Cytotoxic Activity Research Articles

Iriomoteolide-1a and -1b: Structure Elucidation by Integrating NMR Spectroscopic Analysis, Theoretical Calculation, and Total Synthesis.

The structure of iriomoteolide-1a, a marine macrolide with potent cytotoxic activity against human cancer cells, has been under scrutiny for more than a decade since the first total synthesis of the proposed structure was achieved by Horne. Here we disclose the correct structure of iriomoteolide-1a. Given a huge number of possible stereoisomers, we adopted an integrated strategy toward the structure elucidation of iriomoteolide-1a: (1) NMR spectroscopic analysis/molecular mechanics-based conformational analysis for configurational reassignment of the macrolactone domain; (2) model synthesis for validating the reassigned configuration of the macrolactone domain; (3) GIAO NMR calculation/DP4+ analysis of side chain stereoisomers; and (4) total synthesis of the most likely structure. Moreover, the correct structure of iriomoteolide-1b, a natural congener, was also determined by an integration of NMR spectroscopic analysis, GIAO NMR calculation/DP4+ analysis, and total synthesis.

Advances in the Synthesis of 3‐Acyl‐2‐Pyridones: Strategies and Methods for Accessing the Versatile Scaffold

ABSTRACTThe syntheses and bioevaluation of 3‐acyl‐2‐pyridones have garnered significant interest in recent years as a novel class of compounds with diverse biological activities. The bioactivities cover a wide range of therapeutic areas including antimicrobial, antitumor, anti‐inflammatory, antifungal, antibiotic, neuritogenic, cytotoxic, and antiviral activities. Therefore, 3‐acyl‐2‐pyridone scaffold offers a versatile platform for the development of new molecules with potential applications in medicinal chemistry. The recent exploration on synthesis and bioevaluation of 3‐acyl‐2‐pyridones has yielded promising results, making them attractive targets for further optimization and development of new therapeutic agents. This review summarizes the available information on total synthesis of 3‐acyl‐2‐pyridone containing natural products, and the other synthetic strategies developed for accessing the 3‐acyl pyridones such as multicomponent synthesis, condensation reaction, microwave‐assisted synthesis, catalytic hydrogenation reactions, metalation reaction, Michael addition, and formylation reactions. The presented information may serve as a valuable resource for researchers working in the field of medicinal chemistry and drug discovery, stimulating further exploration and development of this intriguing scaffold.

Seven new aconitine-type diterpenoid alkaloids from the roots of Aconitum apetalum.

Seven new aconitine-type C19-diterpenoid alkaloids, apetaldines K-Q (1-7), were isolated from the roots of Aconitum apetalum (Huth) B. Fedtsch. Their structures were established on the basis of extensive spectroscopic analyses (HRESIMS, 1D and 2D NMR). Among them, compounds 1 and 2 possess a unique 2-(E)-(2-methylbut-2-enamido)benzoate moiety at the C-18 position. Furthermore, cytotoxic activities of these diterpenoid alkaloids were also evaluated.

A recombinant fragment antigen-binding (Fab) of trastuzumab displays low cytotoxic profile in adult human cardiomyocytes: first evidence and the key implication of FcγRIIA receptor.

Fragment crystallizable gamma receptors (FcγRs) mediate various cellular responses with significant cardiovascular implications. They contribute to the anticancer activity of trastuzumab (TRZ), a recombinant humanized monoclonal antibody that interferes with human epidermal growth factor receptor 2 (HER2), thereby blocking its physiological function in cardiac cells. This is responsible for cardiac complications that hamper TRZ clinical application. In this study we investigated the involvement of FcγRs in the TRZ cardiotoxicity. We used a recombinant antigen-binding fragment (Fab) of TRZ (rFab-HER2) to examine whether the absence of the Fc region resulted in fewer cardiomyocyte toxicity while preserving TRZ's ability to inhibit HER2. When exposed to rFab-HER2, AC16 human adult ventricular cardiomyocytes were less vulnerable to damage and death, than to TRZ. Specifically, TRZ exhibited cytotoxicity at a lower concentration (150 µg/mL, corresponding to ~1 µM) compared to rFab-HER2 (250 µg/mL, corresponding to ~5 µM). Like TRZ, rFab-HER2 negatively modulated HER2 levels in cardiomyocyte (without inducing cytotoxic activity in BJ human fibroblast cells that either did not express or express very low levels of HER2) and inhibited the downstream ERK/AKT cascades. But rFab-HER2 did not alter cardiomyocyte mitochondrial dynamic balance, and affect apoptosis and inflammation, while it limited cytosolic and mitochondrial ROS indicators. On contrary, the Fc region (50-250 μg/mL) exerted direct cytotoxic action on cardiomyocytes (but not on human fibroblasts that lacked Fc receptors). TRZ (150 μg/mL) markedly upregulated the expression level of FcγRIIA (a FcγRs strongly involved in TRZ-induced antibody-dependent cellular toxicity) in cardiomyocytes, whereas the Fab fragment (150 μg/mL) had no effect. Our results demonstrate that Fc region plays an important pathogenic role in TRZ-induced cardiomyocyte toxicity. In addition, targeting FcγRIIA might contribute to the off-target effects of TRZ therapy.

Pyrrolopyrimidinehydrazide‐2‐chlorobenzaldehyde Metal Complexes: Synthesis, Characterization, and Extraordinary Exploration Through in Vitro, in Vivo Cytotoxicity, and Cutting‐Edge Computational Analyses

ABSTRACTThis study reports the successful synthesis and characterization of five novel metal complexes (1–5) derived from the pyrrolopyrimidinehydrazide‐2‐chlorobenzaldehyde ligand, HPPHoCBA (L). The metal complexes demonstrated non‐electrolytic behavior and distinct geometries, as confirmed through comprehensive physicochemical analyses. Importantly, the synthesized complexes exhibited significantly enhanced antimicrobial, antioxidant, and cytotoxic activities compared to the ligand HPPHoCBA (L). Molecular docking studies revealed superior binding affinities of Pd(II) (1) and Cd(II) (4) complexes, which were further substantiated by pharmacophore modeling. Additionally, density functional theory (DFT) and molecular electrostatic potential (MEP) analyses provided insights into the stability and reactivity of these complexes, suggesting their potential in future therapeutic applications. These findings underscore the potential biomedical and industrial applications of the synthesized metal complexes.

Erinacenones A–L: Twelve New Isoindolinone Alkaloids from the Edible and Medicinal Mushroom Hericium erinaceus

A total of twelve previously unreported isoindolin-1-one compounds, erinacenones A–L (1–12), were isolated from liquid cultures of the medicinal fungus Hericium erinaceus. Their structures were elucidated based on spectroscopic data analysis. The absolute configuration of 12 was determined by comparing its optical rotations with values reported in the literature. The most distinctive feature of these compounds is that their nitrogen atoms are connected to different parts of the special structure moieties. Among them, compounds 3 and 4, as well as 10 and 11, are two pairs of isomers differing only by a small change in the position of one double bond. Compounds 4 and 5 were found to show cytotoxic activities, with IC50 values of 24.7 and 18.4 μM, respectively, against MCF-7 cell lines.

Anti-DENV-2 Activity of Ethanolic Extracts from Arachis hypogaea L.: Peanut Skin as a Relevant Resource of Bioactive Compounds against Dengue Virus

Dengue is an emerging disease of high impact on human health. Plants are an important source of new antivirals and Arachis hypogaea stands for its biological properties. The aim of this study was to evaluate the cytotoxicity and antiviral activity and elucidate the antiviral mechanism of ethanolic extracts from A. hypogaea against dengue virus 2 (DENV-2). The skin or tegument ethanolic extract (TEEs) and seed ethanolic extract (SEEs) were obtained. Cytotoxicity was evaluated by MTT and Neutral Red Uptake (NRU). Antiviral activity was evaluated at different stages of the viral replication cycle by the lysis plaque reduction method. The 50% inhibitory concentration (IC50) and selectivity index (SI) were determined. Antiviral activity was further determined by RT-qPCR. The CC50 values were 169 (NRU) and 65 (MTT) µg/mL for TEE. In addition, the CC50 values were >1400 (NRU) and 636 (MTT) µg/mL for SEE. The TEE demonstrated 99.9 ± 0.1% viral inhibition. The TEE presented an IC50 = 3.47 and SI of 48.7 (NRU) and 18.73 (MTT). Its mechanism of antiviral action is broad and it acts in the viral adsorption–penetration stage and inhibits the first steps of infection in the post-penetration stage. It is also capable of acting as virucidal and as prophylactic. Studies of RT-qPCR indicated that the TEE inhibited viral RNA synthesis. These findings suggest that the TEE from A. hypogaea could be a promising antiviral candidate for treating DENV-2 infections.

In Vitro and In Vivo Biological Evaluation of Novel 1,4-Naphthoquinone Derivatives as Potential Anticancer Agents.

A novel library of naphthoquinone derivatives (3-5 aa) was synthesized and evaluated for their anticancer properties. Specifically, compounds 5 i, 5 l, 5 o, 5 q, 5 r, 5 s, 5 t, and 5 v demonstrated superior cytotoxic activity against the cancer cell lines that were studied. All the studied compounds exhibited a higher selectivity index (SI) and a favourable safety profile than the standard drug doxorubicin. Notably, compound 5 v displayed a greater cytotoxic effect on MCF-7 cells (IC50=1.2 μM, and 0.9 μM at 24 h and 48 h, respectively) compared to the standard drug doxorubicin (IC50=2.4 μM, and 2.1 μM at 24 h and 48 h, respectively). To further investigate the mechanism of cytotoxic effect, additional anticancer studies were conducted with 5 v in MCF-7 cells. The studies are including morphological changes, AO/EB (acridine orange/ethidium bromide) double staining, apoptosis analysis, cell colony assay, SDS-PAGE and Western blotting, cell cycle analysis, and detecting reactive oxygen species (ROS) assay. The findings showed that 5 v triggered cytotoxic effects in MCF-7 cells through the initiation of cell cycle arrest at the G1/S phase and necrosis. In vivo ecotoxicity studies indicated that 5 v had lower toxicity towards zebrafish larvae (LC50=50.15 μM) and had an insignificant impact on cardiac functions. In vivo xenotransplantation of MCF-7 cells in zebrafish larvae demonstrated a significant reduction in tumour volume in the xenograft. Approximately 95 % of the zebrafish larvae with 5 v xenografts survived after 10 days of the treatment. Finally, a computational modelling study was conducted on four protein receptors, namely ER, EFGR, BRCA1, and VEFGR2. The findings highlight the importance of the aminonaphthoquinone moiety, amide linkage, and propyl thio moiety in enhancing the anticancer properties. 5 v exhibited superior drug-likeness features and docking scores (-9.1, -7.1, -8.9, and -10.9 kcal/mol) compared to doxorubicin (-7.2, -6.1, -6.9, and -7.3 kcal/mol) against ER, EFGR, BRCA1, and VEGFR2 receptors, respectively. Therefore, the notable antitumor effects of naphthoquinone derivatives (3-5 aa) suggest that these molecular frameworks may play a role in the development of promising anticancer agents for cancer treatment.

Physico-chemical properties and biological evaluation of graphene quantum dots for anticancer drug susceptibility

Graphene quantum dots (GQDs) possess unique optical and biocompatible properties, making them suitable candidates for biomedical and pharmaceutical applications. This study reports the hydrothermal synthesis of pristine-GQD and doped variants: Nitrogen-GQD and Sulfur-GQD. The materials underwent thorough characterization techniques such as UV–vis, fluorescence, XRD, FE-TEM/SEM, EDX, and Raman spectroscopy. The particle sizes of these GQDs range from 2 to 5 nm. We conducted a comprehensive study through MTT assays to evaluate the potential cytotoxic effect of GQD and the doped variants. This study demonstrated their synergistic interactions with an anti-cancer drug, methotrexate (MTX), and also improvement of cytocompatibility in the presence of folic acid (FA). Systematic MD simulations revealed a compacting effect on the dynamic behavior of GQD and its variants in the presence of drugs. Fluorescence spectroscopy and computational modeling suggest non-intercalative surface interactions between GQDs and the drugs. The cytotoxic activity of pristine GQD on HeLa cervical cancer cells is higher than that of N-GQD and S-GQD. When treated with GQD-IC50–MTX-IC50, only 5.6 % of HeLa cells remained viable. The doped variants exhibited bio-compatibility when tested on normal HEK cell lines. Overall, this study emphasizes the potential of GQDs for targeted cancer therapy through an interdisciplinary approach involving material characterization, computational modeling, and biological assays.

WS6 and 5-iodotubercidin small molecules and growth factors; TGF, HGF, and EGF synergistically enhance proliferation of β-like human induced pluripotent stem cells (iPSCs)

Abstract Objectives It has been shown that growth factors and small molecules play an essential role in the proliferation of β cells and insulin production. In this study, we investigated the effects of small molecules (WS6 and 5-iodotubercidin) and growth factors (TGFβ, HGF, and EGF) on the proliferation of β-like human ipSCs. Methods iPSCs derived β cells were treated with small molecules and growth factors. Cytotoxic activity of small molecules and growth factors was determined using MTT assay. Insulin gene expression and secretion were measured by qPCR and ELISA, respectively. The protein expression of insulin was evaluated by western blot as well. Results Simltananeous addition of WS6 and Harmine into the culture media increased insulin gene expression compared to treatment by each molecule alone (p < 0.05). It was found that the simultaneous recruitment of EGH, HGF, and TGF-β increased insulin expression compared to treatment by each molecule alone (p < 0.05). Results showed that EGF, HGF, TGF-β growth factors increased insulin gene expression, eventually leading to insulin secretion from β cells (p < 0.05). Conclusions Growth factors and small molecules synergistically enhanced the proliferation of β cells and insulin production.

Combinatorial Effects of 5-Fluorouracil and Menadione on Wnt/β-Catenin Pathway in Human Colorectal Cancer Cells.

The incidence and mortality rates of colorectal cancer (CRC) are alarmingly high, and the scientific community is consistently engaged in developing newer therapeutic options for cancer cure or prevention. The fluoropyrimidine drug, 5-fluorouracil (5FU), remains the first line of treatment against CRC; nevertheless, relapses frequently occur since the cells gain resistance over time through various mechanisms. Studies have highlighted the significance of combinatorial treatment of a Wnt signaling inhibitor and 5FU as a better treatment strategy to overcome 5FU resistance. Small molecules that specifically target and disrupt β-catenin-TCF interaction, a crucial step of the Wnt signaling, are promising in CRC treatment. In this study, we investigated the synergistic cytotoxic activity of menadione with 5FU as the former has previously been shown to downregulate Wnt signaling in CRC cells. Docking and experimental results suggest that the drug combination interfered with key protein-protein interactions in the β-catenin-TCF complex, exerted synergistic anti-cancerous effects in CRC cells, and downregulated the expression of Wnt signaling proteins. Taken together, our data suggest that the simultaneous binding of 5FU and menadione to β-catenin can block Wnt signaling by disrupting β-catenin-TCF interaction and inhibit the proliferation of CRC cells.

Overcoming Irinotecan Resistance by Targeting Its Downstream Signaling Pathways in Colon Cancer

Among the most popular chemotherapeutic agents, irinotecan, regarded as a prodrug belonging to the camptothecin family that inhibits topoisomerase I, is widely used to treat metastatic colorectal cancer (CRC). Although immunotherapy is promising for several cancer types, only microsatellite-instable (~7%) and not microsatellite-stable CRCs are responsive to it. Therefore, it is important to investigate the mechanism of irinotecan function to identify cellular proteins and/or pathways that could be targeted for combination therapy. Here, we have determined the effect of irinotecan treatment on the expression/activation of tumor suppressor genes (including p15Ink4b, p21Cip1, p27Kip1, and p53) and oncogenes (including OPN, IL8, PD-L1, NF-κB, ISG15, Cyclin D1, and c-Myc) using qRT-PCR, Western blotting, immunofluorescence (IF), and RNA sequencing of tumor specimens. We employed stable knockdown, neutralizing antibodies (Abs), and inhibitors of OPN, p53, and NF-κB to establish downstream signaling and sensitivity/resistance to the cytotoxic activities of irinotecan. Suppression of secretory OPN and NF-κB sensitized colon cancer cells to irinotecan. p53 inhibition or knockdown was not sufficient to block or potentiate SN38-regulated signaling, suggesting p53-independent effects. Irinotecan treatment inhibited tumor growth in syngeneic mice. Analyses of allograft tumors from irinotecan-treated mice validated the cell culture results. RNA-seq data suggested that irinotecan-mediated activation of NF-κB signaling modulated immune and inflammatory genes in mice, which may compromise drug efficacy and promote resistance. In sum, these results suggest that, for CRCs, targeting OPN, NF-κB, PD-L1, and/or ISG15 signaling may provide a potential strategy to overcome resistance to irinotecan-based chemotherapy.

One‐Step Synthesis of Novel Erlotinib Analogs Catalyzed by Nano‐CuO as Potent Anticancer Agent

ABSTRACTTwenty new substituted erlotinib analogs with anticancer activity were produced with good to excellent yields through the one‐step reaction of erlotinib, aromatic aldehydes, and cyclic secondary amines such as piperidine, morpholine, pyrrolidine, N‐methylpiperazine, or imidazole using nano‐CuO in choline chloride: urea (ChCl:urea) solvent under ultrasound irradiation at 80°C. MTT protocol was applied to investigate the cytotoxicity of all produced substituted erlotinib analogs in A431 (human epidermoid carcinoma cell) and HU02 (foreskin fibroblast) cell lines. The results illustrated that at a concentration of less than 10 μM, the growth of A431 cells could be inhibited by the produced compounds. Compared to erlotinib as positive control, the highest cytotoxic activity with IC50 equal to 2.58 ± 0.57 μM belonged to compound 4c carrying 4‐fluorobenzene with piperidine substitution. All of the synthesized compounds showed significant cytotoxic activity on A431, while showing no apparent cytotoxicity to HU02. The reasons for the stronger cytotoxic activity 4c can be most probably attributed to the two phenomena of greater solubility of the fluoro derivative and the flexibility of piperidine. Based on this study, compound 4c is the most promising compound with anticancer properties.

Enhanced Biological Potential and Phytochemical Profiling of Phoenix Dactylifera Leaves (Deglet Nour and Alig) by Kombucha Fermentation: Focus on Polyphenols, Antioxidant, Antidiabetic, and Cytotoxic Activities.

The date palm, scientifically known as Phoenix dactylifera, is an important cultural and economic source of wealth in southern Tunisia. It produces considerable agricultural waste, including palm leaves, the disposal of which is often a challenge. Our study addresses the sustainable conversion of date palm leaves into a valuable product through kombucha fermentation, focusing on two widely used varieties in Tunisia: Deglet Nour and Alig. HPLC-RI analysis showed a significant difference in the fermentation process between the treated samples, which is reflected in the highest sugar consumption and metabolite production in Alig palm. Unfermented and fermented date palm leaves were sequentially extracted with solvents of increasing polarity to evaluate their chemical composition and bioactivity. The results showed that kombucha fermentation significantly increased the total phenolic content, with the highest amounts in the ethyl acetate fraction. In terms of antioxidant activity, the ethyl acetate extracts showed a high percentage inhibitory activity (82.76%) against the DPPH radical found in fermented Palm Alig, which also exhibited the most important antidiabetic capacity (resulting in an IC50 value of 20 µg/mL). The chemical analyses resulted in the detection of 19 compounds by HPLC-DAD and 50 volatiles by GC-MS, which are mainly found in kombucha extracts.

Structural and Biological Comparative Studies on M(II)-Complexes (M = Co, Mn, Cu, Ni, Zn) of Hydrazone-s-Triazine Ligand Bearing Pyridyl Arm

The molecular and supramolecular structures of some M(II) complexes (M = Co, Mn, Cu, Ni, Zn) with a hydrazone-s-triazine ligand (BMPyTr) were discussed based on single crystal X-ray diffraction (SCXRD), Hirshfeld and DFT analyses. A new Co(II) complex of the same ligand was synthesized and its structure was confirmed to be [Co(BMPyTr)Cl2]·H2O based on FTIR and UV–Vis spectra, elemental analysis and SCXRD. The geometry around Co(II) was a distorted square pyramidal configuration (τ5 = 0.4), where Co(II) ion is coordinated to one NNN-tridentate ligand (BMPyTr) and two Cl- ions. A Hirshfeld analysis indicated all potential contacts within the crystal structure, where the percentages of O⋯H, N⋯H, C⋯H, and H⋯H contacts in one unit were 11.2, 9.3, 11.4, and 45.9%, respectively, while the respective values for the other complex unit were 10.3, 8.8, 10.6, and 48.0%. According to DFT calculations, the presence of strongly coordinating anions, such as Cl-, in addition to the large metal ion size, were found to be the main reasons for the small M-BMPyTr interaction energies in the cases of [Mn(BMPyTr)Cl2] (260.79 kcal/mol) and [Co(BMPyTr)Cl2]·H2O (307.46 kcal/mol) complexes. Interestingly, the Co(II) complex had potential activity against both Gram-positive (S. aureus and B. subtilis) and Gram-negative (E. coli and P. vulgaris) bacterial strains with inhibition zone diameters of 13, 15, 16, and 18 mm, respectively. Also, the new [Co(BMPyTr)Cl2]·H2O (IC50 = 131.2 ± 6.8 μM) complex had slightly better cytotoxic activity against HCT-116 cell line compared to BMPyTr (145.3 ± 7.1 μM).

In vitro inhibitory effect of berberine against rotavirus combined with its antioxidant, anti-inflammatory, and cytotoxicity activities.

Although berberine (BBR) is well known as a traditional medicine used in treatment of gastrointestinal diseases, its potent against viral gastroenteritis has not been specifically reported. This study aims to investigate the antiviral activity of BBR against rotavirus and evaluate its cytotoxicity and pharmacological efficacies, including antioxidant and anti-inflammatory activities in vitro. Using ultraviolet-visible absorption spectroscopy, the saturation concentration of BBR was determined as 2261 µg/mL, indicating that BBR is a poor water-soluble compound. The inhibition rate of NO production of BBR solution at a concentration of 238 µg/mL was similar to that of Cardamonin 0.3 µM with a cell viability of 92,46±0.35%, revealing the anti-inflammatory activity of BBR. The cytotoxicity of BBR solution depended on its concentration, whereby the 50% cytotoxicity concentration (CC50) of BBR after 96 h exposure was 664 µg/mL. Investigation of cytopathic effects (CPE) of MA104 cells treated with BBR and BBR-incubated rotavirus indicates that BBR could effectively inhibit the replication of rotavirus. CPEs were not observed in the cells inoculated with rotavirus (100TCID50) which was pre-incubated with BBR for 96 hours at BBR concentration of 283 µg/mL. Therefore, the study provides reliable results to demonstrate the ability of BBR to inhibit the replication of rotavirus.

Anticancer Potential of Ethanolic Extract of Xylopia aethiopica (Dunal) A. Rich (Annonaceae) Dried Fruits on Breast Adenocarcinoma: In Vitro and In Vivo Evidences.

Breast cancer incidence and mortality rate in Cameroonian women is incredibly high, thus there is need for more effective therapy. Xylopia aethiopica dry fruits are traditionally used for both nutritional and medicinal purposes, including the management of diverse ailments such as cancer. This study evaluated the in vitro and in vivo anti-mammary cancer potential of X. aethiopica. The cytotoxic activity of the ethanolic extract of X. aethiopica dry fruits was assessed at different concentrations against MDA-MB 231 and MCF-7 cells using the MTT assay. Additionally, clone formation, apoptosis/necrosis, cell adhesion, cell migration, and chemotaxis were examined. Furthermore, the chemo-preventive potential of X. aethiopica dry fruit extract (XAE) was evaluated on breast tumors induced by DMBA in 42 female rats of age 45-55 days (~80 g). The normal (NOR) and negative (DMBA) control groups were daily treated with the vehicle, while the positive (Tamox) and test (XAE) groups were administered tamoxifen (3.3 mg/kg) and X. aethiopica extract (75, 150, and 300 mg/kg BW), respectively for 20 weeks. Parameters such as tumor volume and burden, tumor incidence, CA 15-3 serum level, inflammatory status, antioxidant and histopathology were evaluated. X. aethiopica significantly (p < 0.05) decreased ER+ (MCF-7) and ER- (MDA-MB 231) breast adenocarcinoma cell growth from 12.5 to 100 μg/mL after 72 h. At the 100 μg/mL concentration, clone formation, cell proliferation, and migration were notably decreased in MDA-MB 231 cells after 48 h, while there was an observed rise in cell adhesion to the collagen extracellular matrix. Additionally, there was a rise in apoptotic cell count (p < 0.01) and caspase-3 activity (p < 0.05) observed in MDA-MB 231 cells following exposure to XAE at 100 μg/mL. XAE, across all tested doses, demonstrated significant reductions in tumor incidence, burden, and volume, akin to tamoxifen, compared to untreated rats (DMBA). Furthermore, there was an elevation in antioxidants (SOD, CAT, and GSH) and a decrease in pro-inflammatory cytokines (INF-γ, TNF-α, IL-12, and IL-6) observed at all tested doses. Overall, X. aethiopica dry fruit displays anticancer potential through caspase-3-dependent apoptosis pathways, alongside antioxidant and anti-inflammatory activities.

Polycyclic polyprenylated acylphloroglucinols (PPAPs) from Garcinia oblongifolia and their antitumoractivity.

Two new polycyclic polyprenylated acylphloroglucinols, along with four previously known compounds, were isolated and identified from the fruits of Garcinia oblongifolia. The structures of these compounds were elucidated through a combination of spectroscopic techniques, including MS, UV, IR, and 1D/2D NMR, as well as their chemical properties. Additionally, the cytotoxic activities of compounds 1‒6 against the H134B cell line were evaluated using the MTT assay, revealing that compounds 1 and 2 exhibit promising antitumor activity.

The Antileishmanial, Antioxidant and Cytotoxic Potential of Cecropia concolor Willd (Urticaceae), an Amazonian Species

Cecropia sp. (Urticaceae) are commonly used in traditional medicine in South American countries for the treatment of different diseases. To date, the species Cecropia concolor Willd, of Amazonian occurrence, has not been investigated for its pharmacological potential. In this study, we described the chemical profile and the antileishmanial, antioxidant and cytotoxic activities of extracts of the leaves of C. concolor. The ethanolic extract and its partition phases (hexane, ethyl acetate and hydroethanolic) were analyzed for their chemical classes and phenolic content. Antileishmanial activity was assessed against Leishmania (L.) amazonensis. The antioxidant activity was evaluated using the DPPH method and in MRC-5 human fibroblast cells. Toxicity was tested against Artemia salina and in human cells (fibroblasts and cancer lines). The leaves of C. concolor have phenolic substances, such as flavonoids, as well as terpenes, steroids and alkaloids. Chlorogenic acid, caffeic acid, schaftoside and vicenin 2 were identified. The hydroethanolic phase showed a high concentration of phenolic compounds and pronounced antioxidant activity. The antileishmanial activity was observed in the ethanolic extract, with a promising effect of the hexane phase. The C. concolor ethanolic extract and its phases are non-toxic, which makes this species of interest in pharmaceutical and cosmetics applications.

Radiotherapy enhances the anti-tumor effect of CAR-NK cells for hepatocellular carcinoma

BackgroundChimeric antigen receptor (CAR)-NK cell therapy has shown remarkable clinical efficacy and safety in the treatment of hematological malignancies. However, this efficacy was limited in solid tumors owing to hostile tumor microenvironment (TME). Radiotherapy is commonly used for solid tumors and proved to improve the TME. Therefore, the combination with radiotherapy would be a potential strategy to improve therapeutic efficacy of CAR-NK cells for solid tumors.MethodsGlypican-3 (GPC3) was used as a target antigen of CAR-NK cell for hepatocellular carcinoma (HCC). To promote migration towards HCC, CXCR2-armed CAR-NK92 cells targeting GPC3 were first developed, and their cytotoxic and migration activities towards HCC cells were evaluated. Next, the effects of irradiation on the anti-tumor activity of CAR-NK92 cells were assessed in vitro and in HCC-bearing NCG mice. Lastly, to demonstrate the potential mechanism mediating the sensitized effect of irradiation on CAR-NK cells, the differential gene expression profiles induced by irradiation were analyzed and the expression of some important ligands for the NK-cell activating receptors were further determined by qRT-PCR and flow cytometry.ResultsIn this study, we developed CXCR2-armed GPC3-targeting CAR-NK92 cells that exhibited specific and potent killing activity against HCC cells and the enhanced migration towards HCC cells. Pretreating HCC cells with irradiation enhanced in vitro anti-HCC effect and migration activity of CXCR2-armed CAR-NK92 cells. We further found that only high-dose (8 Gy) but not low-dose (2 Gy) irradiation in one fraction could significantly enhanced in vivo anti-HCC activity of CXCR2-armed CAR-NK92 cells. Irradiation with 8 Gy significantly up-regulated the expression of NK cell-activating ligands on HCC cells.ConclusionsOur results indicate the evidence that irradiation could efficiently enhance the anti-tumor effect of CAR-NK cells in solid tumor model. The combination with radiotherapy would be an attractive strategy to improve therapeutic efficacy of CAR-NK cells for solid tumors.