RESUMEN
Cisplatin is a chemotherapy drug that causes a plethora of DNA lesions and inhibits DNA transcription and replication, resulting in the induction of apoptosis in cancer cells. However, over time, patients develop resistance to cisplatin due to repeated treatment and thus the treatment efficacy is limited. Therefore, identifying an alternative therapeutic strategy combining cisplatin treatment along with targeting factors that drive cisplatin resistance is needed. CRISPR/Cas9 system-based genome-wide screening for the deubiquitinating enzyme (DUB) subfamily identified USP28 as a potential DUB that governs cisplatin resistance. USP28 regulates the protein level of microtubule-associated serine/threonine kinase 1 (MAST1), a common kinase whose expression is elevated in several cisplatin-resistant cancer cells. The expression level and protein turnover of MAST1 is a major factor driving cisplatin resistance in many cancer types. Here we report that the USP28 interacts and extends the half-life of MAST1 protein by its deubiquitinating activity. The expression pattern of USP28 and MAST1 showed a positive correlation across a panel of tested cancer cell lines and human clinical tissues. Additionally, CRISPR/Cas9-mediated gene knockout of USP28 in A549 and NCI-H1299 cells blocked MAST1-driven cisplatin resistance, resulting in suppressed cell proliferation, colony formation ability, migration and invasion in vitro. Finally, loss of USP28 destabilized MAST1 protein and attenuated tumor growth by sensitizing cells to cisplatin treatment in mouse xenograft model. We envision that targeting the USP28-MAST1 axis along with cisplatin treatment might be an alternative therapeutic strategy to overcome cisplatin resistance in cancer patients.
Asunto(s)
Cisplatino , Neoplasias , Animales , Humanos , Ratones , Carcinogénesis/genética , Línea Celular Tumoral , Proliferación Celular , Transformación Celular Neoplásica , Cisplatino/farmacología , Cisplatino/uso terapéutico , Resistencia a Antineoplásicos , Proteínas Asociadas a Microtúbulos , Microtúbulos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Proteínas Serina-Treonina Quinasas/genética , Ubiquitina TiolesterasaRESUMEN
Platinum-based drugs are widely recognized efficient anti-tumor agents, but faced with multiple undesirable effects. Here, four dinuclear platinum(II) complexes, [{Pt(1,2-pn)Cl}2(µ-pydz)]Cl2 (C1), [{Pt(ibn)Cl}2(µ-pydz)]Cl2 (C2), [{Pt(1,3-pn)Cl}2(µ-pydz)]Cl2 (C3) and [{Pt(1,3-pnd)Cl}2(µ-pydz)]Cl2 (C4), were designed (pydz is pyridazine, 1,2-pn is ( ±)-1,2-propylenediamine, ibn is 1,2-diamino-2-methylpropane, 1,3-pn is 1,3-propylenediamine, and 1,3-pnd is 1,3-pentanediamine). Interactions and binding ability of C1-C4 complexes with calf thymus DNA (CT-DNA) has been monitored by viscosity measurements, UV-Vis, fluorescence emission spectroscopy and molecular docking. Binding affinities of C1-C4 complexes to the bovine serum albumin (BSA) has been monitored by fluorescence emission spectroscopy. The tested complexes exhibit variable cytotoxicity toward different mouse and human tumor cell lines. C2 shows the most potent cytotoxicity, especially against mouse (4T1) and human (MDA-MD468) breast cancer cells in the dose- and time-dependent manner. C2 induces 4T1 and MDA-MD468 cells apoptosis, further documented by the accumulation of cells at sub-G1 phase of cell cycle and increase of executive caspase 3 and caspase 9 levels in 4T1 cells. C2 exhibits anti-proliferative effect through the reduction of cyclin D3 and cyclin E expression and elevation of inhibitor p27 level. Also, C2 downregulates c-Myc and phosphorylated AKT, oncogenes involved in the control of tumor cell proliferation and death. In order to measure the amount of platinum(II) complexes taken up by the cells, the cellular platinum content were quantified. However, C2 failed to inhibit mouse breast cancer growth in vivo. Chemical modifications of tested platinum(II) complexes might be a valuable approach for the improvement of their anti-tumor activity, especially effects in vivo.
Asunto(s)
Antineoplásicos , Neoplasias de la Mama , Complejos de Coordinación , Piridazinas , Humanos , Animales , Ratones , Femenino , Platino (Metal)/farmacología , Platino (Metal)/química , Albúmina Sérica Bovina/química , Simulación del Acoplamiento Molecular , Ligandos , ADN/química , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/química , Piridazinas/farmacología , Complejos de Coordinación/farmacología , Complejos de Coordinación/químicaRESUMEN
Efficient metal-free synthesis of benzo[b]azepines and oxindoles is achieved via a radical relay cascade strategy employing halogen atom transfer (XAT) for aryl radical generation followed by intramolecular hydrogen atom transfer (HAT). Optimization yielded moderate to substantial yields under visible light irradiation. Preliminary biological assessments revealed promising anti-tumor activity for select compounds. This study underscores the potential of XAT-mediated radical relay cascades in medicinal chemistry and anticancer drug discovery.
RESUMEN
We have previously shown the immunostimulatory effects by Nozawana (Brassica rapa L.). In this report, we determined the characteristics of Nozawana polysaccharide (NPS) and evaluated the immunomodulatory effects and anti-tumor activity of NPS mediated by macrophage activation. The molecular weight of NPS was determined by gel filtration chromatography with an average molecular weight of approximately 100.6 kDa. HPLC analysis showed that NPS contained glucose, galacturonic acid, galactose, and arabinose. NPS increased cytokine and nitric oxide (NO) production by macrophages in a Toll-like receptor (TLR)2 and TLR4-dependent manner. Furthermore, NPS induced apoptosis significantly against 4T1 murine breast cancer cells cultured in conditioned medium from NPS-treated macrophages through tumor necrosis factor-α. In tumor-bearing mouse model, tumor growth was significantly reduced in NPS-treated mice compared with control mice. These results support the potential use of NPS as an immunotherapeutic material found in health food products.
Asunto(s)
Brassica rapa , Receptor Toll-Like 2 , Animales , Ratones , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 4/metabolismo , Brassica rapa/metabolismo , Macrófagos/metabolismo , Polisacáridos/farmacología , Polisacáridos/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Activación de MacrófagosRESUMEN
Antarctica harbors a microbial diversity still poorly explored and of inestimable biotechnological value. Cold-adapted microorganisms can produce a diverse range of metabolites stable at low temperatures, making these compounds industrially interesting for biotechnological use. The present work investigated the biotechnological potential for antimicrobial and antitumor activity of filamentous fungi and bacteria isolated from marine sediment samples collected at Deception Island, Antarctica. A total of 89 microbial isolates were recovered from marine sediments and submitted to an initial screening for L-glutaminase with antitumoral activity and for antimicrobial metabolites. The isolates Pseudogymnoascus sp. FDG01, Pseudogymnoascus sp. FDG02, and Penicillium sp. FAD33 showed potential antiproliferative action against human pancreatic carcinoma cells while showing no toxic effect on non-tumor cells. The microbial extracts from unidentified three bacteria and four filamentous fungi showed antibacterial activity against at least one tested pathogenic bacterial strain. The isolate FDG01 inhibited four bacterial species, while the isolate FDG01 was active against Micrococcus luteus in the minimal inhibitory concentration of 0.015625 µg mL -1. The results pave the way for further optimization of enzyme production and characterization of enzymes and metabolites found and reaffirm Antarctic marine environments as a wealthy source of compounds potentially applicable in the healthcare and pharmaceutical industry.
Asunto(s)
Ascomicetos , Hongos , Humanos , Regiones Antárticas , Ascomicetos/metabolismo , Sedimentos Geológicos/microbiología , Antibacterianos/metabolismo , Antibacterianos/farmacología , Bacterias/metabolismo , Preparaciones Farmacéuticas/metabolismoRESUMEN
The synthesis of compounds based on fragments derived from natural products (NPs) serves as a source of inspiration for the design of pseudo-natural products (PNPs), to identify bioactive molecules that exhibit similar characteristics to NPs. These novel molecular scaffolds exhibit previously unexplored biological activities as well. This study reports the development and synthesis of a novel pentacyclic ring system, the indole-pyrimidine-quinoline (IPQ) scaffold. The design of this scaffold was based on the structural characteristics of four natural products, namely tryptanthrin, luotonin A, rutaecarpine, and camptothecin. Several successive steps accomplished the effective synthesis of the IPQ scaffold. The constituent components of the pentacycle, containing the indole, quinazolinone, pyrimidone, and quinoline units, possess significant biological significance. Compound 1a demonstrated noteworthy anti-tumor activity efficacy against A549 cell lines among the tested compounds. The compound 1a was observed to elicit cell cycle arrest in both the G2/M and S phases, as well as trigger apoptosis in A549 cells. These effects were attributed to its ability to modulate the activation of mitochondrial-related mitogen-activated protein kinase (MAPK) signaling pathways.
Asunto(s)
Antineoplásicos , Productos Biológicos , Quinolinas , Antineoplásicos/química , Apoptosis , Productos Biológicos/farmacología , Productos Biológicos/química , Camptotecina/farmacología , Puntos de Control del Ciclo Celular , Línea Celular Tumoral , Quinolinas/farmacología , Indoles/química , Indoles/farmacología , PirimidinasRESUMEN
The combination of steroid structure and selenocyano group offers high potential for the design and synthesis of new potential anti-tumor drugs. Beginning with estradiol, a series of 2-selenocyano-3-selenocyanoalkyloxyestradiol derivatives with remarkable antiproliferative activity was synthesized. Additionally, a 2,4-bisselenocyanoestradiol was synthesized by directly selenocyanating estradiol diacetate. It was found that the cytotoxicity of 2-selenocyano-3-selenocyanoalkyloxyestradiol derivatives was significantly increased in comparison to the corresponding monoselenocyanate precursor, whereas the cytotoxicity of the 2, 4-bisselenocyanoestradiol derivative was significantly reduced compared to the respective monosubstituted precursor. The introduction of the second selenocyano group at different locations of estradiol shows a various impact on the cytotoxicity of the compounds. Among them, compound 3e showed the best cytotoxicity, with an IC50 value of less than 5 µM against the tested tumor cells, and strong inhibitory activities against HeLa and MCF-7 cell xenograft tumors in zebrafish, suppressing tumor cell migration and neovascularization. Notably, compound 3e was more effective at inhibiting neovascularization of MCF-7 cell xenograft tumors than the positive control 2-methoxyestradiol. Furthermore, compound 3e showed excellent anti-oxidative stress effect in zebrafish. Therefore, these estrogen bisselenocyanate compounds may be promising anti-tumor agents, warranting further investigation.
Asunto(s)
Antineoplásicos , Pez Cebra , Animales , Humanos , Relación Estructura-Actividad , Células MCF-7 , Antineoplásicos/química , Estradiol/farmacología , Estrógenos , Estructura Molecular , Ensayos de Selección de Medicamentos Antitumorales , Proliferación Celular , Línea Celular TumoralRESUMEN
Two series of 2,4-diarylaminopyrimidine derivatives containing sulfonamide moiety were designed and synthesized for screening as inhibitors of focal adhesion kinase (FAK). Most compounds significantly inhibited the enzymatic activities of FAK, and the best compound was 7b (IC50 = 0.27 nM). A majority of aminoethyl sulfonamide derivatives could effectively inhibit the proliferation of human cancer cell lines (HCT116, A549, MDA-MB-231 and Hela) expressing high levels of FAK. Particularly, compounds 7b, 7c, and 7o exhibited more significant efficacy against all of four cancer cell lines within concentrations of 1.5 µM. Furthermore, these three compounds displayed higher selectivity of cancer cells over normal cells (SI value > 14), compared to the positive control TAE226 (SI value = 1.63). Interestingly, introduction of dithiocarbamate moiety to the aminoethyl sulfonamide derivatives can indeed improve the antiproliferative activities against A549 cells. Especially, compound 8d demonstrated most significant cytotoxicity activity against A549 cells with an IC50 value of 0.08 µM, which is 20-fold superior to parent compound 7k. Additionally, compound 7b, which display the best anti-FAK potency, can inhibit the clone formation and migration of HCT-116 cells, and cause cell cycle arrest at G2/M phase, inducing apoptosis by promoting ROS production. Overall, these results suggest that 7b is a valuable FAK inhibitor that deserves further optimization to improve its druggability.
Asunto(s)
Antineoplásicos , Humanos , Antineoplásicos/farmacología , Apoptosis , Línea Celular Tumoral , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Proteína-Tirosina Quinasas de Adhesión Focal , Simulación del Acoplamiento Molecular , Estructura Molecular , Inhibidores de Proteínas Quinasas/farmacología , Relación Estructura-Actividad , Sulfonamidas/farmacología , Pirimidinas/química , Pirimidinas/farmacologíaRESUMEN
Structurally diverse cyclopenta[4,5]pyrrolo[1,2-a]indoles heterocycles were smoothly constructed in good to excellent yields (up to 99 %) with excellent diastereoselectivities (>19:1 dr) through a novel and facile strategy based on BF3-catalyzed Friedel-Crafts alkylation/Aldol/Dehydrative cyclization cascade reaction. The anti-proliferative activity of these newly synthesized polycyclic indoles was screened, and all the functionalized reductive derivatives exhibited favorable anti-tumor activity. Notably, compound 4ae displayed the remarkable inhibitory activity against MCF-7 and HeLa cells with IC50 values of 4.62 µM and 7.71 µM, respectively. Mechanistically, the representative compound 4ae could effectively induce apoptosis of MCF-7 cells in crediting to up-regulate the relative expression of apoptotic protein BAX/Bcl-2, subsequently activate Pro-caspase 9 and cleave PARP, simultaneously block the cell cycle through down- and up-regulate the expression of cyclin B1 and p53, respectively. Moreover, compound 4ae also exhibited promising antineoplastic efficacy in subcutaneous MCF-7 xenograft mice which manifest significant shrunken tumors conspicuous nuclear apoptotic signal and minimal systemic toxicity. This strategy not only established a novel and efficient method for the assembly of structurally complex indole heterocycles, but also provided a series of compounds possessing attractive anti-cancer activity, which holds immense potential for future biomedical applications.
Asunto(s)
Antineoplásicos , Animales , Humanos , Ratones , Antineoplásicos/farmacología , Apoptosis , Ciclo Celular , Línea Celular Tumoral , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Células HeLa , Indoles/farmacología , Células MCF-7 , Estructura Molecular , Compuestos Policíclicos/síntesis química , Compuestos Policíclicos/química , Compuestos Policíclicos/farmacologíaRESUMEN
INTRODUCTION: Bisphosphonates (P-C-Ps) also called diphosphonates are the structural analogs of naturally occurring pyrophosphates. Bisphosphonates are traditionally used and shown to provide long-term success in the treatment and prevention of osteoporosis and other bone loss pathologies. Furthermore, bisphosphonates are gaining popularity in the present era of cancer therapeutics and prevention. The usage of bisphosphonates as adjuvant or neoadjuvant therapy, either as a single agent or combined with other chemotherapy, has been studied in different solid tumors. This review aims to present the various roles of bisphosphonates in solid tumors. DATA SOURCES: Articles in MEDLINE/PubMed and the National Institutes of Health Clinical Trials Registry (http://www. Clinicaltrials.gov) between 1 January 2011 and 1 February 2022 were extracted using MeSH terms "bisphosphonates/diphosphosphonates and mechanism," "bisphosphonates and breast cancer," "bisphosphonates and prostate cancer," "bisphosphonates and lung cancer," "bisphosphonates and cancer risk," and "bisphosphonates and adverse events." Manual searches of some major oncology journals were also conducted. DISCUSSION: This review article focuses on the antitumor activity of bisphosphonates, safety profile, and the role of bisphosphonates as preventive, neoadjuvant, and adjuvant chemotherapy. A significant improvement in overall survival and cancer-specific survival and recurrence-free survival with the usage of bisphosphonates is noted in breast cancer patients, particularly in post-menopausal women. Though great progress has been achieved in over 20 years, further research is needed to identify the subgroup of patients that are most likely to benefit from adjuvant bisphosphonate therapy and to determine regimens with greater efficacy and better safety profile.
RESUMEN
Chlamydomonas reinhardtii polysaccharides (CRPs) are bioactive compounds derived from C. reinhardtii, yet their potential in cancer therapy remains largely unexplored. This study optimized the ultrasound-assisted extraction conditions using response surface methodology and proceeded with the isolation and purification of these polysaccharides. The optimal extraction conditions were identified as a sodium hydroxide concentration of 1.5%, ultrasonic power of 200 W, a solid-to-liquid ratio of 1:25 g/mL, an ultrasonic treatment time of 10 min, and a water bath duration of 2.5 h, yielding an actual extraction rate of 5.71 ± 0.001%, which closely aligns with the predicted value of 5.639%. Infrared analysis revealed that CRP-1 and CRP-2 are α-pyranose structures containing furoic acid, while CRP-3 and CRP-4 are ß-pyranose structures containing furoic acid. Experimental results demonstrated that all four purified polysaccharides inhibited the proliferation of cervical (HeLa) hepatoma (HepG-2) and colon (HCT-116) cancer cells, with CRP-4 showing the most significant inhibitory effect on colon cancer and cervical cancer, achieving inhibition rates of 60.58 ± 0.88% and 40.44 ± 1.44%, respectively, and significantly reducing the migration of HeLa cells. DAPI staining confirmed that the four purified polysaccharides inhibit cell proliferation and migration by inducing apoptosis in HeLa cells. CRP-1 has the most significant inhibitory effect on the proliferation of liver cancer cells. This study not only elucidates the potential application of C. reinhardtii polysaccharides in cancer therapy but also provides a scientific basis for their further development and utilization.
Asunto(s)
Antineoplásicos , Proliferación Celular , Chlamydomonas reinhardtii , Polisacáridos , Polisacáridos/farmacología , Polisacáridos/aislamiento & purificación , Polisacáridos/química , Humanos , Antineoplásicos/farmacología , Antineoplásicos/aislamiento & purificación , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Células HeLa , Células Hep G2 , Células HCT116 , Animales , Línea Celular TumoralRESUMEN
Searching for natural products with anti-tumor activity is an important aspect of cancer research. Seaweed polysaccharides from brown seaweed have shown promising anti-tumor activity; however, their structure, composition, and biological activity vary considerably, depending on many factors. In this study, 16 polysaccharide fractions were extracted and purified from three large brown seaweed species (Sargassum horneri, Scytosiphon lomentaria, and Undaria pinnatifida). The chemical composition analysis revealed that the polysaccharide fractions have varying molecular weights ranging from 8.889 to 729.67 kDa, and sulfate contents ranging from 0.50% to 10.77%. Additionally, they exhibit different monosaccharide compositions and secondary structures. Subsequently, their anti-tumor activity was compared against five tumor cell lines (A549, B16, HeLa, HepG2, and SH-SY5Y). The results showed that different fractions exhibited distinct anti-tumor properties against tumor cells. Flow cytometry and cytoplasmic fluorescence staining (Hoechst/AO staining) further confirmed that these effective fractions significantly induce tumor cell apoptosis without cytotoxicity. qRT-RCR results demonstrated that the polysaccharide fractions up-regulated the expression of Caspase-3, Caspase-8, Caspase-9, and Bax while down-regulating the expression of Bcl-2 and CDK-2. This study comprehensively compared the anti-tumor activity of polysaccharide fractions from large brown seaweed, providing valuable insights into the potent combinations of brown seaweed polysaccharides as anti-tumor agents.
Asunto(s)
Antineoplásicos , Apoptosis , Polisacáridos , Sargassum , Algas Marinas , Undaria , Humanos , Polisacáridos/farmacología , Polisacáridos/química , Polisacáridos/aislamiento & purificación , Apoptosis/efectos de los fármacos , Algas Marinas/química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Sargassum/química , Undaria/química , Línea Celular Tumoral , Animales , Phaeophyceae/química , Células Hep G2 , Células HeLa , Ratones , Algas ComestiblesRESUMEN
Among female oncology patients, cervical cancer stands as the fourth most prevalent malignancy, exerting significant impacts on their health. Over 600,000 women received the diagnosis of cervical cancer in 2020, and the illness claimed over 300,000 lives globally. Curdepsidone A, a derivative of depsidone, was isolated from the secondary metabolites of Curvularia sp. IFB-Z10. In this study, we revised the molecular structure of curdepsidone A and investigated the fundamental mechanism of the anti-tumor activity of curdepsidone A in HeLa cells for the first time. The results demonstrated that curdepsidone A caused G0/G1 phase arrest, triggered apoptosis via a mitochondrial apoptotic pathway, blocked the autophagic flux, suppressed the PI3K/AKT pathway, and increased the accumulation of reactive oxygen species (ROS) in HeLa cells. Furthermore, the PI3K inhibitor (LY294002) promoted apoptosis induced by curdepsidone A, while the PI3K agonist (IGF-1) eliminated such an effect. ROS scavenger (NAC) reduced curdepsidone A-induced cell apoptosis and the suppression of autophagy and the PI3K/AKT pathway. In conclusion, our results revealed that curdepsidone A hindered cell growth by causing cell cycle arrest, and promoted cell apoptosis by inhibiting autophagy and the ROS-mediated PI3K/AKT pathway. This study provides a molecular basis for the development of curdepsidone A as a new chemotherapy drug for cervical cancer.
Asunto(s)
Apoptosis , Autofagia , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Especies Reactivas de Oxígeno , Transducción de Señal , Humanos , Células HeLa , Especies Reactivas de Oxígeno/metabolismo , Apoptosis/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Autofagia/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/metabolismo , Neoplasias del Cuello Uterino/patología , Femenino , Antineoplásicos/farmacologíaRESUMEN
A new alkaloids, aplysingoniopora A (1), and new configuration pregnane type steroid compound, 9,17-α-pregn-1,4,20-en-3-one (2), and two known pregnane type steroid compounds (3 and 4) were isolated from hydranth of Goniopora columna corals. The compounds structures and absolute configurations were determined by extensive spectroscopic analysis, MS data, single-crystal X-ray diffraction analysis and quantum chemical calculation. The anticancer effect of the compounds were explored in human non-small-cell lung cancer (NSCLC) A549â cell lines. As the results, the compound 3 and 4 induces toxicity and has proliferation inhibitory effects on A549 cells (IC50=58.99â µM and 58.77â µM, respectively) inâ vitro.
Asunto(s)
Alcaloides , Antozoos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Animales , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Alcaloides/farmacología , Alcaloides/química , Esteroides/farmacología , Esteroides/química , Pregnanos/farmacología , Estructura MolecularRESUMEN
Based on computer-aided drug design (CADD), the active groups of the known active small molecule compounds that can bind to EGFR target protein were analyzed through the molecular docking method. Then, 12 novel asiatic acid derivatives were synthesized by introducing active groups at ring A and C-28 positions of asiatic acid. The structures of these novel compounds were determined by NMR and MS. Furthermore, the anti-tumor activities of these derivatives on human lung cancer cells (A549) and human breast cancer cells (MCF-7) were evaluated by MTT assay. In conclusion, compounds I4 and II3 have stronger anti-cancer activity than parent compounds, the activities were stronger than gefitinib and comparable to afatinib, which may be potential candidate compounds for tumor therapy.
Asunto(s)
Antineoplásicos , Triterpenos Pentacíclicos , Humanos , Antineoplásicos/química , Relación Estructura-Actividad , Línea Celular Tumoral , Simulación del Acoplamiento Molecular , Proliferación Celular , Diseño de Fármacos , Estructura Molecular , Ensayos de Selección de Medicamentos AntitumoralesRESUMEN
BACKGROUND: Immunoglobulin superfamily 6 (IGSF6) is a novel member of the immunoglobulin superfamily and has been implicated in various diseases. However, the specific role of IGSF6 in the anti-tumor immunity within lung adenocarcinoma (LUAD) remains unclear. METHODS: We analyzed the IGSF6 expression in LUAD using data from TCGA, and we performed qRT-PCR and western blotting to validate these findings using tissue samples obtained from LUAD patients. Images of IHC staining were obtained from HPA. To assess the clinical relevance of IGSF6 expression, we utilized UALCAN and SPSS to analyze its association with major clinical features of LUAD. Additionally, we employed ROC curves and survival analysis to evaluate the potential diagnostic and prognostic value of IGSF6 in LUAD. To gain insights into the functional implications of IGSF6, we performed enrichment analysis using the R software clusterProfiler package. Moreover, we utilized TIMER2.0 and TISIDB to investigate the relationship between IGSF6 and immune infiltrates in LUAD. The proportion of tumor-infiltrating immune cells in LUAD was assessed using FCM, and their correlation with IGSF6 expression in tumor tissues was analyzed. The localization of IGSF6 protein on macrophages was confirmed using the HPA and FCM. To determine the regulatory role of IGSF6 on macrophage activity in LUAD, we employed ELISA, FCM, and tumor-bearing models. RESULTS: We discovered that both IGSF6 mRNA and protein levels were significantly decreased in LUAD. Additionally, we observed a negative correlation between IGSF6 expression and TNM stages as well as pathologic stages in LUAD. Notably, IGSF6 exhibited high sensitivity and specificity in diagnosing LUAD, and was positively associated with the survival rate of LUAD patients. Furthermore, IGSF6 expression was closely linked to gene sets involved in immune response. IGSF6 expression showed a positive correlation with immune infiltrates exhibiting anti-tumor activity, particularly M1 macrophages. We confirmed the predominant localization of the IGSF6 protein on the membrane of M1 macrophages. Importantly, the knockdown of IGSF6 resulted in a reduction in the anti-tumor activity of M1 macrophages, thereby promoting tumor progression. CONCLUSION: IGSF6 is a molecule that is essential for the anti-tumor activity of macrophages in LUAD.
Asunto(s)
Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Humanos , Adenocarcinoma del Pulmón/genética , Western Blotting , Inmunoglobulinas/genética , Neoplasias Pulmonares/genética , Macrófagos , PronósticoRESUMEN
BCR-ABL1 kinase is a key driver of the pathophysiology of chronic myeloid leukemia (CML). Current treatments need to broaden the chemical diversity of BCR-ABL1 kinase inhibitors to overcome drug resistance. We designed and synthesized a series of aromatic amide derivatives based on several generations of BCR-ABL1 kinase inhibitors. Biological studies showed that compared with Imatinib, these compounds showed significant proliferation inhibitory activities of HL-60 and K562 in cell activity assay. Compounds 4g and 4j exhibited significant anti-tumor activity against the K562 cells with IC50 values of 6.03 ± 0.49 µM and 5.66 ± 2.06 µM respectively. Compounds 4g and 4j, as potential BCR-ABL1 inhibitors, inhibit the phosphorylation of ABL1 and CRKL in a dose-dependent manner. Therefore, compounds 4g and 4j can be used as a starting point for further optimization.
Asunto(s)
Amidas , Proteínas de Fusión bcr-abl , Humanos , Amidas/farmacología , Resistencia a Antineoplásicos , Inhibidores de Proteínas Quinasas/farmacología , Mesilato de Imatinib/farmacología , Células K562 , ApoptosisRESUMEN
Primary liver cancer is one of the most common malignant cancers of the digestive system that lacks effective chemotherapeutic drugs in clinical settings. Camptothecin (CPT) and its derivatives have been approved for cancer treatment; however, their application is limited by their systemic toxicity. For lead optimization in new drug discovery stages, fluorination is an effective and robust approach to increase the bioavailability and optimize the pharmacokinetics of candidate compounds, thereby improving their efficacy. To obtain new and highly active CPT derivatives, we designed, synthesized, and evaluated two new fluorinated CPT derivatives, 9-fluorocamptothecin (A1) and 7-ethyl-9-fluorocamptothecin (A2), in this study. In vitro, A1 and A2 exhibited more robust anti-tumor activity than topotecan (TPT) in various cancer cells, particularly hepatocellular carcinoma (HCC) cells. In vivo, A1 and A2 exhibited greater anti-tumor activity than TPT in both AKT/Met induced primary HCC mouse models and implanted HepG2 cell xenografts. Acute toxicity tests revealed that A1 and A2 were not lethal and did not cause significant body weight loss at high doses. Moreover, A1 and A2 exhibited no significant toxicity in the mouse liver, heart, lung, spleen, kidney, and hematopoietic systems at therapeutic doses. Mechanistically, A1 and A2 blocked HCC cell proliferation by inhibiting the enzymatic activity of Topo I, subsequently inducing DNA damage, cell cycle arrest, and apoptosis. In summary, our results indicate that fluorination improves the anti-tumor activity of CPT while decreasing its toxicity and highlight the application potential of fluorination products A1 and A2 in clinical settings.
Asunto(s)
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Animales , Ratones , Camptotecina/farmacología , Camptotecina/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , ADN-Topoisomerasas de Tipo I/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Topotecan/farmacología , Inhibidores de Topoisomerasa I/farmacología , Inhibidores de Topoisomerasa I/uso terapéutico , Antineoplásicos/farmacología , Antineoplásicos/uso terapéuticoRESUMEN
Polyphenols such as resveratrol, honokiol and nordihydroguaiaretic acid are widely existing in nature products or synthetic compounds with interesting biological activities. Inspired by their structural feature, a total of 49 1,3-diaryl propane-based polyphenols were designed and synthesized through Claisen rearrangement reaction. New compounds were initially assessed for their anti-proliferative activities against various cancer cell lines (PC-3, U87MG, U251, HCT116) at a concentration of 50 µM, and the results guided the SAR of this series of compounds. Further screening of selected compounds against seven cancer cell lines (three additional colon cancer cell lines namely COLO205, HT29 and SW480 were chosen) led to the identification of two advanced leads 2t and 3t with IC50 values ranging from 8.2 ± 0.1 to 19.3 ± 1.9 µM. Both compounds also showed promising anti-proliferative activities against COLO205 in dose- and time-dependent manners. Furthermore, 2t and 3t exhibited good anti-tumor efficacy in COLO205 xenografted mice model with TGI values ranging from 38% to 58%. These results warrant the further investigation of this series of compounds.
Asunto(s)
Productos Biológicos , Neoplasias del Colon , Animales , Ratones , Polifenoles/farmacología , Polifenoles/uso terapéutico , Propano , Resveratrol , Modelos Animales de EnfermedadRESUMEN
Velvet antler is a traditional Chinese medicine with various pharmacological values, which is an important raw material for traditional Chinese medicinal wine. Nevertheless, the chemical compositions and bioactivities of velvet antler residue used for making medicinal wine are rarely reported, leading to a waste of resources. In this study, a velvet antler protein (VA-pro) was extracted from velvet antler residue by simulating the gastrointestinal digestion, and its composition, structural characteristics and in vivo anti-tumor activities were determined and investigated. VA-pro possessed high purity with a relatively low molecular weight as 22.589 kDa under HPLC, one- and two-dimensional electrophoresis, and it contained high contents of Pro, Gly, Glu and Ala. Besides, the secondary structure of VA-pro was dominated by ß-turn and ß-sheet, and VA-pro possessed similar protein sequence, isoelectric point and amino acid compositions to hypothetical protein G4228_020061. The in vivo results substantiated that VA-pro could improve the body weights and immune organ indices, increase the expressions of sera cytokines and regulate the distributions of T and B lymphocytes subsets in peripheral blood of S180 tumor-bearing mice. Furthermore, VA-pro could effectively inhibit solid S180 tumors growth by inducing S phase cell cycle arrest mediated through mitochondria. To summarize, our study provided theoretical support that VA-pro had the potential to be used as an immunopotentiator in immunocompromised or cancer-bearing hosts.