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1.
J Ethnopharmacol ; 300: 115729, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36162544

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: The North-eastern parts of India have immense therapeutic floras, Ottelia alismoides is an aquatic plant that has been in use for a long time in traditional medicine for treating diseases like cancer, tuberculosis, diabetes, febrifuge, hemorrhoids, and rubefacient. In lung and skin carcinoma cells with a high rate of proliferation and metastasis including drug resistance and non-specific target activity, generates important challenges towards their treatment strategy. Thus, finding novel therapeutic targets to treat lung and skin cancer progression is essential to enhance the patients' survival with treatment. AIM OF THE STUDY: The purpose of this study was to evaluate the apoptotic potential of acetone extract of O. alismoides (L.) Pers. (OA-AC) and to identify the compounds responsible for this effect, HRLC-MS-QTOF analysis of the extract has been undertaken along with in-silico molecular docking analysis of the identified compounds. MATERIALS AND METHODS: A549 and A431 cells were treated with acetone extract of O. alismoides (OA-AC) at 24 h and 48 h exposure and cell cycle phase distribution was evaluated and also apoptosis induction activity was evaluated by OA-EtBr staining and Mitochondrial outer membrane potential assay. Western blotting was performed for the evaluation of apoptotic protein expression. At last, the HR-LCMS of OA-AC was analyzed to identify the compounds responsible for the apoptotic activity of the extract. RESULTS: The cell cycle phase distribution analysis in A549 and A431 cells at 24hrs exposure with 10 µg/mL and 25 µg/mL of OA-AC showed a potent arrest or blockage at the G2/M phase of the cell cycle with reduced expression of cyclin B and p-Cdc2. At 48 h exposure, apoptosis was observed in these cancer cells with elevated expression of Bax, p21 and cleaved caspase 3 and reduced expression of the Bcl2. CONCLUSION: AO-EtBr staining of these cancer cells reveals that the death induced by OA-AC was apoptotic in nature with depolarization of mitochondrial membrane due to loss or damage of the mitochondrial membrane. The HRLC-MS-QTOF analysis of OA-AC depicted 14 major isolable compounds and molecular docking analysis displayed 4 compounds that might act as an inhibitor of cyclin B for G2/M phase arrest that leads to apoptotic induction in the cells.


Assuntos
Carcinoma , Hydrocharitaceae , Acetona , Apoptose , Carcinoma/tratamento farmacológico , Caspase 3 , Ciclo Celular , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Pontos de Checagem da Fase G2 do Ciclo Celular , Humanos , Hydrocharitaceae/metabolismo , Irritantes , Simulação de Acoplamento Molecular , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína X Associada a bcl-2
2.
Phytomedicine ; 108: 154493, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36265256

RESUMO

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a malignancy with high incidence in several regions of China, and the prognosis of patients with ESCC is unfavorable. Evodiamine (Evo), a small molecule derived from the traditional Chinese herb Evodia rutaecarpa, has shown anti-cancer efficacy in numerous human malignancies but not in ESCC. PURPOSE: To determine whether Evo induces cell-cycle arrest and apoptosis in ESCC in vitro and in vivo and elucidate the underlying mechanisms. METHODS: ATPlite and colony formation assay were used to validate the inhibiting effect of Evo on three ESCC cells in vitro; Two subcutaneous tumor models of ESCC cells were used to evaluate the anti-ESCC effect of Evo and assess the biosafety of Evo in vivo; RNAseq and Database of KEGG pathway analysis provided a direction for the mechanistic study of Evo; FACS was used to detect Evo-induced cell cycle arrest and cell apoptosis in ESCC cells; Western blot and QPCR were respectively used to detect the level of related genes and proteins in Evo-treated ESCC cells; SiRNA and other experimental techniques were used to identify the molecular mechanism of Evo-induced ESCC cell cycle arrest and cell apoptosis. RESULTS: Evo significantly suppressed the growth of ESCC both in vitro and in vivo. Mechanistically, Evo induced M-phase cell-cycle arrest by inactivation of CUL4A E3 ligase, which mediates degradation blockage of p53 and transcriptional activation of p21. With the prolonged treatment time, Evo triggered both Noxa-dependent intrinsic and DR4-dependent extrinsic cell apoptosis in two ESCC cell lines. CONCLUSION: Our findings revealed the anti-tumor efficacy and mechanisms of Evo, providing a solid scientific basis for Evo as an attractive choice for ESCC treatment.


Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Proteína Supressora de Tumor p53 , Neoplasias Esofágicas/tratamento farmacológico , Linhagem Celular Tumoral , Apoptose , Pontos de Checagem do Ciclo Celular , Proliferação de Células , Proteínas Culina
3.
FASEB J ; 36(12): e22654, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36421014

RESUMO

The therapeutic toxicity and resistance to currently available treatment options are major clinical challenges for the management of lung cancer. As a novel strategy, we synthesized analogues of a known flavonol, fisetin, which has shown anti-tumorigenic potential against cancer in cell culture with no adverse effects in animal models. We studied the synthetic analogues of fisetin for their anti-cancer potential against lung cancer cells, toxicity in mice and efficacy in a xenograft model. Brominated fisetin analogues were screened for their effects on the viability of A549 and H1299 lung cancer cells, and three analogues (3a, 3b, 3c), showed improved activity compared to fisetin. These analogues were more effective in restricting lung cancer cell proliferation, inducing G2 M phase cell cycle arrest and apoptosis. The fisetin analogues also downregulated EGFR/ERK1/2/STAT3 pathways. Fisetin analogue-induced apoptosis was accompanied by a higher Bax to Bcl-2 expression ratio. Based on the in vitro studies, the most effective fisetin analogue 3b was evaluated for in vivo toxicity, wherein it did not show any hepatotoxicity or adverse health effects in mice. Furthermore, analogue 3b showed greater antitumor efficacy (p < .001) as compared to its parent compound fisetin in a human lung cancer cell xenograft study in athymic mice. Together, our data suggest that the novel fisetin analogue 3b is more effective in restricting lung cancer cell growth, both in vitro as well as in vivo, without any apparent toxicity, supporting its further development as a novel anti-lung cancer agent.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Camundongos , Animais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Sistema de Sinalização das MAP Quinases , Neoplasias Pulmonares/tratamento farmacológico , Flavonoides/farmacologia , Flavonóis/farmacologia , Pontos de Checagem do Ciclo Celular , Apoptose , Receptores ErbB , Fator de Transcrição STAT3
4.
Curr Biol ; 32(22): R1262-R1264, 2022 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-36413966

RESUMO

How do very large cells coordinate their entry into mitosis? A new study shows that the bistability of the Cdk/Cyclin system allows cells to generate either 'trigger waves' or 'sweep waves' that drive cells into mitosis in different ways with distinct consequences.


Assuntos
Ciclinas , Mitose , Ciclo Celular , Proteínas de Ciclo Celular/genética , Pontos de Checagem do Ciclo Celular
5.
Sci Rep ; 12(1): 19752, 2022 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-36396667

RESUMO

Sunitinib, a VEGF blockade, is used to treat clear cell renal cell carcinoma (ccRCC). However, the anti-cancer treatment effects of sunitinib do not last long in ccRCC patients. Ginsenoside, a natural medicine extracted from ginseng, has been studied in cancer treatment and shown to have anti-tumor effects and low toxicity. We assessed cell viability and cell cycle analysis in ccRCC cell lines after treatment with ginsenoside and sunitinib. DNA damage was evaluated by measuring 8-OHdG levels and comet assay. ROS levels, reflecting the cause of oxidative stress, were also measured. Ginsenoside significantly enhanced the inhibition of cell viability by sunitinib, a result that was also confirmed in the xenograft model. In cell cycle analysis, combination treatment of ginsenoside and sunitinib enhanced G2M arrest in comparison with single-treatment groups. In addition, DNA damage was increased by ginsenoside and sunitinib according to the comet assay, and the level of 8-OHdG, which reflects oxidative DNA damage, also increased. We verified that ginsenoside enhances the efficacy of sunitinib to inhibit the proliferation of ccRCC cells via induction of oxidative DNA damage. The combination therapy of sunitinib and ginsenoside suggested the possibility of effectively treating ccRCC patients.


Assuntos
Carcinoma de Células Renais , Ginsenosídeos , Neoplasias Renais , Humanos , Carcinoma de Células Renais/patologia , Sunitinibe/farmacologia , Ginsenosídeos/farmacologia , Neoplasias Renais/patologia , Pontos de Checagem do Ciclo Celular
6.
Sci Rep ; 12(1): 19076, 2022 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-36352170

RESUMO

The anticancer properties of quinolones is a topic of interest among researchers in the scientific world. Because these compounds do not cause side effects, unlike the commonly used cytostatics, they are considered a promising source of new anticancer drugs. In this work, we designed a brief synthetic pathway and obtained a series of novel 8-phenyltetrahydroquinolinone derivatives functionalized with benzyl-type moieties at position 3. The compounds were synthesized via classical reactions such as nucleophilic substitution, solvent lysis, and condensation. Biological evaluation revealed that 3-(1-naphthylmethyl)-4-phenyl-5,6,7,8-tetrahydro-1H-quinolin-2-one (4a) exhibited potent cytotoxicity toward colon (HTC-116) and lung (A549) cancer cell lines. Analysis of the mechanism of action of compounds showed that compound 4a induced cell cycle arrest at the G2/M phase, leading to apoptotic cell death via intrinsic and extrinsic pathways. Taken together, the findings of the study suggest that tetrahydroquinolinone derivatives bearing a carbonyl group at position 2 could be potential lead compounds to develop anticancer agents for the treatment of lung cancers.


Assuntos
Antineoplásicos , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Apoptose , Antineoplásicos/farmacologia , Pontos de Checagem do Ciclo Celular , Pulmão , Proliferação de Células , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Relação Estrutura-Atividade , Estrutura Molecular
7.
Int J Mol Sci ; 23(21)2022 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-36361531

RESUMO

Non-small cell lung cancer (NSCLC) accounts for 85~90% of lung cancer cases, with a poor prognosis and a low 5-year survival rate. Sphingosine kinase-1 (SPHK1), a key enzyme in regulating sphingolipid metabolism, has been reported to be involved in the development of NSCLC, although the underlying mechanism remains unclear. In the present study, we demonstrated the abnormal signature of SPHK1 in NSCLC lesions and cell lines of lung cancers with a potential tumorigenic role in cell cycle regulation. Functionally, ectopic Pre-B cell leukemia homeobox-1 (PBX1) was capable of restoring the arrested G1 phase induced by SPHK1 knockdown. However, exogenous sphingosine-1-phosphate (S1P) supply had little impact on the cell cycle arrest by PBX1 silence. Furthermore, S1P receptor S1PR3 was revealed as a specific switch to transport the extracellular S1P signal into cells, and subsequently activated PBX1 to regulate cell cycle progression. In addition, Akt signaling partially participated in the SPHK1/S1PR3/PBX1 axis to regulate the cell cycle, and the Akt inhibitor significantly decreased PBX1 expression and induced G1 arrest. Targeting SPHK1 with PF-543 significantly inhibited the cell cycle and tumor growth in preclinical xenograft tumor models of NSCLC. Taken together, our findings exhibit the vital role of the SPHK1/S1PR3/PBX1 axis in regulating the cell cycle of NSCLC, and targeting SPHK1 may develop a therapeutic effect in tumor treatment.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Pontos de Checagem do Ciclo Celular/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Lisofosfolipídeos/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool) , Fator de Transcrição 1 de Leucemia de Células Pré-B , Proteínas Proto-Oncogênicas c-akt/metabolismo , Esfingosina/metabolismo , Animais
8.
ACS Nano ; 16(11): 18555-18567, 2022 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-36341683

RESUMO

Recent advances in tumor immunotherapy mainly tend to remodel the immunosuppressive tumor microenvironment (TME) for immune enhancement. However, the complexity of TME makes it unlikely to achieve satisfactory therapeutic effects with any single intervention alone. Here, we focus on exposing intrinsic features of tumor cells to trigger direct pleiotropic antitumor immunity. We develop a photosensitive nanointerferer that is engineered with a nanoscale metal-organic framework decorated with tumor cell membranes for targeted delivery of a photosensitizer and small interfering RNA, which is used to knock down cyclin-dependent kinase 4 (Cdk4). Cdk4 blockade can arrest the cell cycle of tumor cells to facilitate antigen exposure and increase the expression level of programmed cell death protein ligand 1 (PD-L1). Under laser irradiation, photodynamic damage triggered by the nanointerferer induces the release of tumor antigens and recruitment of dendritic cells (DCs), thereby promoting the antitumor activity of CD8+ T cells in combination with anti-PD-L1 antibodies. Ultimately, these events markedly retard tumor progression in a mouse model of ectopic colon tumor with negligible adverse effects. This study provides an alternative treatment for effective antitumor immunity by exciting the intrinsic potential of tumor cells to initiate immune responses while reducing immune-related toxicities.


Assuntos
Linfócitos T CD8-Positivos , Neoplasias do Colo , Camundongos , Animais , Imunoterapia , Microambiente Tumoral , Pontos de Checagem do Ciclo Celular , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Linhagem Celular Tumoral
9.
Sci Rep ; 12(1): 20302, 2022 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-36434030

RESUMO

The cell division cycle is regulated by a complex network of interacting genes and proteins. The control system has been modeled in many ways, from qualitative Boolean switching-networks to quantitative differential equations and highly detailed stochastic simulations. Here we develop a continuous-time stochastic model using seven Boolean variables to represent the activities of major regulators of the budding yeast cell cycle plus one continuous variable representing cell growth. The Boolean variables are updated asynchronously by logical rules based on known biochemistry of the cell-cycle control system using Gillespie's stochastic simulation algorithm. Time and cell size are updated continuously. By simulating a population of yeast cells, we calculate statistical properties of cell cycle progression that can be compared directly to experimental measurements. Perturbations of the normal sequence of events indicate that the cell cycle is 91% robust to random 'flips' of the Boolean variables, but 9% of the perturbations induce lethal mistakes in cell cycle progression. This simple, hybrid Boolean model gives a good account of the growth and division of budding yeast cells, suggesting that this modeling approach may be as accurate as detailed reaction-kinetic modeling with considerably less demands on estimating rate constants.


Assuntos
Saccharomycetales , Modelos Biológicos , Ciclo Celular , Divisão Celular , Pontos de Checagem do Ciclo Celular
10.
Int J Mol Sci ; 23(22)2022 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-36430237

RESUMO

Group VIA phospholipase A2 (iPLA2ß) play diverse biological functions in epithelial cells and macrophages. Global deletion in iPLA2ß-null (KO) mice leads to protection against hepatic steatosis in non-alcoholic fatty liver disease, in part, due to the replenishment of the loss of hepatocellular phospholipids. As the loss of phospholipids also occurs in hepatocellular carcinoma (HCC), we hypothesized that global deletion in KO mice may lead to protection against HCC. Here, HCC induced by diethylnitrosamine (DEN) was chosen because DEN causes direct injury to the hepatocytes. Male wild-type (WT) and KO mice at 3-5 weeks of age (12-13 mice/group) were subjected to a single intraperitoneal treatment with 10 mg/kg DEN, and mice were killed 12 months later. Analyses of histology, plasma cytokines, and gene expression were performed. Due to the low-dose DEN used, we observed a liver nodule in 3 of 13 WT and 2 of 12 KO mice. Only one DEN-treated WT mouse was confirmed to have HCC. DEN-treated KO mice did not show any HCC but showed suppressed hepatic expression of cell-cycle cyclinD2 and BCL2 as well as inflammatory markers IL-1ß, IL-10, and VCAM-1. Notably, DEN-treated KO mice showed increased hepatic necrosis and elevated levels of plasma lactate dehydrogenase suggesting an exacerbation of liver injury. Thus, global iPLA2ß deficiency in DEN-treated mice rendered HCC protection by an induction of cell-cycle arrest. Our results suggest the role of iPLA2ß inhibition in HCC treatment.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Masculino , Camundongos , Animais , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Dietilnitrosamina/toxicidade , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pontos de Checagem do Ciclo Celular
11.
Int J Mol Sci ; 23(22)2022 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-36430404

RESUMO

Cancer recurrence and metastasis, following successful treatment, constitutes a critical threat in clinical oncology and are the leading causes of death amongst cancer patients. This phenomenon is largely attributed to metastatic tumor dormancy, a rate-limiting stage during cancer progression, in which disseminated cancer cells remain in a viable, yet not proliferating state for a prolonged period. Dormant cancer cells are characterized by their entry into cell cycle arrest and survival in a quiescence state to adapt to their new microenvironment through the acquisition of mutations and epigenetic modifications, rendering them resistant to anti-cancer treatment and immune surveillance. Under favorable conditions, disseminated dormant tumor cells 're-awake', resume their proliferation and thus colonize distant sites. Due to their rarity, detection of dormant cells using current diagnostic tools is challenging and, thus, therapeutic targets are hard to be identified. Therefore, unraveling the underlying mechanisms required for keeping disseminating tumor cells dormant, along with signals that stimulate their "re-awakening" are crucial for the discovery of novel pharmacological treatments. In this review, we shed light into the main mechanisms that control dormancy induction and escape as well as emerging therapeutic strategies for the eradication of metastatic dormant cells, including dormancy maintenance, direct targeting of dormant cells and re-awakening dormant cells. Studies on the ability of the metastatic cancer cells to cease proliferation and survive in a quiescent state before re-initiating proliferation and colonization years after successful treatment, will pave the way toward developing innovative therapeutic strategies against dormancy-mediated metastatic outgrowth.


Assuntos
Recidiva Local de Neoplasia , Segunda Neoplasia Primária , Humanos , Recidiva Local de Neoplasia/patologia , Pontos de Checagem do Ciclo Celular , Divisão Celular , Epigênese Genética , Microambiente Tumoral/fisiologia
12.
Int J Med Sci ; 19(13): 1953-1964, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36438926

RESUMO

Background: Cedrol is a natural sesquiterpene alcohol found in Cedrus atlantica, which has been proven to have a broad spectrum of biological activities, such as antimicrobial, anti-inflammatory, analgesic, anxiolytic, and anti-cancer effects. However, the underlying anticancer mechanisms and in vivo inhibitory effects of cedrol on colorectal cancer (CRC) have not been elucidated. In the present study, we investigated the anti-CRC potential of cedrol using in vitro and in vivo models. Methods: The effects of cedrol on cell viability, cell cycle progression, and apoptosis of HT-29 and CT-26 cells were detected by MTT, flow cytometry, and TUNEL assays. Western blotting was used to measure protein expression for molecular signaling analyses. Results: Cedrol inhibited HT-29 and CT-26 cell proliferation in a time- and dose-dependent manner, with IC50 values of 138.91 and 92.46 µM, respectively. Furthermore, cedrol induced cell cycle arrest at the G0/G1 phase by regulating the expression of cell cycle regulators, such as CDK4 and cyclin D1, and triggered apoptosis through extrinsic (FasL/caspase-8) and intrinsic (Bax/caspase-9) pathways. In addition, cedrol in combination with the clinical drug 5-fluorouracil exhibited synergistic inhibitory effects on CRC cell growth. Importantly, cedrol treatment suppressed the progression of CRC and improved the survival rate of animals at a well-tolerated dose. Conclusion: These results suggest that cedrol has an anti-cancer potential via induction of cell cycle arrest and apoptosis, and it could be considered as an effective agent for CRC therapy.


Assuntos
Caspases , Neoplasias Colorretais , Animais , Pontos de Checagem do Ciclo Celular , Apoptose , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo
13.
Front Immunol ; 13: 922183, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36325324

RESUMO

ß-Carbolines are potentially strong alkaloids with a wide range of bioactivities, and their dimers exhibit stronger antitumor activity other than the monomers. However, the detailed mechanisms of the ß-carboline dimers in inhibiting sarcoma (SARC) remain unclear. The results showed that ß-carboline-3-carboxylic acid dimers Comp1 and Comp2, which were synthesized in our lab and modified at the N9 position and linked at the C3 position, exhibited effective inhibition activity on MG-63 proliferation (IC50 = 4.6µM). Meanwhile, the large scale transcriptome profiles of SARC from The Cancer Genome Atlas (TCGA) were analyzed, and found that abnormal expression of genes relevant to apoptosis, cell cycle, and signaling pathways of Hedgehog, HIF, Ras involved in the SARC pathogenesis. Interestingly, both dimers could promote the apoptosis and arrest the cell cycle in S phase to inhibit proliferation of MG-63. Moreover, Comp1 and Comp2 inhibited the expression CDK2, CCNA2, DBF4, and PLK1 associated with various immune cells and cell cycle in MG-63. Remarkably, drug-target interaction network analysis showed that numerous proteins involved in cell cycle were the potential targets of Comp1 and Comp2, especially CCNA2. Further molecular docking, isothermal titration calorimetry (ITC) and Cellular Thermal Shift Assay (CETSA) confirmed that both dimers could directly interact with CCNA2, which is significantly correlated with CD4+ T cells, by strong hydrophobic interactions (Kd=5.821 ×106 N). Meanwhile, the levels of CCNA2 and CDK2 were inhibited to decrease in MG-63 by both dimer treatments at transcription and protein levels, implying that Comp1 and Comp2 blocked the interaction between CCNA2 and CDK2 through competitive binding with CCNA2 to arrest the cell cycle of MG-63 cells in the S phase. Additionally, the transcriptome profiles of ß-carboline-treated mice from Gene Expression Omnibus (GEO) were obtained, and found that similar antitumor mechanism was shared among ß-carboline derivatives. Overall, our results elucidated the antitumor mechanisms of Comp1 and Comp2 through dual-suppressing the function of CCNA2 to profoundly arrest cell cycle of MG-63, then effectively inhibited cell proliferation of MG-63. These results provide new insights into the antitumor mechanism of ß-carboline dimers and new routes of various novel cancer-related drug targets for future possible cancer therapy.


Assuntos
Antineoplásicos , Sarcoma , Animais , Camundongos , Simulação de Acoplamento Molecular , Linhagem Celular Tumoral , Carbolinas/farmacologia , Carbolinas/química , Pontos de Checagem do Ciclo Celular , Proliferação de Células , Antineoplásicos/farmacologia , Antineoplásicos/química
14.
Nutrients ; 14(21)2022 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-36364815

RESUMO

Colorectal cancer (CRC) is one of the diseases with the highest rates of prevalence and mortality despite therapeutic methods in the world. In particular, there are not enough methods to treat metastasis of CRC cells to distant organs. Cannabis sativa Linne (C. sativa) is a popular medicinal plant used by humans to treat many diseases. Recently, extracts of C. sativa have shown diverse pharmacological effects as a result of choosing different extraction methods. In this study, we performed experiments to confirm the inhibitory effect and related mechanisms of supercritical extract of C. sativa on metastatic CRC cells. The effect of SEC on the viability of CRC cell lines, CT26 and HCT116, was determined using CCK reagent. Flow cytometry was performed to confirm whether SEC can promote cell cycle arrest and apoptosis. Additionally, SEC reduced proliferation of CT26 and HCT116 cells without causing toxicity to normal colon cell line CCD-18Co cells. SEC treatment reduced colony formation in both CRC cell lines, promoted G0/G1 phase arrest and apoptosis in CT26 and HCT116 cells through AMPK activation and MAPKs such as ERK, JNK, and p38 inactivation. Moreover, oral administration of SEC decreased pulmonary metastasis of CT26 cells. Our research demonstrates the inhibitory effect of SEC on CRC cell proliferation and metastasis. Thus, SEC might have therapeutic potential for CRC treatment.


Assuntos
Cannabis , Neoplasias Colorretais , Neoplasias Pulmonares , Humanos , Proteínas Quinases Ativadas por AMP , Linhagem Celular Tumoral , Neoplasias Colorretais/patologia , Pontos de Checagem do Ciclo Celular , Apoptose , Neoplasias Pulmonares/patologia , Proliferação de Células
15.
J Cell Biol ; 221(12)2022 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-36214847

RESUMO

Centrosomes play a crucial role during immune cell interactions and initiation of the immune response. In proliferating cells, centrosome numbers are tightly controlled and generally limited to one in G1 and two prior to mitosis. Defects in regulating centrosome numbers have been associated with cell transformation and tumorigenesis. Here, we report the emergence of extra centrosomes in leukocytes during immune activation. Upon antigen encounter, dendritic cells pass through incomplete mitosis and arrest in the subsequent G1 phase leading to tetraploid cells with accumulated centrosomes. In addition, cell stimulation increases expression of polo-like kinase 2, resulting in diploid cells with two centrosomes in G1-arrested cells. During cell migration, centrosomes tightly cluster and act as functional microtubule-organizing centers allowing for increased persistent locomotion along gradients of chemotactic cues. Moreover, dendritic cells with extra centrosomes display enhanced secretion of inflammatory cytokines and optimized T cell responses. Together, these results demonstrate a previously unappreciated role of extra centrosomes for regular cell and tissue homeostasis.


Assuntos
Centrossomo , Células Dendríticas , Pontos de Checagem do Ciclo Celular , Movimento Celular , Centrossomo/metabolismo , Quimiotaxia , Citocinas/metabolismo , Células Dendríticas/metabolismo , Humanos , Centro Organizador dos Microtúbulos , Mitose , Proteínas Serina-Treonina Quinases/metabolismo , Linfócitos T/metabolismo
16.
Int J Mol Sci ; 23(19)2022 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-36232965

RESUMO

The yeast Saccharomyces cerevisiae has been used for bread making and beer brewing for thousands of years. In addition, its ease of manipulation, well-annotated genome, expansive molecular toolbox, and its strong conservation of basic eukaryotic biology also make it a prime model for eukaryotic cell biology and genetics. In this review, we discuss the characteristics that made yeast such an extensively used model organism and specifically focus on the DNA damage response pathway as a prime example of how research in S. cerevisiae helped elucidate a highly conserved biological process. In addition, we also highlight differences in the DNA damage response of S. cerevisiae and humans and discuss the challenges of using S. cerevisiae as a model system.


Assuntos
Fenômenos Biológicos , Saccharomyces cerevisiae , Biologia , Pontos de Checagem do Ciclo Celular , Dano ao DNA , Células Eucarióticas , Humanos , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo
17.
Int J Mol Sci ; 23(19)2022 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-36233133

RESUMO

Cytolethal distending toxins (Cdt) are produced by a diverse group of pathogens. One Cdt-producing organism, Aggregatibacter actinomycetemcomitans, plays a critical role in the pathogenesis of a unique form of periodontitis, formerly referred to as localized aggressive periodontitis. The active Cdt subunit, CdtB, is a potent phosphatidylinositol (PI) 3,4,5-triphosphate phosphatase capable of inducing PI-3-kinase signaling blockade, a requisite for Cdt-induced toxicity in lymphocytes. In this study, we extended our observations to include the oral keratinocyte response to AaCdt using cell lines and primary gingival keratinocytes. All three exhibited G2/M arrest when exposed to AaCdt toxin within 24 h. Toxin-treated cells exhibited reduced levels of pAkt and pGSK3ß within 6 h. Pre-treatment with GSK3ß kinase inhibitors, LY2090314, CHIR99021 and Tideglusib, abrogated Cdt-induced G2/M arrest. None of the oral epithelial cells exhibited evidence of apoptosis. Cells remained arrested in the G2/M phase for at least 72 h without evidence of DNA damage response activation (H2AX phosphorylation). Cdt-treated cells displayed increased phosphorylation of the cyclin dependent kinase 1 (CDK1); moreover, the GSK3 inhibitors blocked this increase and reduced total CDK1 levels. This study further clarifies the potential mechanism(s) contributing to Cdt toxicity and toxin-mediated pathogenesis.


Assuntos
Aggregatibacter actinomycetemcomitans , Periodontite Agressiva , Apoptose , Toxinas Bacterianas , Proteína Quinase CDC2/metabolismo , Ciclo Celular , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Pontos de Checagem da Fase G2 do Ciclo Celular , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Queratinócitos , Fosfatidilinositóis/metabolismo , Monoéster Fosfórico Hidrolases/metabolismo
18.
Molecules ; 27(19)2022 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-36235222

RESUMO

Human glioblastoma multiforme (GBM) is one of the most malignant brain tumors, with a high mortality rate worldwide. Conventional GBM treatment is now challenged by the presence of the blood-brain barrier (BBB), drug resistance, and post-treatment adverse effects. Hence, developing bioactive compounds isolated from plant species and identifying molecular pathways in facilitating effective treatment has become crucial in GBM. Based on pharmacodynamic studies, andrographolide has sparked the interest of cancer researchers, who believe it may alleviate difficulties in GBM therapy; however, it still requires further study. Andrographolide is a bicyclic diterpene lactone derived from Andrographis paniculata (Burm.f.) Wallich ex Nees that has anticancer properties in various cancer cell lines. The present study aimed to evaluate andrographolide's anticancer effectiveness and potential molecular pathways using a DBTRG-05MG cell line. The antiproliferative activity of andrographolide was determined using the WST-1 assay, while scratch assay and clonogenic assay were used to evaluate andrographolide's effectiveness against the cancer cell line by examining cell migration and colony formation. Flowcytometry was also used to examine the apoptosis and cell cycle arrest induced by andrographolide. The mRNA and protein expression level involved in the ERK1/2/c-Myc/p53 signaling pathway was then assessed using qRT-PCR and Western blot. The protein-protein interaction between c-Myc and p53 was determined by a reciprocal experiment of the co-immunoprecipitation (co-IP) using DBTRG-05MG total cell lysate. Andrographolide significantly reduced the viability of DBTRG-05MG cell lines in a concentration- and time-dependent manner. In addition, scratch and clonogenic assays confirmed the effectiveness of andrographolide in reducing cell migration and colony formation of DBTRG-05MG, respectively. Andrographolide also promoted cell cycle arrest in the G2/M phase, followed by apoptosis in the DBTRG-05MG cell line, by inducing ERK1/2, c-Myc, and p53 expression at the mRNA level. Western blot results demonstrated that c-Myc overexpression also increased the production of the anti-apoptotic protein p53. Our findings revealed that c-Myc and p53 positively interact in triggering the apoptotic signaling pathway. This study successfully discovered the involvement of ERK1/2/c-Myc/p53 in the suppression of the DBTRG-05MG cell line via cell cycle arrest followed by the apoptosis signaling pathway following andrographolide treatment.


Assuntos
Diterpenos , Glioblastoma , Apoptose , Proteínas Reguladoras de Apoptose/metabolismo , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Diterpenos/farmacologia , Diterpenos/uso terapêutico , Pontos de Checagem da Fase G2 do Ciclo Celular , Glioblastoma/metabolismo , Humanos , Lactonas/farmacologia , Sistema de Sinalização das MAP Quinases , RNA Mensageiro/metabolismo , Transdução de Sinais , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
19.
Molecules ; 27(19)2022 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-36235266

RESUMO

Lung adenocarcinoma (LADC) is the most prevalent lung cancer sub-type, and targeted therapy developed in recent years has made progress in its treatment. Erdafitinib, a potent and selective pan-FGFR tyrosine kinase inhibitor, has been confirmed to be effective for the treatment of LADC; however, the molecular mechanism responsible for this effect is unclear. The in vitro study showed that erdafitinib exhibited an outstanding anti-cancer activity in human LADC cell line A549 by inducing S-phase cell-cycle arrest and cell apoptosis. The mechanistic study based on the transcriptomic data revealed that erdafitinib exerted its anti-cancer effect by affecting the cell cycle-related pathway, and CDK2 was the regulatory target of this drug. In addition, CDK2 overexpression significantly attenuated the anti-cancer effect of erdafitinib by affecting the transcriptional activity and expression of E2F1, as well as the expression of CDK1. The in vivo study showed that erdafitinib presented an obvious anti-cancer effect in the A549 xenograft mice model, which was accompanied by the reduced expression of CDK2. Thus, this study demonstrates the anti-cancer effect of erdafitinib against LADC for the first time based on in vitro and in vivo models, whose activity is achieved by targeting CDK2 and regulating downstream E2F1-CDK1 signaling. This study may be helpful for expanding the clinical application of erdafitinib in treating LADC.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Animais , Apoptose , Carcinogênese/genética , Ciclo Celular , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Quinase 2 Dependente de Ciclina/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis , Quinoxalinas
20.
Molecules ; 27(20)2022 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-36296495

RESUMO

In the current study, new benzimidazole-based 1,3,4-oxadiazole derivatives have been synthesized and characterized by NMR, IR, MS, and elemental analysis. The final compounds were screened for cytotoxicity against MDA-MB-231, SKOV3, and A549 cell lines and EGFR for inhibitory activities. Compounds 10 and 13 were found to be the most active against all the tested cell lines, comparable to doxorubicin, and exhibited significant inhibition on EGFR kinase, with IC50 0.33 and 0.38 µM, respectively, comparable to erlotinib (IC50 0.39 µM). Furthermore, these two compounds effectively suppressed cell cycle progression and induced cell apoptosis in MDA-MB-231, SKOV3, and A549 cell lines. The docking studies revealed that these compounds showed interactions similar to erlotinib at the EGFR site. It can be concluded that the synthesized molecules effectively inhibit EGFR, can arrest the cell cycle, and may trigger apoptosis and therefore, could be used as lead molecules in the development of new anticancer agents targeting EGFR kinase.


Assuntos
Antineoplásicos , Inibidores de Proteínas Quinases , Ensaios de Seleção de Medicamentos Antitumorais , Cloridrato de Erlotinib/farmacologia , Inibidores de Proteínas Quinases/química , Receptores ErbB/metabolismo , Antineoplásicos/química , Linhagem Celular Tumoral , Simulação de Acoplamento Molecular , Proliferação de Células , Apoptose , Pontos de Checagem do Ciclo Celular , Benzimidazóis/farmacologia , Doxorrubicina/farmacologia , Relação Estrutura-Atividade
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