RESUMEN

Uterine leiomyosarcoma (uLMS) is the most common type of uterine sarcoma, associated with poor prognosis, high rates of recurrence, and metastasis. Currently, the molecular mechanism of the origin and development of uLMS is limited. Bromodomain and extra-terminal (BET) proteins are involved in both physiological and pathological events. However, the role of BET proteins in the pathogenesis of uLMS is unknown. Here, we show for the first time that BET protein family members, BRD2, BRD3, and BRD4, are aberrantly overexpressed in uLMS tissues compared to the myometrium, with a significant change by histochemical scoring assessment. Furthermore, inhibiting BET proteins with their small, potent inhibitors (JQ1 and I-BET 762) significantly inhibited the uLMS proliferation dose-dependently via cell cycle arrest. Notably, RNA-sequencing analysis revealed that the inhibition of BET proteins with JQ1 and I-BET 762 altered several critical pathways, including the hedgehog pathway, EMT, and transcription factor-driven pathways in uLMS. In addition, the targeted inhibition of BET proteins altered several other epigenetic regulators, including DNA methylases, histone modification, and m6A regulators. The connections between BET proteins and crucial biological pathways provide a fundamental structure to better understand uterine diseases, particularly uLMS pathogenesis. Accordingly, targeting the vulnerable epigenome may provide an additional regulatory mechanism for uterine cancer treatment.

Asunto(s)

Leiomiosarcoma , Factores de Transcripción , Neoplasias Uterinas , Humanos , Femenino , Leiomiosarcoma/metabolismo , Leiomiosarcoma/patología , Leiomiosarcoma/genética , Neoplasias Uterinas/metabolismo , Neoplasias Uterinas/patología , Neoplasias Uterinas/genética , Factores de Transcripción/metabolismo , Proliferación Celular , Azepinas/farmacología , Regulación Neoplásica de la Expresión Génica , Triazoles/farmacología , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Línea Celular Tumoral , Epigénesis Genética , Puntos de Control del Ciclo Celular/efectos de los fármacos , Puntos de Control del Ciclo Celular/genética , Persona de Mediana Edad , Proteínas que Contienen Bromodominio , Benzodiazepinas , Proteínas

RESUMEN

Melanoma is a malignant skin cancer associated with high mortality rates and drug resistance, posing a significant threat to human health. The combination of chemotherapy and photodynamic therapy (PDT) represents a promising strategy to enhance antitumor efficacy through synergistic anti-cancer effects. Topical delivery of chemotherapeutic drugs and photosensitizers (PS) offers a non-invasive and safe way to treat melanoma. However, the effectiveness of these treatments is often hindered by challenges such as limited skin permeability and instability of the PS. In this study, transfersomes (TFS) were designed to facilitate transdermal delivery of the chemotherapeutic drug 5-Fluorouracil (5-FU) and the PS Imperatorin (IMP) for combined chemo-photodynamic therapy for melanoma. The cytotoxic and phototoxic effects of TFS-mediated PDT (TFS-UVA) were investigated in A375 cells and nude mice. The study also demonstrated that TFS-UVA generated intracellular ROS, induced G2/ M phase cell cycle arrest, and promoted cell apoptosis. In conclusion, this study indicated that 5-FU/ IMP-TFS serves as an effective transdermal therapeutic strategy for chemo-PDT in treating melanoma.

Asunto(s)

Apoptosis , Puntos de Control del Ciclo Celular , Fluorouracilo , Melanoma , Fotoquimioterapia , Fármacos Fotosensibilizantes , Fotoquimioterapia/métodos , Animales , Humanos , Apoptosis/efectos de los fármacos , Melanoma/tratamiento farmacológico , Melanoma/patología , Ratones , Fluorouracilo/farmacología , Fluorouracilo/administración & dosificación , Línea Celular Tumoral , Puntos de Control del Ciclo Celular/efectos de los fármacos , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/administración & dosificación , Ratones Desnudos , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Especies Reactivas de Oxígeno/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Administración Tópica , Furocumarinas/farmacología , Furocumarinas/administración & dosificación , Furocumarinas/química

RESUMEN

Sangre de drago, the sap of Croton lechleri Müll. Arg. tree, has been used for centuries in traditional medicine owing to its diverse biological activities. Extracts derived from different parts of the species contain a multitude of phytochemicals with varied applications. Twigs, however, are among the least studied parts of the plant. This study unveils new biological activities of Croton lechleri twig extracts recovered by applying Soxhlet and advanced green techniques. For all extracts, total phenolic content and antioxidant activity were determined. Subsequently, four were selected, and their cytotoxic effects were assessed on both normal (HaCat) and malignant melanoma (A375) skin cell lines using the MTT assay and trypan blue exclusion assay. All showed dose-dependent cytotoxicity, with the Soxhlet ethanol extract demonstrating the highest selectivity towards A375 cells over HaCat cells. The extracts induced apoptosis and necrosis, as confirmed by Annexin V/PI dual-labeling and flow cytometry, highlighting their ability to trigger programmed cell death in cancer cells. The selective inhibition of cell cycle progression in A375 compared to HaCat observed both for Soxhlet ethanol and pressurized ethanol extracts induces cell cycle arrest at multiple points, primarily in the G1 and G2/M phases, and significantly reduces DNA synthesis as evidenced by the decrease in the S-phase population, confirmed by the EdU assay. Consequently, the Soxhlet extract composition was analyzed using LC-MS, which revealed their richness in polyphenolic compounds, particularly flavonoids from the flavonol subclass.

Asunto(s)

Antioxidantes , Apoptosis , Croton , Extractos Vegetales , Croton/química , Humanos , Extractos Vegetales/farmacología , Extractos Vegetales/química , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Antioxidantes/farmacología , Antioxidantes/química , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Puntos de Control del Ciclo Celular/efectos de los fármacos , Fitoquímicos/farmacología , Fitoquímicos/química , Supervivencia Celular/efectos de los fármacos , Fenoles/farmacología , Fenoles/química

RESUMEN

PURPOSE: Therapeutic management of colorectal cancer (CRC) does not yet yield promising long-term results. Therefore, there is a need for further investigation of possible therapeutic options. Various experiments have studied the effects of apigenin on CRC and have shown conflicting results. This systematic review and meta-analysis investigates the currently existing evidence on the effect of apigenin on CRC. METHODS: Medline, Embase, Scopus, and Web of Science databases were searched for articles related to apigenin and its effect on CRC in the preclinical setting. Cell viability, growth inhibition, apoptosis, and cell cycle arrest for in-vitro, and body weight, tumor size, and mortality in in-vivo studies were extracted as outcomes. RESULTS: Thirty-nine articles investigating colorectal adenocarcinoma were included in this meta-analysis. Thirty-seven of these studies had data for in vitro experiments, with eight studies having data for in vivo experiments. Six articles had both in vitro and in vivo assessments. Our analysis showed apigenin reduces cell viability and induces growth inhibition, apoptosis, and cell cycle arrest in in vitro studies. The few in vivo studies indicate that apigenin decreases tumor size while showing no effects on the body weight of animal colorectal adenocarcinoma models. CONCLUSION: Our results demonstrated that apigenin, through reducing cell viability, inducing growth inhibition, apoptosis, and cell cycle arrest, and also by decreasing the tumor size, can be considered as a possible adjuvant agent in the management of colorectal adenocarcinoma. However, further in vivo studies are needed before any efforts to translate the current evidence into clinical studies.

Asunto(s)

Adenocarcinoma , Apigenina , Apoptosis , Neoplasias Colorrectales , Apigenina/farmacología , Apigenina/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Humanos , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Apoptosis/efectos de los fármacos , Animales , Supervivencia Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos

RESUMEN

BACKGROUND: Glioblastoma multiforme (GBM) is the most malignant brain tumor, with a poor prognosis and life expectancy of 14-16 months after diagnosis. The standard treatment for GBM consists of surgery, radiotherapy, and chemotherapy with temozolomide. Most patients become resistant to treatment after some time, and the tumor recurs. Therefore, there is a need for new drugs to manage GBM. Eslicarbazepine (ESL) is a well-known antiepileptic drug belonging to the dibenzazepine group with anticancer potentials. In this study, for the first time, we evaluated the potential effects of ESL on C6 cell growth, both in vitro and in vivo, and examined its molecular effects. METHODS: To determine the effect of ESL on the c6 cell line, cell viability, proliferation, and migration were evaluated by MTT assay, colony formation, and wound healing assay. Also, apoptosis and cell cycle were examined by flow cytometry, qRT-PCR, and western blotting. In addition, an intracranial model in Wistar rats was used to investigate the effect of ESL in vivo, and the tumor size was measured using both Caliper and MRI. RESULTS: The obtained results are extremely consistent and highly encouraging. C6 cell viability, proliferation, and migration were significantly suppressed in ESL-treated C6 cells (p < 0.001), as determined by cell-based assays. ESL treatment led to significant enhancement of apoptosis (p < 0.01), as determined by flow cytometry, and upregulation of genes involved in cell apoptosis, such as the Bax/Bcl2 ratio at RNA (p < 0.05) and protein levels (5.37-fold). Flow cytometric analysis of ESL-treated cells revealed G2/M phase cell cycle arrest. ESL-treated cells demonstrated 2.49-fold upregulation of p21 alongside, 0.22-fold downregulation of cyclin B1, and 0.34-fold downregulation of cyclin-dependent kinase-1 at the protein level. Administration of ESL (30 mg/kg) to male rats bearing C6 intracranial tumors also suppressed the tumor volume and weight (p < 0.01). CONCLUSIONS: Based on these novel findings, ESL has the potential for further experimental and clinical studies in glioblastoma.

Asunto(s)

Apoptosis , Neoplasias Encefálicas , Puntos de Control del Ciclo Celular , Proliferación Celular , Dibenzazepinas , Animales , Ratas , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/metabolismo , Dibenzazepinas/farmacología , Dibenzazepinas/uso terapéutico , Glioma/tratamiento farmacológico , Glioma/patología , Glioma/metabolismo , Supervivencia Celular/efectos de los fármacos , Ratas Wistar , Modelos Animales de Enfermedad , Humanos , Movimiento Celular/efectos de los fármacos , Masculino , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico

RESUMEN

Inhibiting the cytotoxic T-lymphocyte-associated protein-4 (CTLA-4)-mediated immune checkpoint system using an anti-CTLA-4 antibody (Ab) can suppress the growth of various cancers, but the detailed mechanisms are unclear. In this study, we established a monoclonal hepatocellular carcinoma cell line (Hepa1-6 #12) and analyzed the mechanisms associated with anti-CTLA-4 Ab treatment. Depletion of CD4+ T cells, but not CD8+ T cells, prevented anti-CTLA-4 Ab-mediated anti-tumor effects, suggesting dependence on CD4+ T cells. Anti-CTLA-4 Ab treatment resulted in recruitment of interferon-gamma (IFN-g)-producing CD4+ T cells, called T-helper 1 (Th1), into tumors, and neutralization of IFN-g abrogated the anti-tumor effects. Moreover, tumor growth suppression did not require major histocompatibility complex (MHC)-I or MHC-II expression on cancer cells. In vitro studies showed that IFN-g can induce cell cycle arrest and apoptosis in tumor cells. Taken together, these data demonstrate that anti-CTLA-4 Ab can exert its anti-tumor effects through Th1-mediated cell cycle arrest and apoptosis.

Asunto(s)

Apoptosis , Antígeno CTLA-4 , Carcinoma Hepatocelular , Puntos de Control del Ciclo Celular , Interferón gamma , Neoplasias Hepáticas , Células TH1 , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/metabolismo , Apoptosis/efectos de los fármacos , Animales , Células TH1/inmunología , Células TH1/efectos de los fármacos , Antígeno CTLA-4/antagonistas & inhibidores , Antígeno CTLA-4/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/metabolismo , Puntos de Control del Ciclo Celular/efectos de los fármacos , Ratones , Línea Celular Tumoral , Interferón gamma/metabolismo , Humanos , Ratones Endogámicos C57BL , Proliferación Celular/efectos de los fármacos , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico

RESUMEN

Breast cancer (BC) is a highly heterogeneous tumor that has surpassed lung cancer as the most frequently diagnosed cancer in women. In clinical practice,the primary approach for treating estrogen receptor alpha (ERα)-positive BC is through endocrine therapy, which involves targeting the ERα using medications like tamoxifen and fulvestrant. However, the problem of de novo or acquired resistance poses a significant clinical challenge, emphasizing the critical need for the development of novel therapeutic strategies. In this regard, we have successfully designed and developed a novel selective estrogen receptor degrader (SERD) called OBHSA, which specifically targets and degrades ERα, demonstrating remarkable efficacy. Our findings revealed the effectiveness of OBHSA in inhibiting the proliferation of various BC cells, including both tamoxifen-sensitive and tamoxifen-resistant BC cells, indicating its great potential to overcome endocrine resistance. In terms of mechanism, we discovered that OBHSA overcame tamoxifen resistance through two distinct pathways. Firstly, OBHSA degraded cyclin D1 in an ERα-dependent manner, thereby blocking the cell cycle. Secondly, OBHSA induced an elevation in intracellular reactive oxygen species, triggering an excessive activation of the unfolded protein response (UPR) and ultimately leading to apoptotic cell death. In summary, our finding demonstrated that OBHSA exerts anti-tumor effects by inducing cell cycle arrest and UPR-mediated apoptosis. These findings hold promise for the development of novel therapeutic drugs targeting endocrine-resistant BC.

Asunto(s)

Apoptosis , Neoplasias de la Mama , Puntos de Control del Ciclo Celular , Resistencia a Antineoplásicos , Receptor alfa de Estrógeno , Tamoxifeno , Respuesta de Proteína Desplegada , Humanos , Tamoxifeno/farmacología , Respuesta de Proteína Desplegada/efectos de los fármacos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Femenino , Resistencia a Antineoplásicos/efectos de los fármacos , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Receptor alfa de Estrógeno/metabolismo , Receptor alfa de Estrógeno/genética , Proliferación Celular/efectos de los fármacos , Línea Celular Tumoral , Antineoplásicos Hormonales/farmacología , Animales , Ratones Desnudos , Ratones , Células MCF-7 , Especies Reactivas de Oxígeno/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Ciclina D1/metabolismo , Ciclina D1/genética

RESUMEN

In the present study, we prepared new sixteen different derivatives. The first series were prepared (methylene)bis(2-(thiophen-2-yl)-1H-indole) derivatives which have (indole and thiophene rings) by excellent yield from the reaction (2 mmol) 2-(thiophen-2-yl)-1H-indole and (1 mmol) from aldehyde. The second series were synthesized (2-(thiophen-2-yl)-1H-indol-3-yl) methyl) aniline derivatives at a relatively low yield from multicomponent reaction of three components 2-(thiophen-2-yl)-1H-indole, N-methylaniline and desired aldehydes. The anticancer effect of the newly synthesized derivatives was determined against different cancers, colon, lung, breast and skin. The counter screening was done against normal Epithelial cells (RPE-1). The effect on cell cycle and mechanisms underlying of the antitumor effect were also studied. All new compounds were initially tested at a single dose of 100 µg/ml against this panel of 5 human tumor cell lines indicated that the compounds under investigation exhibit selective cytotoxicity against HCT-116 cell line and compounds (4g, 4a, 4c) showed potent anticancer activity against HCT-116 cell line with the inhibitory concentration IC50 values were, 7.1±0.07, 10.5± 0.07 and 11.9± 0.05 µΜ/ml respectively. Also, the active derivatives caused cell cycle arrest at the S and G2/M phase with significant(p < 0.0001) increase in the expression levels of tumor suppressors miR-30C, and miR-107 and a tremendous decrease in oncogenic miR-25, IL-6 and C-Myc levels. It is to conclude that the anticancer activity could be through direct interaction with tumor cell DNA like S-phase-dependent chemotherapy drugs. Which can interact with DNA or block DNA synthesis such as doxorubicin, cisplatin, or 5-fluorouracil and which were highly effective in killing the cancer cells. This data ensures the efficiency of the 3 analogues on inducing cell cycle arrest and preventing cancer cell growth. The altered expressions explained the molecular mechanisms through which the newly synthesized analogues exert their anticancer action.

Asunto(s)

Antineoplásicos , Puntos de Control del Ciclo Celular , Proliferación Celular , Indoles , MicroARNs , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Células HCT116 , Puntos de Control del Ciclo Celular/efectos de los fármacos , Indoles/farmacología , Indoles/química , Indoles/síntesis química , Regulación hacia Abajo/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales

RESUMEN

Teff (Eragrostis tef), a gluten-free cereal crop cultivated originally in Northeast Africa, is increasingly utilized due to its nutritional and health benefits. The aim of the present study was to investigate the effects of ethanol extract obtained from raw and thermally treated teff, referred to as RTE and TTE, respectively, on uncontrolled growth and activated metastasis using human cancer cell lines. Both RTE and TTE contained flavones, such as orientin (luteolin 8-C-glucoside) and vitexin (apigenin 8-C-glucoside), and phenolic acids, such as protocatechuic acid and p-coumaric acid. TTE showed higher total phenol, protocatechuic acid, and p-coumaric acid contents, but lower orientin content compared to RTE. RTE and TTE significantly suppressed cell growth of H1299 human lung cancer cells, with TTE exhibiting more pronounced effects than RTE, while both extracts had only minimal effects on the growth of non-malignant human umbilical vein endothelial cells. The growth-inhibitory activities of RTE and TTE in H1299 cells were associated with apoptosis induction and cell cycle arrest at the G2/M phase. TTE produced an additional effect on inducing cell cycle arrest at the S phase in H1299 cells, potentially contributing to its stronger growth-inhibitory effects. Moreover, both RTE and TTE effectively inhibited key events in metastasis, such as invasion, migration, and adhesion, in H1299 cells under non-cytotoxic conditions, with TTE showing stronger effects. In HCT116 human colon cancer cells, a similar pattern of inhibition was demonstrated against the metastatic events, accompanied by reduced levels of matrix metalloproteinase-2 and -9. Our results indicate that teff extracts exhibit in vitro anti-growth and anti-metastatic activities, which are enhanced by thermal treatment of teff.

Asunto(s)

Apoptosis , Movimiento Celular , Proliferación Celular , Extractos Vegetales , Humanos , Extractos Vegetales/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Antineoplásicos Fitogénicos/farmacología , Metástasis de la Neoplasia/prevención & control , Puntos de Control del Ciclo Celular/efectos de los fármacos , Hidroxibenzoatos/farmacología , Adhesión Celular/efectos de los fármacos , Metaloproteinasa 9 de la Matriz/metabolismo , Calor , Metaloproteinasa 2 de la Matriz/metabolismo

RESUMEN

Secreted proteins regulate the balance between cellular proliferation and G0 arrest and therefore play important roles in tumour dormancy. Tumour dormancy presents a significant clinical challenge for breast cancer patients, where non-proliferating, G0-arrested cancer cells remain at metastatic sites, below the level of clinical detection, some of which can re-enter proliferation and drive tumour relapse. Knowing which secreted proteins can regulate entry into and exit from G0 allows us to manipulate their signalling to prevent tumour relapse. To identify novel secreted proteins that can promote breast cancer G0 arrest, we performed a secretome-wide, image-based screen for proteins that increase the fraction of cells in G0 arrest. From a secretome library of 1282 purified proteins, we identified 29 candidates that promote G0 arrest in non-transformed and transformed breast epithelial cells. The assay we have developed can be adapted for use in other perturbation screens in other cell types. All datasets have been made available for re-analysis and our candidate proteins are presented for alternative bioinformatic refinement or further experimental follow up.

Asunto(s)

Neoplasias de la Mama , Humanos , Neoplasias de la Mama/patología , Femenino , Puntos de Control del Ciclo Celular , Fase de Descanso del Ciclo Celular , Secretoma , Línea Celular Tumoral

RESUMEN

The salivary glands are often damaged during head and neck cancer radiotherapy. This results in chronic dry mouth, which adversely affects quality of life and for which there is no long-term cure. Mouse models of salivary gland injury are routinely used in regenerative research. However, there is no clear consensus on the radiation regime required to cause injury. Here, we analysed three regimes of γ-irradiation of the submandibular salivary gland. Transcriptional analysis, immunofluorescence and flow cytometry was used to profile DNA damage, gland architecture and immune cell changes 3 days after single doses of 10 or 15 Gy or three doses of 5 Gy. Irrespective of the regime, radiation induced comparable levels of DNA damage, cell cycle arrest, loss of glandular architecture, increased pro-inflammatory cytokines and a reduction in tissue-resident macrophages, relative to those observed in non-irradiated submandibular glands. Given these data, coupled with the fact that repeated anaesthetic can negatively affect animal welfare and interfere with saliva secretion, we conclude that a single dose of 10 Gy irradiation is the most refined method of inducing acute salivary gland injury in a mouse model.

Asunto(s)

Daño del ADN , Fraccionamiento de la Dosis de Radiación , Ratones Endogámicos C57BL , Glándulas Salivales , Animales , Glándulas Salivales/efectos de la radiación , Glándulas Salivales/patología , Glándula Submandibular/efectos de la radiación , Glándula Submandibular/patología , Rayos gamma/efectos adversos , Citocinas/metabolismo , Ratones , Masculino , Macrófagos/efectos de la radiación , Macrófagos/patología , Macrófagos/metabolismo , Puntos de Control del Ciclo Celular/efectos de la radiación , Relación Dosis-Respuesta en la Radiación , Femenino

RESUMEN

Anaplastic thyroid cancer (ATC), an aggressive malignancy with virtually 100% disease-specific mortality, has long posed a formidable challenge in oncology due to its resistance to conventional treatments and the severe side effects associated with current regimens such as doxorubicin chemotherapy. Consequently, there was urgent need to identify novel candidate compounds that could provide innovative therapeutic strategies for ATC. Ophiopogonin D' (OPD'), a triterpenoid saponin extracted, yet its roles in ATC has not been reported. Our data demonstrated that OPD' potently inhibited proliferation and metastasis of ATC cells, promoting cell cycle arrest and apoptosis. Remarkably, OPD' impeded growth and metastasis of ATC in vitro and in vivo, displaying an encouraging safety profile. Regulator of G-protein signalling 4 (RGS4) expression was significantly up-regulated in ATC compared to normal tissues, and this upregulation was suppressed by OPD' treatment. Mechanistically, we elucidated that the transcription factor JUN bound to the RGS4 promoter, driving its transactivation. However, OPD' interacted with JUN, attenuating its transcriptional activity and thereby disrupting RGS4 overexpression. In summary, our research revealed that OPD' bound with JUN, which in turn resulted in the suppression of transcriptional activation of RGS4, thereby eliciting cell cycle arrest and apoptosis in ATC cells. These findings could offer promise in the development of high-quality candidate compounds for treatment in ATC.

Asunto(s)

Apoptosis , Proliferación Celular , Proteínas RGS , Saponinas , Transducción de Señal , Espirostanos , Carcinoma Anaplásico de Tiroides , Humanos , Carcinoma Anaplásico de Tiroides/tratamiento farmacológico , Carcinoma Anaplásico de Tiroides/metabolismo , Carcinoma Anaplásico de Tiroides/patología , Saponinas/farmacología , Proteínas RGS/metabolismo , Proteínas RGS/genética , Proliferación Celular/efectos de los fármacos , Animales , Línea Celular Tumoral , Transducción de Señal/efectos de los fármacos , Apoptosis/efectos de los fármacos , Espirostanos/farmacología , Ratones , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Proteínas Proto-Oncogénicas c-jun/metabolismo , Ratones Desnudos , Neoplasias de la Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/metabolismo , Neoplasias de la Tiroides/genética , Ensayos Antitumor por Modelo de Xenoinjerto , Metástasis de la Neoplasia

RESUMEN

Primary effusion lymphoma (PEL) is a malignant B-cell lymphoma attributable to Kaposi sarcoma-associated herpesvirus (KSHV) infection. PEL is characterized by invasive behavior, showing recurrent effusions in body cavities. The clinical outcome and typical prognosis in patients with PEL are poor and potentially lethal. Clarification of the pathogenesis in PEL is urgently needed in order to develop novel therapies. PEL cells generally lack B-cell surface markers, and we therefore hypothesized that the B-cell transcription factor, PAX5, would be down-regulated in PEL. The expression of PAX5 is detected from the pro-B to the mature B-cell stage and is indispensable for the differentiation of B-cells. PAX5 was silenced in PEL cells via its promoter methylation. Up-regulation of PAX5 induced several genes coding for B-cell surface marker mRNA, but not protein level. PAX5 inhibited cell growth via G1 cell cycle arrest. PAX5 bound to RB and increased its protein expression. RB/E2F-regulated genes were significantly down-regulated in microarray analysis and PCR experiments. To elucidate the in vivo role of PAX5, we examined the restoration of PAX5 in a PEL mouse model. The ascites volume and organ invasions were significantly suppressed by PAX5 restoration. Reduction of PAX5 has played a crucial role in the oncogenesis of PEL, and PAX5 is a tumor suppressor in PEL. Targeting PAX5 could represent a novel therapeutic strategy for patients with PEL.

Asunto(s)

Puntos de Control del Ciclo Celular , Herpesvirus Humano 8 , Linfoma de Efusión Primaria , Factor de Transcripción PAX5 , Factor de Transcripción PAX5/metabolismo , Factor de Transcripción PAX5/genética , Linfoma de Efusión Primaria/virología , Linfoma de Efusión Primaria/metabolismo , Linfoma de Efusión Primaria/genética , Linfoma de Efusión Primaria/patología , Linfoma de Efusión Primaria/etiología , Animales , Humanos , Herpesvirus Humano 8/genética , Ratones , Puntos de Control del Ciclo Celular/genética , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Genes Supresores de Tumor , Proliferación Celular , Infecciones por Herpesviridae/metabolismo , Infecciones por Herpesviridae/complicaciones , Infecciones por Herpesviridae/genética , Infecciones por Herpesviridae/virología , Regiones Promotoras Genéticas , Modelos Animales de Enfermedad

RESUMEN

Recent research found artesunate could inhibit ocular fibrosis; however, the underlying mechanisms are not fully known. Since the ocular fibroblast is the main effector cell in fibrosis, we hypothesized that artesunate may exert its protective effects by inhibiting the fibroblasts proliferation. TGF-ß1-induced ocular fibroblasts and glaucoma filtration surgery (GFS)-treated rabbits were used as ocular fibrotic models. Firstly, we analyzed fibrosis levels by assessing the expression of fibrotic marker proteins, and used Ki67 immunofluorescence, EdU staining, flow cytometry to determine cell cycle status, and SA-ß-gal staining to assess cellular senescence levels. Then to predict target genes and pathways of artesunate, we analyzed the differentially expressed genes and enriched pathways through RNA-seq. Western blot and immunohistochemistry were used to detect the pathway-related proteins. Additionally, we validated the dependence of artesunate's effects on HO-1 expression through HO-1 siRNA. Moreover, DCFDA and MitoSOX fluorescence staining were used to examine ROS level. We found artesunate significantly inhibits the expression of fibrosis-related proteins, induces cell cycle arrest and cellular senescence. Knocking down HO-1 in fibroblasts with siRNA reverses these regulatory effects of artesunate. Mechanistic studies show that artesunate significantly inhibits the activation of the Cyclin D1/CDK4-pRB pathway, induces an increase in cellular and mitochondrial ROS levels and activates the Nrf2/HO-1 pathway. In conclusion, the present study identifies that artesunate induces HO-1 expression through ROS to activate the antioxidant Nrf2/HO-1 pathway, subsequently inhibits the cell cycle regulation pathway Cyclin D1/CDK4-pRB in an HO-1-dependent way, induces cell cycle arrest and senescence, and thereby resists periorbital fibrosis.

Asunto(s)

Artesunato , Puntos de Control del Ciclo Celular , Senescencia Celular , Fibroblastos , Fibrosis , Hemo-Oxigenasa 1 , Artesunato/farmacología , Artesunato/uso terapéutico , Animales , Senescencia Celular/efectos de los fármacos , Conejos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Hemo-Oxigenasa 1/metabolismo , Hemo-Oxigenasa 1/genética , Fibroblastos/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Humanos , Células Cultivadas , Factor de Crecimiento Transformador beta1/metabolismo , Masculino

RESUMEN

BACKGROUND: Reynoutria multiflora (Thunb.) Moldenke (Polygonum multiflorum Thunb, PM) is a medicinal plant that was an element of traditional Chinese medicine (TCM) for centuries as a treatment for a wide range of conditions. Recent studies reported that PM suppressed prostate cancer growth in an AR-dependent manner. However, its role and mechanism in the treatment of advanced prostate cancer remain to be explored. This study aims to explore the anti-tumor role and potential mechanism of PM on prostate cancer. METHODS: Cell viability, colony formation, fluorescence-activated cell sorting (FACS), and wound-healing assays were conducted to evaluate the tumor suppression effect of PM on lethal prostate cancer models in vitro. A xenograft mice model was established to detect the impact of PM on tumor growth and evaluate its biosafety in vivo. Integrative network pharmacology, RNA-seq, and bioinformatics were applied to determine the mechanisms of PM in prostate cancer. Molecular docking, cellular thermal shift assay (CETSA), CRISPR-Cas13, RT-qPCR, and WB were collaboratively employed to identify the potential anti-tumor ingredient derived from PM and its corresponding targets. RESULTS: PM significantly suppressed the growth of prostate cancer and sensitized prostate cancer to AR antagonists. Mechanistically, PM induced G2/M-phase cell-cycle arrest by modulating the phosphorylation of CDK1. Additionally, polygalacic acid derived from PM and its structural analog suppress prostate cancer growth by targeting CDC25B, a master regulator of the cell cycle that governs CDK1 phosphorylation. CONCLUSION: PM and its ingredient polygalacic acid suppress lethal prostate cancer growth by regulating the CDC25B-CDK1 axis to induce cell cycle arrest.

Asunto(s)

Proteína Quinasa CDC2 , Puntos de Control del Ciclo Celular , Proliferación Celular , Neoplasias de la Próstata , Fosfatasas cdc25 , Masculino , Fosfatasas cdc25/metabolismo , Fosfatasas cdc25/antagonistas & inhibidores , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/metabolismo , Humanos , Proteína Quinasa CDC2/metabolismo , Proteína Quinasa CDC2/antagonistas & inhibidores , Proliferación Celular/efectos de los fármacos , Animales , Ratones , Puntos de Control del Ciclo Celular/efectos de los fármacos , Relación Estructura-Actividad , Estructura Molecular , Ensayos de Selección de Medicamentos Antitumorales , Relación Dosis-Respuesta a Droga , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Supervivencia Celular/efectos de los fármacos , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/patología , Neoplasias Experimentales/metabolismo , Ratones Desnudos , Células Tumorales Cultivadas

RESUMEN

Triphenylphosphine substitution reactions of [RuCl(PPh3)2(tpm)]Cl, 1, featuring tris(pyrazolyl)methane (tpm) as ligand, with the chlorambucil-decorated pyridine ligand PyCA, 3-aminopyridine (PyNH2) and 4-pyridinemethanol (PyOH) afforded the corresponding pyridine complexes 2-4 in high yields. PyCA was preliminarily obtained via esterification of 4-pyridinemethanol with chlorambucil. The new compounds PyCA and 2-3 were characterized by IR and multinuclear NMR spectroscopy. Additionally, the structure of 3 was ascertained by single crystal X-ray diffraction. The in vitro anti-proliferative activity of 2-4 and PyCA was determined against a panel of cancer cell lines, outlining 2 as the most performing compound. Targeted studies were subsequently undertaken using 2 to elucidate mechanistic aspects, including the assessment of ruthenium cellular uptake, cell cycle arrest, production of reactive oxygen species (ROS), western blotting and DNA damage (comet test). Overall, data highlight that the anticancer activity provided by 2 primarily affects the mitochondria pathway with a potential additional contribution from DNA damage.

Asunto(s)

Antineoplásicos , Proliferación Celular , Clorambucilo , Complejos de Coordinación , Daño del ADN , Rutenio , Humanos , Clorambucilo/farmacología , Clorambucilo/química , Clorambucilo/síntesis química , Daño del ADN/efectos de los fármacos , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Rutenio/química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Proliferación Celular/efectos de los fármacos , Línea Celular Tumoral , Especies Reactivas de Oxígeno/metabolismo , Ligandos , Puntos de Control del Ciclo Celular/efectos de los fármacos

RESUMEN

Roberts syndrome (RBS) is an autosomal recessive disorder with profound growth deficiency and limb reduction caused by ESCO2 loss-of-function variants. Here, we elucidate the pathogenesis of limb reduction in an Esco2fl/fl;Prrx1-CreTg/0 mouse model using bulk- and single-cell-RNA-seq and gene co-expression network analyses during embryogenesis. Our results reveal morphological and vascular defects culminating in hemorrhage of mutant limbs at E12.5. Underlying this abnormal developmental progression is a pre-apoptotic, mesenchymal cell population specific to mutant limb buds enriched for p53-related signaling beginning at E9.5. We then characterize these p53-related processes of cell cycle arrest, DNA damage, cell death, and the inflammatory leukotriene signaling pathway in vivo. In utero treatment with pifithrin-α, a p53 inhibitor, rescued the hemorrhage in mutant limbs. Lastly, significant enrichments were identified among genes associated with RBS, thalidomide embryopathy, and other genetic limb reduction disorders, suggesting a common vascular etiology among these conditions.

Asunto(s)

Apoptosis , Proteínas Cromosómicas no Histona , Cohesinas , Modelos Animales de Enfermedad , Deformidades Congénitas de las Extremidades , Proteína p53 Supresora de Tumor , Animales , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genética , Apoptosis/genética , Ratones , Proteínas Cromosómicas no Histona/metabolismo , Proteínas Cromosómicas no Histona/genética , Deformidades Congénitas de las Extremidades/genética , Deformidades Congénitas de las Extremidades/patología , Deformidades Congénitas de las Extremidades/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Femenino , Tolueno/análogos & derivados , Tolueno/farmacología , Ectromelia/genética , Ectromelia/metabolismo , Ectromelia/patología , Benzotiazoles/farmacología , Transducción de Señal , Masculino , Daño del ADN , Puntos de Control del Ciclo Celular/genética , Puntos de Control del Ciclo Celular/efectos de los fármacos , Esbozos de los Miembros/metabolismo , Hemorragia/patología , Hemorragia/genética , Hipertelorismo , Proteínas de Homeodominio , Anomalías Craneofaciales

RESUMEN

PURPOSE: Malignant and aggressive, small cell lung cancer (SCLC) constitutes about 15% of all diagnosed lung cancer cases. With primary therapeutic options such as chemotherapy accompanied by debilitating side effects, interest has been soaring in the therapeutic competencies of herbs. The pharmacological driving force behind the beneficial properties of Nigella sativa is the quinone, thymoquinone (TQ). The anti-cancer effects of TQ on different cancers have been extensively studied. Nonetheless, only one paper in the entire National Center for Biotechnology Information (NCBI) database describes its effects on SCLC. A more detailed investigation is required. METHODS: The current study examined the impact of TQ in vitro on five SCLC cell lines and in vivo in a nude mouse xenograft model. The following in vitro effects of TQ on SCLC were evaluated: (a) cell viability; (b) apoptosis; (c) cell cycle arrest; (d) intracellular reactive oxygen species (ROS) levels, and (e) protein expression in concomitant signaling pathways. For the in vivo effects of TQ on SCLC, (a) tumor volume was measured, and (b) selected protein expression in selected concomitant signaling pathways was determined by Western blotting. RESULT: In general, TQ reduced cell viability, induced apoptosis and cell cycle arrest, depleted ROS, and altered protein expression in associated signaling pathways. Furthermore, TQ exhibited a tumor-suppressive effect in an H446 SCLC xenograft model. CONCLUSION: The cytotoxic impact of TQ arising from anti-cancer mechanisms was elucidated. The positive results obtained in this study warrant further investigation.

Asunto(s)

Apoptosis , Benzoquinonas , Neoplasias Pulmonares , Nigella sativa , Especies Reactivas de Oxígeno , Carcinoma Pulmonar de Células Pequeñas , Ensayos Antitumor por Modelo de Xenoinjerto , Benzoquinonas/farmacología , Benzoquinonas/uso terapéutico , Animales , Nigella sativa/química , Humanos , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/patología , Ratones , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Apoptosis/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ratones Desnudos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Transducción de Señal/efectos de los fármacos

RESUMEN

Patulin (PAT) is a fungal toxin prevalent in apples and apple products and associated with several toxic effects, potentially harming multiple organs, including the kidneys, liver, and colon. However, the precise molecular mechanism through which PAT affects the intestines remains comprehensively unclear. Therefore, this study aims to investigate the molecular effects of PAT on the intestinal epithelium. Gene expression profiling was conducted, hypothesizing that PAT induces cell cycle arrest and apoptosis through the PI3K-Akt signaling pathway. Cell cycle analysis, along with Annexin-V and propidium iodide staining, confirmed that PAT induced G2/M phase arrest and apoptosis in IPEC-J2 cells. Additionally, PAT activated the expression of cell cycle-related genes (CDK1, CCNB1) and apoptosis-related genes (BCL6, CASP9). Treatment with SC79, an AKT activator, mitigated cell cycle arrest and apoptosis. To identify natural products that could mitigate the harmful effects of PAT in small intestinal epithelial cells in pigs, the high-throughput screening of a natural product library was conducted, revealing 10-Eicosanol as a promising candidate. In conclusion, our study demonstrates that 10-Eicosanol alleviates PAT-induced cell cycle arrest and apoptosis in IPEC-J2 cells by activating AKT.

Asunto(s)

Apoptosis , Puntos de Control del Ciclo Celular , Células Epiteliales , Mucosa Intestinal , Patulina , Proteínas Proto-Oncogénicas c-akt , Animales , Apoptosis/efectos de los fármacos , Patulina/farmacología , Patulina/toxicidad , Proteínas Proto-Oncogénicas c-akt/metabolismo , Porcinos , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular , Transducción de Señal/efectos de los fármacos

RESUMEN

In this work, we performed anti-proliferative assays for the compound N-(2-hydroxyphenyl)-2-propylpentanamide (HO-AAVPA) on breast cancer (BC) cells (MCF-7, SKBR3, and triple-negative BC (TNBC) MDA-MB-231 cells) to explore its pharmacological mechanism regarding the type of cell death associated with G protein-coupled estrogen receptor (GPER) expression. The results show that HO-AAVPA induces cell apoptosis at 5 h or 48 h in either estrogen-dependent (MCF-7) or -independent BC cells (SKBR3 and MDA-MB-231). At 5 h, the apoptosis rate for MCF-7 cells was 68.4% and that for MDA-MB-231 cells was 56.1%; at 48 h, that for SKBR3 was 61.6%, that for MCF-7 cells was 54.9%, and that for MDA-MB-231 (TNBC) was 43.1%. HO-AAVPA increased the S phase in MCF-7 cells and reduced the G2/M phase in MCF-7 and MDA-MB-231 cells. GPER expression decreased more than VPA in the presence of HO-AAVPA. In conclusion, the effects of HO-AAVPA on cell apoptosis could be modulated by epigenetic effects through a decrease in GPER expression.

Asunto(s)

Apoptosis , Neoplasias de la Mama , Puntos de Control del Ciclo Celular , Receptores de Estrógenos , Receptores Acoplados a Proteínas G , Humanos , Apoptosis/efectos de los fármacos , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores de Estrógenos/metabolismo , Femenino , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Puntos de Control del Ciclo Celular/efectos de los fármacos , Células MCF-7 , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/química , Amidas/farmacología , Amidas/química