Strong Cytotoxicity Research Articles

Biological activities of different plant species belonging to the Asteraceae family

Achillea biebersteinii and Anthemis tinctoria, which are widely distributed species of the Asteraceae family, are used in folk medicine in the form of herbal tea or extract in the treatment of many diseases. The aim of this study was to investigate the chemical content, antimicrobial, antioxidant, enzyme inhibitor activities and cytotoxic effects of 80% ethanol extract of these two species and make a comparative analysis. In accordance with the data obtained, the major component of A. biebersteinii was determined as Cyclododecane (14.47%), while that of A. tinctoria was determined as Phytol (23.15%). A. biebersteinii, which showed moderate activity in terms of antimicrobial activity, produced more active inhibition than A. tinctoria did. Both plants showed high levels of antioxidant activity. The total phenol and total flavonoid contents of A. tinctoria were higher than those of A. biebersteinii. It was determined that there was no significant activity when the extracts were compared with galanthamine, which is the reference drug in terms of enzyme inhibitory activity. When the in vitro anticancer activity of human breast cancer cell line was examined, it was determined that A. tinctoria had a cytotoxic effect at high concentrations (IC50;0.82mg/mL), and A. biebersteinii showed strong cytotoxicity at all concentrations (IC50;<0.0625mg/mL). These two plants of the same family were evaluated in terms of many different biological parameters and it was revealed that A. biebersteinii was more active than A. tinctoria. However, in vivo studies are needed to determine whether these plants can be used as phytotherapeutic agents.

Induced pluripotent stem cell-derived dendritic cell vaccine therapy genetically modified on the ubiquitin-proteasome system.

We previously reported that dendritic cells (DCs) transduced with the full-length tumor-associated antigen (TAA) gene induced TAA-specific cytotoxic T lymphocytes (CTLs) to elicit antitumor responses. To overcome the issue of quantity and quality of DCs required for DC vaccine therapy, we focused on induced pluripotent stem cells (iPSCs) as a new tool for obtaining DCs and reported efficacy of iPSCs-derived DCs (iPSDCs). However, in clinical application of iPSDC vaccine therapy, further enhancement of the antitumor effect is necessary. In this study, we targeted mesothelin (MSLN) as a potentially useful TAA, and focused on the ubiquitin-proteasome system to enhance antigen-presenting ability of iPSDCs. The CTLs induced by iPSDCs transduced with MSLN gene (iPSDCs-MSLN) from healthy donors showed cytotoxic activity against autologous lymphoblastoid cells (LCLs) expressing MSLN (LCLs-MSLN). The CTLs induced by iPSDCs transduced ubiquitin-MSLN fusion gene exhibited higher cytotoxic activity against LCLs-MSLN than the CTLs induced by iPSDCs-MSLN. The current study was designed that peripheral T-cell tolerance to MSLN could be overcome by the immunization of genetically modified iPSDCs simultaneously expressing ubiquitin and MSLN, leading to a strong cytotoxicity against tumors endogenously expressing MSLN. Therefore, this strategy may be promising for clinical application as an effective cancer vaccine therapy.

Establishment of a novel NFAT-GFP reporter platform useful for the functional avidity maturation of HLA class II-restricted TCRs

CD4+ T cells that recognize antigenic peptides presented on HLA class II are essential for inducing an optimal anti-tumor immune response, and adoptive transfer of tumor antigen-specific TCR-transduced CD4+ T cells with high responsiveness against tumor is a promising strategy for cancer treatment. Whereas a precise evaluation method of functional avidity, an indicator of T cell responsiveness against tumors, has been established for HLA class I-restricted TCRs, it remains unestablished for HLA class II-restricted TCRs. In this study, we generated a novel platform cell line, CD4-2D3, in which GFP reporter was expressed by NFAT activation via TCR signaling, for correctly evaluating functional avidity of HLA class II-restricted TCRs. Furthermore, using this platform cell line, we succeeded in maturating functional avidity of an HLA class II-restricted TCR specific for a WT1-derived helper peptide by substituting amino acids in complementarity determining region 3 (CDR3) of the TCR. Importantly, we demonstrated that transduction of an avidity-maturated TCR conferred strong cytotoxicity against WT1-expressing leukemia cells on CD4+ T cells, compared to that of its original TCR. Thus, CD4-2D3 cell line should be useful not only to evaluate TCR functional avidity in HLA class II-restricted TCRs but also to screen appropriate TCRs for clinical applications such as cancer immunotherapy.

Synthesis and Biological Activities of 11- and 12-Substituted Benzophenanthridinone Derivatives as DNA Topoisomerase IB and Tyrosyl-DNA Phosphodiesterase 1 Inhibitors.

Herein, a series of 11- or 12-substituted benzophenanthridinone derivatives was designed and synthesized for the discovery of dual topoisomerase IB (TOP1) and tyrosyl-DNA phosphodiesterase 1 (TDP1) inhibitors. Enzyme-based assays indicated that two compounds 12 and 38 showed high TOP1 inhibitory potency (+++), and four compounds 35, 37, 39 and 43 showed good TDP1 inhibition with IC50 values ranging from 10 to 18 μM. 38 could induce cellular TOP1cc formation, resulting in the highest cytotoxicity against HCT-116 cells (0.25 μM). The most potent TDP1 inhibitor 43 (10 μM) could induce cellular TDP1cc formation and enhance topotecan-induced DNA damage and showed strong synergistic cytotoxicity with topotecan in both MCF-7 and MCF-7/TDP1 cells.

Bioactive secondary metabolites from endophytic strains of Neocamarosporium betae collected from desert plants.

Endophytic fungi from desert plants belong to a unique microbial community that has been scarcely investigated chemically and could be a new resource for bioactive natural products. In this study, 13 secondary metabolites (1-13) with diverse carbon skeletons, including a novel polyketide (1) with a unique 5,6-dihydro-4H,7H-2,6-methanopyrano[4,3-d][1,3]dioxocin-7-one ring system and three undescribed polyketides (2, 7, and 11), were obtained from the endophytic fungus Neocamarosporium betae isolated from two desert plant species. Different approaches, including HR-ESI-MS, UV spectroscopy, IR spectroscopy, NMR, and CD, were used to determine the planar and absolute configurations of the compounds. The possible biosynthetic pathways were proposed based on the structural characteristics of compounds 1-13. Compounds 1, 3, 4, and 9 exhibited strong cytotoxicity toward HepG2 cells compared with the positive control. Several metabolites (2, 4-5, 7-9, and 11-13) were phytotoxic to foxtail leaves. The results support the hypothesis that endophytic fungi from special environments, such as desert areas, produce novel bioactive secondary metabolites.

Dioncophyllidine E: The first configurationally semi-stable, 7,3′-coupled naphthyldihydroisoquinoline alkaloid, from Ancistrocladus abbreviatus, with antiausterity activity against PANC-1 human pancreatic cancer cells

The discovery of a new naphthylisoquinoline alkaloid, dioncophyllidine E (4), from the tropical liana Ancistrocladus abbreviatus (Ancistrocladaceae) is described. Due to its rare 7,3′-coupling type, combined with the lack of an oxygen function at C-6, it is configurationally semi-stable at the biaryl axis, and thus occurs as a pair of slowly interconverting atropo-diastereomers, 4a and 4b. Its constitution was assigned mainly by 1D and 2D NMR. The absolute configuration at the stereocenter, C-3, was elucidated by oxidative degradation. The absolute axial configuration of the individual atropo-diastereomers was established by their HPLC resolution, combined with online electronic circular dichroism (ECD) investigations, providing nearly mirror-imaged LC-ECD spectra. These were assigned to the respective atropisomers by ECD comparison with a related, but configurationally stable alkaloid, ancistrocladidine (5). Dioncophyllidine E (4a/4b) exhibits a strong preferential cytotoxicity against PANC-1 human pancreatic cancer cells under nutrient-deprived conditions, with a PC50 value of 7.4 µM, suggesting its potential as an agent against pancreatic cancer.

Control release of α-mangostin by a novel dual-polysaccharides delivery system for colitis treatment under simulated gastrointestinal conditions

The poor hydrophilia and strong cytotoxicity of α-mangostin, a major component of xanthones from pericarps of mangosteen (Garcinia Mangostana L.), restrict its application in functional food. To overcome its shortage, a series of alginate/xanthan gum or alginate/κ-carrageenan hydrogels loaded with α-mangostin were fabricated and their anti-inflammatory effects were investigated under gastrointestinal tract (GIT). With the increased concentration of polysaccharides, the release of α-mangostin was slower due to denser microstructure and hardness. The digestive profile suggested that the release of α-mangostin in 0.3% alginate/0.15% xanthan gum (0.15%X-αM), 0.3% alginate/0.2% xanthan gum (0.25%X-αM) and 0.3% alginate/0.3% κ-carrageenan (0.3%C-αM) hydrogels were faster than the others. The cytotoxicity of α-mangostin loaded in hydrogels was dramatically reduced. However, the anti-inflammatory effect of the three intestinal digestive fluids was still maintained at 71.9% ± 1.2%, 83.1% ± 2.0%, and 70.6% ± 3.3% in LPS-induced Raw246.7 cells. In addition, the three intestinal digestive fluids (50 μM of α-mangostin) showed good inhibition of inflammatory cytokines (TNF-α, IL-6, and IL-1β) and the expression of iNos and Cox-2 respectively. Given these data, xanthan gum/κ-carrageenan-alginate composite hydrogels can be a good colonic target delivery system for bioactive compounds, which can be applied in functional foods to improve human health and wellness.

Sedeveria pink ruby Extract-Mediated Synthesis of Gold and Silver Nanoparticles and Their Bioactivity against Livestock Pathogens and in Different Cell Lines.

Biological synthesis of metal nanoparticles has a significant impact in developing sustainable technologies for human, animal, and environmental safety. In this study, we synthesized gold and silver nanoparticles (NPs) using Sedeveria pink ruby (SP) extract and characterized them using UV-visible spectrophotometry, FESEM-EDX, HR-TEM, XRD, and FT-IR spectroscopy. Furthermore, antimicrobial and antioxidant activities and cytotoxicity of the synthesized NPs were evaluated. UV-visible absorption spectra showed λmax at 531 and 410 nm, corresponding to the presence of SP gold NPs (SP-AuNPs) and SP silver NPs (SP-AgNPs). Most NPs were spherical and a few were triangular rods, measuring 5-30 and 10-40 nm, respectively. EDX elemental composition analysis revealed that SP-AuNPs and SP-AgNPs accounted for >60% and 30% of NPs, respectively. Additionally, some organic moieties were present, likely derived from various metabolites in the natural plant extract, which acted as stabilizing and reducing agents. Next, the antimicrobial activity of the NPs against pathogenic microbes was tested. SP-AgNPs showed potent antibacterial activity against Escherichia coli and Yersinia pseudotuberculosis. Moreover, at moderate and low concentrations, both NPs exhibited weak cytotoxicity in chicken fibroblasts (DF-1) and macrophages (HD11) as well as human intestinal cancer cells (HT-29). Meanwhile, at high concentrations, the NPs exhibited strong cytotoxicity in both chicken and human cell lines. Therefore, the synthesized SP-AuNPs and SP-AgNPs may act as promising materials to treat poultry diseases.

Indolocarbazole alkaloid Loonamycin A inhibits triple-negative breast cancer cell stemness and Notch signalling.

Enrichment for therapy-resistant cancer stem cells hampers the treatment of triple-negative breast cancer. Targeting these cells via suppression of Notch signalling can be a potential therapeutic strategy. This study aimed to uncover the mode of action of a new indolocarbazole alkaloid loonamycin A against this incurable disease. The anticancer effects were examined in triple-negative breast cancer cells using in vitro methods, including cell viability and proliferation assays, wound-healing assay, flow cytometry and mammosphere formation assay. RNA-seq technology was used to analyse the gene expression profiles in loonamycin A-treated cells. Real-time RT-PCR and western blot were to evaluate the inhibition of Notch signalling. Loonamycin A has stronger cytotoxicity than its structural analog rebeccamycin. Besides inhibiting cell proliferation and migration, loonamycin A reduced CD44high/CD24low/- sub-population, mammosphere formation, as well as the expression of stemness-associated genes. Co-administration of loonamycin A enhanced antitumour effects of paclitaxel by inducing apoptosis. RNA sequencing results showed that loonamycin A treatment caused the inhibition of Notch signalling, accompanied by the decreased expression of Notch1 and its targeted genes. These results reveal a novel bioactivity of indolocarbazole-type alkaloids and provide a promising Notch-inhibiting small molecular candidate for triple-negative breast cancer therapy.

Low-dose Pimecrolimus, an FDA-approved Calcineurin Inhibitor, Sensitizes Drug-resistant Cancer Cells via Strong P-gp Inhibition.

Co-treatment with calcineurin inhibitors, such as tacrolimus and cyclosporin A, can sensitize chemotherapy-resistant cancer cells with P-glycoprotein (P-gp)-over-expression. Pimecrolimus (PIME) is a clinically available calcineurin inhibitor with a structure similar to that of tacrolimus. Whether PIME can sensitize P-gp-over-expressing resistant cancer cells remains unclear. Cell viability assay, annexin V analyses, cellular morphology and density observation with a microscope, western-blotting, fluorescence-activated cell sorting (FACS), and analysis for P-gp inhibitory activity were performed to investigate the mechanism of action. PIME exhibited strong cytotoxicity to vincristine (VIC)-treated drug-resistant cell lines (KBV20C and MCF-7/ADR) over-expressing P-gp. Co-treatment with VIC and PIME increased apoptosis and down-regulated the ERK signaling pathway, resulting in G2 arrest. PIME could be co-administered with vinorelbine or eribulin to sensitize resistant KBV20C or MCF-7/ADR cancer cells. Moreover, PIME strongly inhibited the efflux of both rhodamine 123 and calcein-AM substrates through P-gp after 4 h of treatment, indicating that VIC+PIME sensitized cancer cells by inhibiting VIC efflux via direct PIME binding to P-gp. Low doses of PIME, tacrolimus, and cyclosporin A showed similar sensitizing efficiencies in resistant KBV20C cells. These drugs showed similar P-gp inhibitory activities using both rhodamine 123 and calcein-AM substrates, suggesting that calcineurin inhibitors generally have strong P-gp inhibitory activities that sensitize drug-resistant cancer cells with P-gp over-expression. PIME, currently used in clinics, can be repositioned for treating patients with P-gp-over-expressing resistant cancer (stem) cells.

A novel azo‐azomethine benzoxazole‐based ligand and its transition metal (II), (III), (IV) complexes: Synthesis, characterization, theoretical studies, biological evaluation, and catalytic application

This work describes the synthesis of a novel multiple dentation azo‐Schiff base dye 2‐((3‐((5‐chlorobenzo[d]oxazol‐2‐yl)diazenyl)‐4‐hydroxybenzylidene)amino)pyridin‐3‐ol (H2L) based mixed heterocyclic bnzoxazole and pyridine moieties in facile two successive steps approach. Firstly is the synthesis of start azo dye 3‐((5‐chlorobenzo[d]oxazol‐2‐yl)diazenyl)‐4‐hydroxybenzaldehyde (CBOAHB) followed by condensation with 3‐hydroxy 2‐amino pyridine. It's novel binuclear Ni (II), Cu (II), Ru (III), and Zr (IV) 2:1 metal‐to‐ligand stoichiometric complexes were synthesized and characterized via various spectroscopic and analytical techniques. The data showed the paramagnetic Ni2+ complex has tetrahedral geometry, while the Cu2+, Ru3+, and diamagnetic Zr4+ complexes have octahedral geometrical structures. Data of the crystallinity, morphology, and average particle size showed that Cu2+ and Ru3+ complexes were formed at the nanoscale. The geometrical structures according to 3D molecular modeling are in good agreement with those proposed by the experiments. The azo start CBOAHB, H2L, and its metal complexes have been examined for their biological and catalytic features. The Zr4+ complex manifested higher antibacterial activity against Staphylococcus aureus (S. aureus), the ligand H2L exhibited higher antibacterial activity against Escherichia coli (E. coli), and the Ni2+ complex showed higher antifungal activity against Candida albicans (C. Albicans). The anticancer activity was evaluated against human hepatocellular carcinoma (HepG‐2), colorectal carcinoma (HCT‐116), and human breast carcinoma (MCF‐7). The ligand H2L has very strong cytotoxicity toward HepG‐2 cells, Ni (II) complex has the strongest cytotoxicity against HCT‐116 cells and Zr (VI) has the strongest cytotoxicity against MCF‐7 cells. The findings of antioxidant activity are in perfect accord with those obtained from anticancer. The heterogeneous catalytic activity was examined for the reduction of Direct Blue 14 dye. Ru (III) complex and Cu (II) complex achieved the highest catalytic activity with the highest degradation % and within a very short time did not exceed 3 min.

PH-Sensitive Fluorescence Emission of Boron/Nitrogen Co-Doped Carbon Quantum Dots

Carbon quantum dots (CQDs) with their strong photoluminescence (PL) activity, high biocompatibility, robust stability, low cytotoxicity, and flexible surface structures have been employed in many fields including chemical sensing, biosensing, photocatalyst, energy storage, and biomedical applications. Of note, CQDs present an intrinsic pH-sensitive PL nature indicating their intense potential for pH-mediated sensing and imaging. Despite the numerous studies performed in the last two decades, the pH-sensitive PL mechanism of CQDs is still under debate and must be clarified to overcome the limitations in practical applications. Therefore, in this report, we performed a systematical study to determine the pH-sensitive PL nature of boron/nitrogen co-doped CQDs (B/N CQDs). In the first part, B/N CQDs with a strong blue emission were fabricated via a hydrothermal synthesis procedure. B/N-CQDs showed a strong blue PL emission with high quantum yield and excitation-dependent nature. Under the low pH conditions (pH 3), B/N-CQDs exhibited a robust green fluorescence emission with a significant red-shift (48 nm) and the loss of the excitation-dependent nature. The change in PL nature originated from the protonation of surface groups, a decrease in negative surface charge (from −20.6 to −1.23 eV), and finally, aggregation of the nanostructure (the size of CQDs from 4.8 to 7.5 nm). However, in the case of alkaline conditions, the deprotonation surface groups significantly enhanced the surface charge and led to the emergence of a negative ‘protective shell’ with a zeta potential of −71.3 eV. In a high pH medium (pH 13), PL spectra showed the loss of excitation-dependent features and a red-shift (35 nm) in emission peak maxima with lower intensity. This report provides significant progress in the clarification of the pH-sensitive PL mechanism of CQDs. We envision that the proposed CQDs would provide unique opportunities in the fabrication of novel pH sensor systems and fluorescence imaging where a wide range of pH sensitivity is required.

Supramolecular Recognition of Cytidine Phosphate in Nucleotides and RNA Sequences.

Supramolecular recognition of nucleotides would enable manipulating crucial biochemical pathways like transcription and translation directly and with high precision. Therefore, it offers great promise in medicinal applications, not least in treating cancer or viral infections. This work presents a universal supramolecular approach to target nucleoside phosphates in nucleotides and RNA. The artificial active site in new receptors simultaneously realizes several binding and sensing mechanisms: encapsulation of a nucleobase via dispersion and hydrogen bonding interactions, recognition of the phosphate residue, and a self-reporting feature-"turn-on" fluorescence. Key to the high selectivity is the conscious separation of phosphate- and nucleobase-binding sites by introducing specific spacers in the receptor structure. We have tuned the spacers to achieve high binding affinity and selectivity for cytidine 5' triphosphate coupled to a record 60-fold fluorescence enhancement. The resulting structures are also the first functional models of poly(rC)-binding protein coordinating specifically to C-rich RNA oligomers, e.g., the 5'-AUCCC(C/U) sequence present in poliovirus type 1 and the human transcriptome. The receptors bind to RNA in human ovarian cells A2780, causing strong cytotoxicity at 800 nM. The performance, self-reporting property, and tunability of our approach open up a promising and unique avenue for sequence-specific RNA binding in cells by using low-molecular-weight artificial receptors.

Dual Effect of Chemo-PDT with Tumor Targeting Nanoparticles Containing iRGD Peptide

Nanotechnology, including self-aggregated nanoparticles, has shown high effectiveness in the treatment of solid tumors. To overcome the limitations of conventional cancer therapies and promote therapeutic efficacy, a combination of PDT and chemotherapy can be considered an effective strategy for cancer treatment. This study presents the development of tumor-targeting polysialic acid (PSA) nanoparticles for chemo-PDT to increase the cellular uptake and cytotoxic effect in cancer cells. Chlorin e6 (Ce6), a photosensitizer, and the iRGD peptide (sequence; cCRGDKGPDC) were conjugated to the amine of N-deacetylated PSA. They generate reactive oxygen species (ROS), especially singlet oxygen (1O2), and target integrin αvβ3 on the cancer cell surface. To offer a chemotherapeutic effect, doxorubicin (Dox) was assembled into the core of hydrophobically modified PSA by connecting it with Ce6; this was followed by its sustained release from the nanoparticles. These nanoparticles are able to generate ROS under 633 nm visible-light irradiation, resulting in the strong cytotoxicity of Dox with anticancer effects in HCT116 cells. PSA nanoparticles with the dual effect of chemo-PDT improve conventional PDT, which has a poor ability to deliver photosensitizers to cancer cells. Using their combination with Dox chemotherapy, rapid removal of cancer cells can be expected.

Folic-acid adorned alginate-polydopamine modified paclitaxel/Zn-CuO nanocomplex for pH triggered drug release and synergistic antitumor efficacy

Targeted chemotherapy is a prominent cancer treatment research trend that intends to boost the efficacy of drug delivery to cancer cells. The present work aimed to design, a folate-decorated biologically inspired alginate-polydopamine capped zinc doped copper oxide nanoparticles (Zn-CuO) loaded with paclitaxel (Zn-CuO@PTX/AlgPDA-FA) as a simple, efficient, and versatile nanoplatform. Interestingly, Zn species doped in CuO frameworks significantly improved paclitaxel (PTX) molecule loading efficiency without requiring any additional functionalization and fostered the increased antitumor efficacy by precisely delivering them in tumor's acidic microenvironment by obliterating the formed coordination connections between the host as well as guest species. According to DLS, average size of nanocomplex was 196 ± 5.01 nm with ȥ-potential −31.4 ± 1.54 mV. PTX encapsulation and loading efficiencies were 75.2 ± 1.54 % and 18.54 ± 2.31 %, respectively. Furthermore, nanocomplex demonstrates high stability and biocompatibility in vitro. Under an acidic environment (pH 5.0), there was greater PTX release compared to normal physiological conditions. Moreover, Zn-CuO@PTX/AlgPDA-FA NPs showed remarkable internalization efficiency in MCF-7 cells and demonstrated strong cytotoxicity with IC50 (150 ± 2.58 μg/mL) along with improved ROS generation and changed mitochondrial membrane potential level. Therefore, our approach could suggest excellent potential for tumor targeting in cancer therapy with reduced off-target toxicity, and desirable therapeutic effects.

Cytotoxicity of black cumin (Nigella sativa L.) seed sprout extract mediated titanium oxide (TiO2) nanoparticles in human lung cancer cells

We report the preparation and cytotoxicity of TiO2 nanoparticles (TiO2 NPs) using black cumin sprout extract. The average size of BC-TiO2 NP was 97.48 ± 1.54 d. nm, with a PDI of 0.31, and zeta potential of −29.1 ± 0.89 mV. The size of NPs varied between the methods (TEM, XRD, and DLS) due to the hydrodynamic properties of BC-TiO2 NPs. The cytotoxicity studies evidenced that BC-TiO2 NPs exhibited a half maximum inhibitory concentration (IC50) of 76.25 ± 1.57 μg/mL for the human lung cancer cell line (A549) and 175.64 ± 3.48 μg/mL for the mouse fibroblast cell line (NIH3T3). In addition, BC-TiO2 NPs triggered the antiproliferative activity in the A549 cell line through nucleus damage, mitochondrial membrane potential loss, and apoptosis-associated membrane changes while showing no toxic effects on egg CAM and RBC. These results revealed that BC-TiO2 NPs exhibited strong cytotoxicity in the A549 cell line while being nontoxic to the NIH3T3 cell line, egg CAM, and RBC.

Graphene Oxide Nanosurface Reduces Apoptotic Death of HCT116 Colon Carcinoma Cells Induced by Zirconium Trisulfide Nanoribbons.

Due to their chemical, mechanical, and optical properties, 2D ultrathin nanomaterials have significant potential in biomedicine. However, the cytotoxicity of such materials, including their mutual increase or decrease, is still not well understood. We studied the effects that graphene oxide (GO) nanolayers (with dimensions 0.1-3 μm and average individual flake thickness less than 1 nm) and ZrS3 nanoribbons (length more than 10 μm, width 0.4-3 μm, and thickness 50-120 nm) have on the viability, cell cycle, and cell death of HCT116 colon carcinoma cells. We found that ZrS3 exhibited strong cytotoxicity by causing apoptotic cell death, which was in contrast to GO. When adding GO to ZrS3, ZrS3 was significantly less toxic, which may be because GO inhibits the effects of cytotoxic hydrogen sulfide produced by ZrS3. Thus, using zirconium trisulfide nanoribbons as an example, we have demonstrated the ability of graphene oxide to reduce the cytotoxicity of another nanomaterial, which may be of practical importance in biomedicine, including the development of biocompatible nanocoatings for scaffolds, theranostic nanostructures, and others.

Tailored chemotherapy for colorectal cancer peritoneal metastases based on a drug-screening platform in patient-derived organoids: a case report.

Peritoneal metastasis from colorectal cancer (CRC) has limited therapeutic options and poor prognosis. Systemic chemotherapy combined with cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) or pressurized intraperitoneal aerosol chemotherapy (PIPAC) have yielded initial promising results. However, standard local therapies with oxaliplatin and mitomycin are not optimal and a better individualized management of these patients remains as an unmet clinical need. Patient-derived organoid (PDO) technology allows to culture in three dimensions normal and cancer stem cells (CSC) that self-organize in multicellular structures that recapitulates some of the features of the particular organ or tumor of origin, emerging as a promising tool for drug-testing and precision medicine. This technology could improve the efficacy of systemic and intraperitoneal chemotherapy and avoid unnecessary treatments and side effects to the patient. Here we report a case of a 45-year-old man with a rectal adenocarcinoma with liver, lymph node and peritoneal metastases. The patient was treated with systemic chemotherapy (FOLFOXIRI plus Bevacizumab) and was subjected to mitomycin-based PIPAC. We generated patient-derived peritoneal carcinomatosis organoids in order to screen the activity of drugs for a personalized treatment. Both 5-FU and SN-38, the active irinotecan derivative, displayed strong cytotoxicity, while the response to oxaliplatin was much lower. Although the development of a colo-cutaneous fistulae prevented from further PIPAC, the patient continued with fluoropirimidine maintenance treatment based on standard clinical practice and the drug-screening test performed on organoids. Our results suggest that the peritoneal implant shows chemoresistance to oxaliplatin, while it might still be sensitive to irinotecan and 5-FU, which supports a potential benefit of these two drugs in the local and/or systemic treatment of our patient. This study shows the strength of the utility of the establishment of organoids for drug response assays and thus, for the personalized treatment of colorectal carcinomatosis patients.

Macrocyclic Pyrrolizidine Alkaloids and Silphiperfolanol Angelate Esters from Solanecio mannii

AbstractThree new compounds, the silphiperfolanol angelate ester umutagarananol (1), the macrocyclic pyrrolizidine alkaloids umutagarinine A and B (2–3), and five known secondary metabolites (4–8) were isolated from the CH2Cl2−MeOH (1 : 1) extract of the roots and the stem bark of Solanecio mannii (Hook. f.) (Asteraceae). The isolated compounds were characterized by NMR and IR spectroscopic, and mass spectrometric analyses, whereas the relative stereochemistry of 4 was established by NAMFIS‐based combined computational and solution NMR analysis. Synthetic modification of 5 provided two new compounds, 2‐angeloyloxy‐4,8‐epoxypresilphiperfolane (9) and 2‐angeloyloxy‐4,8‐epoxypresilphi‐perfolane (10). The crude extracts and the isolated constituents showed weak antibacterial activities (EC50 0.7–13.3 mM) against the Gram‐negative Escherichia coli and the Gram‐positive Bacillus subtilis. Compounds 2, 3 and 4 exhibited strong cytotoxicity against MCF‐7 human breast cancer cells, with EC50 values of 35.6, 21.7 and 12.5 μM, respectively.

Mixed Nanoscale Liposomes Co-Encapsulating Curcumin and Berberine Inhibit Activated Hepatic Stellate Cell-Induced Drug Resistance and Tumor Metastasis

The combination therapy based on nanoscale materials has been proven an effective approach for cancer treatment. In this study, berberine (BBR) and curcumin (CUR) were loaded into mixed liposomes (CUR-GL/BBR-HL). To simulate a tumor microenvironment (TME), the dual-cell research model (SMMC7721 + LX-2) and orthotopic tumor-bearing mice model were established for antiproliferation and antimetastasis evaluation. The results showed that the mixed liposomes exhibited strong cytotoxicity and antimigration effect against the dual-cell research model. Notably, CUR-GL/BBR-HL effectively inhibited the activation of hepatic stellate cells (HSCs), extracellular matrix deposition, and tumor angiogenesis in vivo, resulting in an enhanced anticancer effect. The anti-HCC mechanism revealed that CUR-GL/BBR-HL could inhibit drug resistance and the metastasis of tumor cells by downregulating the expression of P-gp and vimentin, respectively. Hence, the combined therapeutic strategy could effectively inhibit cancer growth, and CUR-GL/BBR-HL might be a potential formulation for anticancer therapy.