with different therapeutic methods provides a new idea and method for tumor treatment. On the basis of the structure of MOF, this paper introduces the advantages of using MOF to load anti-tumor drugs and reviews the application of MOF in tumor therapy. [ABSTRACT FROM AUTHOR]

Unsymmetrical bisacridines (UAs) represent a novel class of anticancer agents. Their high cytotoxicity towards multiple human cancer cell lines and inhibition of human tumor xenograft growth in nude mice signal their potential for cancer treatment. Therefore, the mechanism of their strong biological activity is broadly investigated. Here, we explore the efflux and metabolism of UAs, as both strongly contribute to the development of drug resistance in cancer cells. We tested two highly cytotoxic UAs, C-2028 and C-2045, as well as their glucuronic acid and glutathione conjugates in human cancer cell lines (HepG2 and LS174T). As a point of reference for cell-based systems, we examined the rate of UA metabolic conversion in cell-free systems. A multiple reaction monitoring (MRM)-mass spectrometry (MS) method was developed in the present study for analysis of UAs and their metabolic conversion in complex biological matrices. Individual analytes were identified by several features: their retention time, mass-to-charge ratio and unique fragmentation pattern. The rate of UA uptake and metabolic transformation was monitored for 24 h in cell extracts and cell culture medium. Both UAs were rapidly internalized by cells. However, C-2028 was gradually accumulated, while C-2045 was eventually released from cells during treatment. UAs demonstrated limited metabolic conversion in cells. The glucuronic acid conjugate was excreted, whereas the glutathione conjugate was deposited in cancer cells. Our results obtained from cell-free and cell-based systems, using a uniform MRM-MS method, will provide valuable insight into the mechanism of UA biological activity in diverse biological models. [Display omitted] • Development of MRM-MS method for analysis of UAs in biological samples. • UA metabolic transformation is high in cell-free and low in cell-based systems. • HepG2 and LS174T cancer cells accumulate C-2028 and release C-2045 over time. • The C-2028 glutathione conjugate is deposited in cancer cells. • The C-2045 glucuronic acid conjugate is promptly released from cancer cells. [ABSTRACT FROM AUTHOR]

Ferroptosis is a form of non-apoptotic and iron-dependent cell death originally identified in cancer cells. Recently, emerging evidence showed that ferroptosis-targeting therapy could be a novel promising anti-tumour treatment. However, systematic analyses of ferroptosis-related genes for the prognosis of non-small cell lung cancer (NSCLC) and the development of antitumor drugs exploiting the ferroptosis process remain rare. This study aimed to identify genes related to ferroptosis and NSCLC and to initially screen lead compounds that induce ferroptosis in tumor cells. We downloaded mRNA expression profiles and NSCLC clinical data from The Cancer Genome Atlas database to explore the prognostic role of ferroptosis-related genes. Four prognosis-associated ferroptosis-related genes were screened using univariate Cox regression analysis and the lasso Cox regression analysis, which could divide patients with NSCLC into high- and low-risk groups. Then, based on differentially expressed risk- and ferroptosis-related genes, the negatively correlated lead compound flufenamic acid (FFA) was screened through the Connective Map database. This project confirmed that FFA induced ferroptosis in A549 cells and inhibited growth and migration in a dose-dependent manner through CCK-8, scratch, and immunofluorescence assays. In conclusion, targeting ferroptosis might be a therapeutic alternative for NSCLC.

Enzyme‐responsive and biocompatible supramolecular nanocarriers (NCs) have attracted intensive attention in the field of biomaterials, and have found many feasible applications, particularly for controlling drug‐release at specific anchor sites where the enzyme is overexpressed. However, the introduction of specific enzyme‐responsive sites in drug nanocarriers that can be enzymatically triggered to release drugs within tumor cells remains a challenge. In this manuscript, an enzyme‐responsive supramolecular nanoparticle, (SBE)7m‐β‐CD ⊃ PS NPs is successfully prepared, based on inducing aggregation of negatively charged cyclodextrin toward positively charged protein. The obtained nanoparticles showed trypsin‐trigger disassemble behavior that is considered as drug vehicles to load antitumor drug celastrol (CSL). Furthermore, CSL‐loaded NPs exhibit controlled release behavior of CSL in response to trypsin (TPS) stimulation. Notably, cell biology experiments reveal that loading CSL by (SBE)7m‐β‐CD ⊃ PS NPs not only reduces cytotoxicity for normal cells but also presents a similar therapeutic effect of free CSL for five tumor cells. The obtained nanoparticle appears to hold practical potential for the controllable release of CSL in tumor cells. [ABSTRACT FROM AUTHOR]

Background: Genetic instability leads to genome mutations, changes in nucleotide sequences, rearrangements, and gains or losses of part of the chromosomes. This instability can initiate and develop cancer. This study evaluated genomic stability in methotrexate and anthocyanin-treated mammary adenocarcinoma model. Seventy albino mice were divided into seven groups: negative control, anthocyanin, methotrexate, Ehrlich's solid tumor; Ehrlich's solid tumor and methotrexate; Ehrlich's solid tumor and anthocyanin; and Ehrlich's solid tumor, methotrexate, and anthocyanin groups. Results: Tumor weight and size were evaluated. Serum arylesterase activity was low in all the induced tumors and those treated with anthocyanin, methotrexate, or both. Poly[adenosine diphosphate (ADP)-ribose] polymerase activity was high, and glutathione S-transferase activity was low in the tumors treated with anthocyanin, methotrexate, or both, compared with that of the untreated tumor. There was an increase in DNA damage in the mice with solid tumors and those injected with methotrexate or methotrexate and anthocyanin, compared with that in the untreated mice. Conclusions: There was a decrease in genetic instability and DNA damage in the tumor-bearing mice treated with anthocyanin, with a concomitant increase in nuclear poly[adenosine diphosphate (ADP)-ribose] polymerase activity, compared with those of the untreated group. Anthocyanin exerted positive effects in the treatment of mammary adenocarcinoma. [ABSTRACT FROM AUTHOR]

Abstract Background CD47 is a widely expressed transmembrane protein located on the surface of somatic cells. It mediates a variety of cellular processes including apoptosis, proliferation, adhesion, and migration. An important role for CD47 is the transmission of a “Don't eat me” signal by interacting with SIRPα on the macrophage surface membrane, thereby preventing the phagocytosis of normal cells. However, cancer cells can take advantage of this autogenous signal to protect themselves from phagocytosis, thus enabling immune escape. Blocking the interaction between CD47 and SIRPα has proven to be effective in removing cancer cells. The treatment of various cancers with CD47 monoclonal antibodies has also been validated. Methods We designed and synthesized a peptide (RS17), which can specifically bind to CD47 and block CD47‐SIRPα signaling. The affinity of RS17 for CD47‐expressing tumor cells was determined, while the inhibition of CD47‐SIRPα signaling was evaluated in vitro and in vivo. Results The results indicated that RS17 significantly promotes the phagocytosis of tumor cells by macrophages and had a similar therapeutic effect compared with a positive control (CD47 monoclonal antibodies). In addition, a cancer xenograft mouse model was established using CD47‐expressing HepG2 cells to evaluate the effect of RS17 on tumor growth in vivo. Using ex vivo and in vivo mouse models, RS17 demonstrated a high inhibitory effect on tumor growth. Conclusions Based on our results, RS17 may represent a novel therapeutic peptide for cancer therapy.

Imatinib mesilate is a well-known antitumor target inhibitor of protein tyrosine kinase, which is effective in different cancer types expressing Bcr / Abl and, in particular, in hemoblastosis. A higher interest to imatinib during the COVID-19 epidemic is explained by the fact that cancer patients are one of the COVID-19 risk groups. Moreover, imatinib target mechanism of action, which is effective in cancer, can have a high potential against the most severe COVID-19 complication such as the disease associated pulmonary fibrosis. COVID-19 associated interstitial pulmonary fibrosis develops as an autoimmune process caused by systemic inflammation with atypical (idiopathic) pneumonia resulting from acute respiratory distress syndrome with the tyrosine kinase mechanism of signaling pathway activation and cellular response. Experi-mental and clinical results showing antifibrotic and dose-related antithrombotic imatinib effect demonstrate perspective use of this antitumor agent to correct COVID-19 associated pneumonia causing a high death rate of patients with COVID-19.The review presents literature data of 2001–2020 discussing pathologic genetic and clinical characteristics of the fibrosis which exacerbates COVID-19 pneumonia in adults. The sequence of the disease processes demonstrates that disease progression with the decreasing oxygen saturation in the peripheral blood intensifies local thrombosis in the lungs. As a result, hypoxia is developing, which is difficult to control and can cause lethal outcome in severe cases. Yet, the conventional antifibrotic and thrombolytic agents can only partially control the process of pneumofibrosis including that of cancer patients. The approximate antifibrotic dose of imatinib 400 mg / day is therapeutic for oncopatho-logy. The antitumor drug registered in many countries and well described side effects and contraindications needs no long-term registration studies for a new indication, therefore, it may be easily prepared for clinical testing.

Background: During the past decades, increasing attention has been given to elucidating the molecular details of interactions between the pharmacological agents and nucleic acids since the drug–DNA complexation may lead to impairment of DNA replication, strand breaking and mutations. A variety of techniques have been developed to characterize the drug-nucleic acid binding, among which the fluorescence dye displacement assay is one of the most informative approaches. Recently, it was demonstrated that cyanine dyes can be successfully employed for the high throughput screening of the interactions between nucleic acids and drugs. To the best of our knowledge, so far, the potential application of cyanine dyes for the drug-displacement studies remains insufficiently evaluated. Objectives: The aim of the present study was to investigate the ability of a novel cyanine dye to serve as a competitor for the potential antitumor compounds, lanthanide complexes bearing europium (III) tris-β-diketonate (EC) for the DNA and RNA binding sites. Materials and methods: Calf thymus DNA, yeast RNA, trimethine cyanine dye and lanthanide complexes bearing europium (III) tris-β-diketonate were used for sample preparation. The fluorescence data were acquired using Perkin-Elmer LS-55 spectrofluorimeter. Results: Using the fluorescence spectroscopy technique we conducted the displacement reaction trimethine cyanine dye/europium coordination complexes in the presence of double stranded DNA and single-stranded RNA. An increase of the EC concentration in the systems AK3-5/DNA or AK3-5/RNA was followed by a gradual reduction in the AK3-5 fluorescence intensity, indicating that europium (III) tris-β-diketonate compounds can serve as competitors for the trimethine cyanine dye on the nucleic acids. Both the drug chemical structure and the type of nucleic acid proved to control the extent of EC-induced decrease of AK3-5 fluorescence in the presence of the DNA or RNA. Conclusion: By recruiting the potential antitumor agents europium chelate complexes as the competitive ligands for the cyanine dye for the DNA and RNA binding sites, we found that a novel trimethine compound can be effectively used in the fluorescence drug displacement assays.

The aim was to assess the possibility of optimizing the costs of drugs for cancer patients in a subject of the Russian Federation considering the expiration of patent protection period.Materials and methods. The possibility of optimizing the costs of antitumor drugs was studied using a model of a hypothetical region with a population of 2 million. A gradual replacement of the reference drugs with expiring patent protection by generics or biosimilars over 5 years was simulated. Two replacement scenarios were analyzed: 1) maintaining the drug consumption at a stable level; 2) increasing the drug consumption to the level identified in a previous retrospective analysis of the pharmaceutical market. The baseline scenario implied that the drug purchases remained unchanged (in physical and monetary terms) at the level of 2018. We calculated the difference between the drug costs in the baseline scenario and the costs of the same drugs replaced with generics or biosimilars for a 5 year period.Results. By gradually replacing the reference drugs with generics or biosimilars in a region with a population of 2 million and keeping the costs of drugs for solid tumors at the 352.2 million rubles for 5 years (baseline scenario), 69.4 million rubles can be saved. That amount represents 19.7% of the base level if the drug consumption remains at the 2018 level. With an increase in the INN consumption after the release of generics/ biosimilars, no saving is expected; on the contrary, expenses will increase by 14.1% to 400 million rubles, although, an 8.45-fold increase in consumption is projected.Conclusion. With the appearance of generics / biosimilars for the treatment of solid malignant tumors, the possibility of fund saving depends on the increase in drug consumption.

Cisplatin (CDDP) is a potent antitumor drug used in first-line chemotherapy against several solid tumors, including breast cancer. However, toxicities and drug resistance limit its clinical application. Thermosensitive liposome (TSL) functionalized with hyaluronic acid (HA) containing cisplatin (TSL-CDDP-HA) was developed by our research group aiming to promote the release of CDDP in the tumor region under hyperthermia conditions, as well as to decrease toxicity. Thus, this study aimed to evaluate this new formulation (HA-coated TSL-CDDP) concerning in vitro behavior and in vivo toxicity compared to non-coated TSL-CDDP and free CDDP. Cytotoxicity assays and nuclear morphology were carried out against triple-negative breast cancer cells (MDA-MB-231), while an in vivo toxicity study was performed using healthy Swiss mice. The results showed an increase (around 3-fold) in cytotoxicity of the cationic formulation (non-coated TSL-CDDP) compared to free CDDP. On the other hand, TSL-CDDP treatment induced the appearance of 2.5-fold more senescent cells with alteration of nuclear morphology than the free drug after hyperthermia condition. Furthermore, the association of liposomal formulations treatment with hyperthermia increased the percentage of apoptotic cells compared to those without heating. The percentage of apoptotic cells was 1.7-fold higher for TSL-CDDP-HA than for TSL-CDDP. For the in vivo toxicity data, the TSL-CDDP treatment was also toxic to healthy cells, inducing nephrotoxicity with a significant increase in urea levels compared to the saline control group (73.1 ± 2.4 vs. 49.2 ± 2.8 mg/mL). On the other hand, the HA-coated TSL-CDDP eliminated the damages related to the use of CDDP since the animals did not show changes in hematological and biochemical examinations and histological analyses. Thus, data suggest that this new formulation is a potential candidate for the intravenous therapy of solid tumors.

In recent years, with the development of nanomaterials, the research of drug delivery systems has become a new field of cancer therapy. Compared with conventional antitumor drugs, drug delivery systems such as drug nanoparticles (NPs) are expected to have more advantages in antineoplastic effects, including easy preparation, high efficiency, low toxicity, especially active tumor-targeting ability. Drug delivery systems are usually composed of delivery carriers, antitumor drugs, and even target molecules. At present, there are few comprehensive reports on a summary of drug delivery systems applied for tumor therapy. This review introduces the preparation, characteristics, and applications of several common delivery carriers and expounds the antitumor mechanism of different antitumor drugs in delivery carriers in detail which provides a more theoretical basis for clinical application of personalized cancer nanomedicine in the future. [ABSTRACT FROM AUTHOR]

In recent years, with the development of nanomaterials, the research of drug delivery systems has become a new field of cancer therapy. Compared with conventional antitumor drugs, drug delivery systems such as drug nanoparticles (NPs) are expected to have more advantages in antineoplastic effects, including easy preparation, high efficiency, low toxicity, especially active tumor-targeting ability. Drug delivery systems are usually composed of delivery carriers, antitumor drugs, and even target molecules. At present, there are few comprehensive reports on a summary of drug delivery systems applied for tumor therapy. This review introduces the preparation, characteristics, and applications of several common delivery carriers and expounds the antitumor mechanism of different antitumor drugs in delivery carriers in detail which provides a more theoretical basis for clinical application of personalized cancer nanomedicine in the future.

Although the clinical application of nanoparticles is still limited by biological barriers and distribution, with the deepening of our understanding of nanoparticles over the past decades, people are gradually breaking through the previous limitations in the diagnosis and treatment of tumors, providing novel strategies for clinical decision makers. The transition of nanoparticles from passive targeting to active tumor-targeting by abundant surface-modified nanoparticles is also a development process of precision cancer treatment. Different particles can be used as targeted delivery tools of antitumor drugs. The mechanism of gold nanoparticles inducing apoptosis and cycle arrest of tumor cells has been discovered. Moreover, the unique photothermal effect of gold nanoparticles may be widely used in tumor therapy in the future, with less side effects on surrounding tissues. Lipid-based nanoparticles are expected to overcome the blood–brain barrier due to their special characteristics, while polymer-based nanoparticles show better biocompatibility and lower toxicity. In this paper, we discuss the development of nanoparticles in tumor therapy and the challenges that need to be addressed.

Chemotherapy is one of the important means of tumor therapy. However, most of the anti-tumor drugs that currently used in clinic are hydrophobic non-specific drugs, which seriously affect the efficacy of drugs. With the development of nanotechnology, drug efficacy can be improved by selecting appropriate biodegradable nanocarriers for achieving the controlled release, targeting and higher bioavailability of drugs. This paper reviewed the research progress of anti-tumor drug nanoparticle carriers, which mainly summarized the materials used for anti-tumor drug nanoparticle carriers and their effects in anti-tumor drugs, as well as the targeted drug delivery methods of anti-tumor drugs based on nanocarriers.

Chemotherapy is one of the important means of tumor therapy. However, most of the anti-tumor drugs that currently used in clinic are hydrophobic non-specific drugs, which seriously affect the efficacy of drugs. With the development of nanotechnology, drug efficacy can be improved by selecting appropriate biodegradable nanocarriers for achieving the controlled release, targeting and higher bioavailability of drugs. This paper reviewed the research progress of anti-tumor drug nanoparticle carriers, which mainly summarized the materials used for anti-tumor drug nanoparticle carriers and their effects in anti-tumor drugs, as well as the targeted drug delivery methods of anti-tumor drugs based on nanocarriers. [ABSTRACT FROM AUTHOR]

The in vitro antitumor activity (e.g. IC50) of anticancer drugs is important for selecting candidate compounds for in vivo drug efficacy study in the early stage of drug discovery. In this study, we investigated the relationship between in vitro IC50 and in vivo EC50 using six heat shock protein 90 (HSP90) inhibitors. IC50 of each compound was calculated from in vitro cell proliferation assays using the NCI-N87 cancer cell line. Each compound was administered to NCI-N87 xenograft mice, and EC50 and the maximum tumour-killing rate constant were calculated from pharmacokinetics/pharmacodynamics analyses using plasma concentrations and tumour volumes. IC50 obtained in vitro was poorly correlated with EC50 obtained in vivo, while a good correlation (r = 0.856) was observed between them when corrected with the unbound fraction ratio. The results of this study using of HSP90 inhibitors as model compounds suggest importance of the consideration of an unbound fraction to evaluate the relationship between IC50 and EC50. These results will contribute to improvement in the prediction accuracy of in vivo drug efficacy from in vitro activity and the efficiency of drug discovery research. [ABSTRACT FROM AUTHOR]

Tissue‐clearing technology is an emerging imaging technique currently utilized not only in neuroscience research but also in cancer research. In our previous reports, tissue‐clearing methods were used for the detection of metastatic tumors. Here, we showed that the cell cycles of primary and metastatic tumors were visualized by tissue‐clearing methods using a reporter system. First, we established cancer cell lines stably expressing fluorescent ubiquitination‐based cell cycle indicator (Fucci) reporter with widely used cancer cell lines A549 and 4T1. Fluorescence patterns of the Fucci reporter were investigated in various tumor inoculation models in mice. Interestingly, fluorescence patterns of the Fucci reporter of tumor colonies were different between various organs, and even among colonies in the same organs. The effects of antitumor drugs were also evaluated using these Fucci reporter cells. Of the three antitumor drugs studied, 5‐fluorouracil treatment on 4T1‐Fucci cells resulted in characteristic fluorescent patterns by the induction of G2/M arrest both in vitro and in vivo. Thus, the combination of a tissue‐clearing method with the Fucci reporter is useful for analyzing the mechanisms of cancer metastasis and drug resistance. [ABSTRACT FROM AUTHOR]

[Display omitted] • Novel PEGylated liposomes boost Idelalisib efficacy and lower toxicity. • Nanosized liposomes with prime entrapment and stability ready for preclinical tests. • Liposomal delivery augments Idelalisib's cytotoxicity in lymphoma B cells. • Idelalisib and nanotechnologies synergize for enhanced cancer therapy. New drugs and technologies are continuously developed to improve the efficacy and minimize the critical side effects of cancer treatments. The present investigation focuses on the development of a liposomal formulation for Idelalisib, a small-molecule kinase inhibitor approved for the treatment of lymphoid malignancies. Idelalisib is a potent and selective antitumor agent, but it is not indicated nor recommended for first-line treatment due to fatal and serious toxicities. Herein, liposomes are proposed as a delivery tool to improve the therapeutic profile of Idelalisib. Specifically, PEGylated liposomes were prepared, and their physicochemical and technological features were investigated. Light-scattering spectroscopy and cryo-transmission electron microscopy revealed nanosized unilamellar vesicles, which were proved to be stable in storage and in simulated biological fluids. The cytotoxicity of the liposome formulation was investigated in a human non-Hodgkin's lymphoma B cell line. Idelalisib was able to induce death of tumor cells if delivered by the nanocarrier system at increased efficacy. These findings suggest that combining Idelalisib and nanotechnologies may be a powerful strategy to increase the antitumor efficacy of the drug. [ABSTRACT FROM AUTHOR]

مقدمه: سامانه‌های دارورسانی حاوی داروهای ضد سرطان، مزایای بسیاری در رهایش دارو نسبت به داروهای خوراکی یا تزریقی در درمان سرطان دارند. بنابراین، ساخت سامانه‌هایی برای تحویل کنترل شده‌ی داروهای ضد سرطان در سال‌های اخیر، توجه زیادی را به خود جلب کرده است. روش‌ها: در این تحقیق، نانوذرات کیتوزان (Chitosan-based nanoparticles یا CsNPs) به روش ژل شدن یونی تهیه شد و به عنوان حامل داروی دوکسوروبیسین (Doxorubicin یا DOX) مورد استفاده قرار گرفت. نانوذرات کیتوزان، قبل و بعد از بارگذاری دارو با استفاده از روش‌های میکروسکوپ الکترونی روبشی (Scanning electron microscope یا SEM)، پراکندگي نور پويا (Dynamic light scattering یا DLS) و پتانسیل زتا مورد ارزیابی قرار گرفتند. یافته‌ها: نتایج آزمون‌های برون‌تن (In vitro) انجام شده بر روی این سیستم از نظر میزان رهایش دارو نشان داد نمونه‌ی ساخته شده گزینه‌ی بسیار مناسبی به عنوان حامل داروی ضد سرطان DOX است؛ چرا که با رهایش کنترل شده‌ی دارو در بازه‌ی زمانی (از 120-0 ساعت) به صورت رهایش آهسته و پیوسته، می‌تواند در مقابله با سلول‌های سرطانی مؤثرتر عمل کند. نتیجه‌گیری: بر اساس یافته‌های این مطالعه، استفاده از سامانه‌ی دارورسانی CsNPs/DOX می‌تواند جایگزین ممتازی به جای استفاده از دزهای متعدد تزریق دوکسوروبیسین برای درمان سرطان سینه باشد و محدودیت‌های مربوط به استفاده از این دارو به شیوه‌ی شیمی‌درمانی را مرتفع نماید.

The present study was undertaken to assess the applicability of the novel trimethine cyanine dye AK3-5 as a competitive ligand for the antitumor agents, Eu(III) coordination complexes (EC), in the DNA-containing systems, using the displacement assay as an analytical instrument. The analysis of fluorescence spectra revealed a strong association of AK3-5 with nucleic acids, with the strength of interaction being higher for the double stranded DNA, compared to the single-stranded RNA. The binding parameters of the cyanine dye have been determined in terms of the McGhee & von Hippel neighbouring site-exclusion model and a classical Langmuir model. The AK3-5 association constant in the presence of DNA was found to be equal to 5.1×104 M-1, which is consistent to those of the well-known DNA intercalators. In turn, the binding of the cyanine to the RNA was characterized by a significantly lower association constant ( ~ 3.4×103 M-1) indicating either the external or “partially intercalated” binding mode. The addition of the europium complexes to the AK3-5-DNA system was followed by the fluorescence intensity decrease, with a magnitude of this effect being dependent on the EC structure. The observed fluorescence decrease of AK3-5 in the presence of europium complexes V7 and V9 points to the competition between the cyanine dye and antitumor drugs for the DNA binding sites. The dependencies of the AK3-5-DNA fluorescence intensity decrease vs. europium complex concentration were analyzed in terms of the Langmuir adsorption model, giving the values of the drug association constant equal to 5.4×104 M-1and 3.9×105 M-1 for the europium complexes V7 and V9, respectively. A more pronounced decrease of the AK3-5 fluorescence in the presence of V5 and V10 was interpreted in terms of the drug-induced quenching of the dye fluorescence, accompanying the competition between AK3-5 and Eu(III) complexes for the DNA binding sites. Cumulatively, the results presented here strongly suggest that AK3-5 can be effectively used in the nucleic acid studies and in the dye-drug displacement assays.

Abstract Background Recombinant human calcineurin B subunit (rhCNB) has been shown to be an immune‐stimulatory protein promoting cytokine production and inducing phenotypic maturation of Dendritic cells (DCs). In vivo, it has good antitumor efficacy, and has potential as an antitumor drug. Exogenous rhCNB was found to be internalized into tumor cells via the Toll‐like receptor 4 (TLR4) complex, but it was not known whether its immuno‐modulatory and antitumor functions involved entry by this same route. Methods The production and secretion of the cytokines and chemokines in innate immune cells induced by rhCNB were determined by ELISA, and the expression of CD40, CD80, CD86, and MHCII was analyzed by FACs. Experimental Lewis lung cancer (LLC) model was prepared in C57 BL/6 wild‐type (WT) mice, TLR4−/− mice or their littermates by the inoculation of LLCs in their right armpit, and then administrated daily intraperitoneal injections (0.2 mL) of normal saline, rhCNB 20 mg/kg, and rhCNB 40 mg/kg, respectively. Results Recombinant human calcineurin B subunit promoted the production of antitumor cytokines by innate immune cells, and culture supernatants of rhCNB‐stimulated immune cells induced apoptosis of LLCs. In addition, rhCNB up‐regulated CD40, CD80, CD86, and MHCII expression in macrophages and DCs in TLR4+ cells but failed to do so in TLR4 deficient cells. rhCNB also induced the formation of CD4+ and CD8+T cells in splenocytes from WT mice, but not from TLR4‐deficient littermates. Intraperitoneal administration of WT C57BL/6 mice with rhCNB resulted in a 50% reduction in LLC tumor growth, but failed to inhibit tumor growth in TLR4−/− littermates. Conclusions The in vivo antitumor and immunomodulatory effects of rhCNB are mediated by the TLR4. This conclusion is important for the further understanding and development of rhCNB as an antitumor drug.

The synthesis and characterization of four platinum(II) complexes using azobenzenes conveniently functionalized as ligands has been carried out. The characteristic photochemical behavior of the complexes due to the presence of azobenzene-type ligands and the role of the ligands in the activation of the complexes has been studied. Their promising cytotoxicity observed in HeLa cells prompted us to study the mechanism of action of these complexes as cytostatic agents. The interaction of the compounds with DNA, studied by circular dichroism, revealed a differential activity of the Pt(II) complexes upon irradiation. The intercalation abilities of the complexes as well as their reactivity with common proteins present in the blood stream allows to confirm some of the compounds obtained as good anticancer candidates. [ABSTRACT FROM AUTHOR]

Electrochemotherapy is an effective strategy for the treatment of solid tumors by exposing tumor cells to electric fields to enhance the bioactivity of non‐permeable or low permeable anticancer drugs, such as cisplatin. To understand the improved efficiency of cisplatin in the electrochemotherapy, the effects of oriented external electric fields (OEEFs) on the geometric structure and relevant electronic properties of cisplatin have been systemically investigated by density functional theory (DFT) computations in this work. Our results reveal that the presence of selective OEEFs on cisplatin can not only weaken its Pt‐Cl bonds, but also enhance the intramolecular charge transfer in it, which effectively accelerates the critical hydrolysis step involved in the mechanism of biological activity for this drug. Moreover, the chosen OEEFs can facilitate the attack of the singly aquated cis‐[Pt(NH3)2(H2O)Cl]+ on DNA, and enlarge the water solubility of cisplatin and its aquated product. These OEEF‐induced geometric and electronic modifications can indeed help to improve the antitumor activity of cisplatin, which provides a deeper insight into the higher efficacy of electrochemotherapy than traditional chemotherapy from a molecular point of view. [ABSTRACT FROM AUTHOR]

Background: CD47 is a widely expressed transmembrane protein located on the surface of somatic cells. It mediates a variety of cellular processes including apoptosis, proliferation, adhesion, and migration. An important role for CD47 is the transmission of a "Don't eat me" signal by interacting with SIRPα on the macrophage surface membrane, thereby preventing the phagocytosis of normal cells. However, cancer cells can take advantage of this autogenous signal to protect themselves from phagocytosis, thus enabling immune escape. Blocking the interaction between CD47 and SIRPα has proven to be effective in removing cancer cells. The treatment of various cancers with CD47 monoclonal antibodies has also been validated. Methods: We designed and synthesized a peptide (RS17), which can specifically bind to CD47 and block CD47‐SIRPα signaling. The affinity of RS17 for CD47‐expressing tumor cells was determined, while the inhibition of CD47‐SIRPα signaling was evaluated in vitro and in vivo. Results: The results indicated that RS17 significantly promotes the phagocytosis of tumor cells by macrophages and had a similar therapeutic effect compared with a positive control (CD47 monoclonal antibodies). In addition, a cancer xenograft mouse model was established using CD47‐expressing HepG2 cells to evaluate the effect of RS17 on tumor growth in vivo. Using ex vivo and in vivo mouse models, RS17 demonstrated a high inhibitory effect on tumor growth. Conclusions: Based on our results, RS17 may represent a novel therapeutic peptide for cancer therapy. [ABSTRACT FROM AUTHOR]

Management of bone metastasis is becoming increasingly important. Thus, local and systemic treatment options have been developed for control. Although systemic administration of anticancer agents is effective for bone metastasis, it is often stopped because of poor general conditions or side effects. Therefore, it is highly desirable to develop a more effective and safer local treatment for bone metastasis. The purpose of the current study was to investigate the antitumor effects and safety of gelatin hydrogel microspheres incorporating cisplatin (GM‐CDDP), which we developed as a sustained release system without harmful substances. First, we assessed GM‐CDDP for its in vitro degradability and potential for sustained release. Second, in vivo antitumor and side effects were evaluated using a murine bone metastasis model of MDA‐MB‐231 human breast cancer cells incorporating GFP. In vitro, initial bursts were observed within 2 h and CDDP was released gradually with gelatin hydrogel degradation, which reached 100% at 48 h. In vivo, local administration of GM‐CDDP (2 mg/kg) significantly suppressed tumor growth and bone osteolysis compared with the control, and local and systemic administration of free CDDP (2 mg/kg; p < 0.05). Local administration of GM‐CDDP significantly reduced loss of body weight and elevation of blood urea nitrogen compared with the systemic administration of free CDDP (p <.05). The current study suggests that local administration of GM‐CDDP achieves higher antitumor effects with a potential for lesser side effects compared with local or systemic administration of free CDDP. [ABSTRACT FROM AUTHOR]

We isolated a novel lectin (AHL) from Artocarpus hypargyreus Hance and showed its immunomodulatory activities. In this study, the amino acid sequence of AHL was determined by cDNA sequencing. AHL cDNA (875bp) contains a 456-bp open reading frame (ORF), which encodes a protein with 151 amino acids. AHL is a new member of jacalin-related lectin family (JRLs), which share high sequence similarities to KM + and Morniga M , and contain the conserved carbohydrate binding domains. The antitumor activity of AHL was also explored using Jurkat T cell lines. AHL exhibits a strong binding affinity to cell membrane, which can be effectively inhibited by methyl- α -D-galactose. AHL inhibits cell proliferation in a time- and dose-dependent manner through apoptosis, evidenced by morphological changes, phosphatidylserine externalization, poly ADP-ribose polymerase (PARP) cleavage, Bad and Bax up-regulation, and caspase-3 activation. We further showed that the activation of ERK and p38 signaling pathways is involved for the pro-apoptotic effect of AHL. [ABSTRACT FROM AUTHOR]