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Licochalcone A (Lico A), a naturally bioactive flavonoid, has shown antitumor activity in several types of cancers. However, few studies have focused on its effect on acute myeloid leukemia (AML). Cell viability and colony formation potential were detected by CCK-8 assay and colony formation assay, respectively. Cell cycle distribution and apoptosis were assessed by flow cytometry. Ferroptosis was assessed by measuring reactive oxygen species (ROS), lipid ROS, malondialdehyde (MDA), and glutathione (GSH). Protein expression levels were determined by immunoblotting and immunohistochemistry (IHC), and mRNA expression was detected by real-time qPCR. The m6A modification of MDM2 mRNA was verified by methylated RNA immunoprecipitation (MeRIP) assay, and the interaction of IGF2BP3 and MDM2 mRNA was analyzed by RIP assay. Actinomycin D was used to evaluate mRNA stability. The efficacy of Lico A in vivo was examined by a murine xenograft model. Lico A suppressed cell proliferation and induced ferroptosis in MOLM-13 and U-937 in vitro, and slowed the growth of xenograft tumors in vivo. IGF2BP3 was highly expressed in human AML specimens and cells, and Lico A suppressed IGF2BP3 expression in AML cells. Lico A exerted the anti-proliferative and pro-ferroptosis effects by downregulating IGF2BP3. Moreover, IGF2BP3 enhanced the stability and expression of MDM2 mRNA through an m6A-dependent manner. Downregulation of IGF2BP3 impeded AML cell proliferation and enhanced ferroptosis via repressing MDM2. Furthermore, Lico A could affect the MDM2/p53 pathway by downregulating IGF2BP3 expression. Lico A exerts the anti-proliferative and pro-ferroptosis activity in AML cells by affecting the IGF2BP3/MDM2/p53 pathway, providing new evidence for Lico A as a promising agent for the treatment of AML.
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Despite available treatments for acute lymphoblastic leukemia (ALL), the disease's high clinical variability necessitates new therapeutic strategies, particularly for patients with high-risk features. The tumor suppressor protein p53, encoded by the TP53 gene and known as the guardian of the genome, plays a crucial role in preventing tumor development. Over 90% of ALL cases initially harbor wild-type TP53. Reactivation of p53, which is encoded from the wild type TP53 but lost its function for several reasons, is an attractive therapeutic approach in cancer treatment. p53 can be activated in a non-genotoxic manner by targeting its primary repressor, the MDM2 protein. Clinical trials involving MDM2 inhibitors are currently being conducted in a growing body of investigation, reflecting of the interest in incorporating these treatments into cancer treatment strategies. Early-phase clinical trials have demonstrated the promise of idasanutlin (RG7388), one of the developed compounds. It is a second-generation MDM2-p53 binding antagonist with enhanced potency, selectivity, and bioavailability. The aim of this study is to evaluate the efficacy of RG7388 as a therapeutic strategy for ALL and to investigate its potential impact on improving treatment outcomes for high-risk patients. RG7388 potently decreased the viability in five out of six ALL cell lines with diverse TP53 mutation profiles, whereas only one cell line exhibited high resistance. RG7388 induced a pro-apoptotic gene expression signature with upregulation of p53-target genes involved in the intrinsic and extrinsic pathways of apoptosis. Consequently, RG7388 led to a concentration-dependent increase in caspase-3/7 activity and cleaved poly (ADP-ribose) polymerase. In this research, RG7388 was investigated with pre-clinical methods in ALL cells as a novel treatment strategy. This study suggests further functional research and in-vivo evaluation, and it highlights the prospect of treating p53-functional ALL with MDM2 inhibitors.
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The recurrence of glioma after treatment has remained an intractable problem for many years. Recently, numerous studies have explored the pivotal role of the mouse double minute 2 (MDM2)/p53 pathway in cancer treatment. Lysine phosphate phosphohistidine inorganic pyrophosphate phosphatase (LHPP), a newly discovered tumor suppressor, has been confirmed in numerous studies on tumors, but its role in glioma remains poorly understood. Expression matrices in The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases were analyzed using gene set enrichment analysis (GSEA), revealing significant alterations in the p53 pathway among glioma patients with high LHPP expression. The overexpression of LHPP in glioma cells resulted in a reduction in cell proliferation, migration, and invasive ability, as well as an increase in apoptosis and alterations to the cell cycle. The present study has identified a novel inhibitory mechanism of LHPP against glioma, both in vivo and in vitro. The results demonstrate that LHPP exerts anti-glioma effects via the MDM2/p53 pathway. These findings may offer a new perspective for the treatment of glioma in the clinic.
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The spiro-oxindole derivatives were synthesized via a 1,3-dipolar cycloaddition approach and characterized by FT-IR, 1H, 13C NMR and mass spectral techniques. The single crystal XRD of 6d further validates the formation of compounds. DFT calculations indicated the reactive nature of compound 6d. Docking studies with 5LAW disclosed the minimum binding energy of - 10.83 kcal/mol for 6d. Furthermore, safe oral bioavailability was ensured by the physicochemical, pharmacokinetic, and toxicity predictions. The anticancer analysis of synthesized compounds showed substantial activity against A549 cells, notably with an IC50 value of 8.13 ± 0.66 µM for 6d compared to standard doxorubicin. 6d was also evaluated for cytotoxicity against L929 healthy cells and A549, showing selectivity towards A549 than healthy cells. AO/EB staining method showed early apoptotic cellular death in the A549 cell line in a dose-dependent manner.
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Calcific aortic valve disease (CAVD) primarily involves osteogenic differentiation in human aortic valve interstitial cells (hVICs). Schisandrol B (SolB), a natural bioactive constituent, has known therapeutic effects on inflammatory and fibrotic disorders. However, its impact on valve calcification has not been reported. We investigated the effect of SolB on osteogenic differentiation of hVICs. Transcriptome sequencing was used to analyze potential molecular pathways affected by SolB treatment. The study also included an in vivo murine model using aortic valve wire injury surgery to observe SolB's effect on valve calcification. SolB inhibited the osteogenic differentiation of hVICs, reversing the increase in calcified nodule formation and osteogenic proteins. In the murine model, SolB significantly decreased the peak velocity of the aortic valve post-injury and reduced valve fibrosis and calcification. Transcriptome sequencing identified the p53 signaling pathway as a key molecular target of SolB, demonstrating its role as a molecular glue in the mouse double minute 2 (MDM2)-p53 interaction, thereby promoting p53 ubiquitination and degradation, which further inhibited p53-related inflammatory and senescence response. These results highlighted therapeutic potential of SolB for CAVD via inhibiting p53 signaling pathway and revealed a new molecular mechanism of SolB which provided a new insight of theraputic mechanism for CAVD.
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Estenosis de la Válvula Aórtica , Válvula Aórtica , Calcinosis , Ciclooctanos , Lignanos , Proteína p53 Supresora de Tumor , Animales , Humanos , Masculino , Ratones , Válvula Aórtica/patología , Válvula Aórtica/efectos de los fármacos , Válvula Aórtica/metabolismo , Estenosis de la Válvula Aórtica/tratamiento farmacológico , Estenosis de la Válvula Aórtica/patología , Calcinosis/tratamiento farmacológico , Calcinosis/patología , Calcinosis/metabolismo , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Senescencia Celular/efectos de los fármacos , Ciclooctanos/farmacología , Modelos Animales de Enfermedad , Inflamación/tratamiento farmacológico , Inflamación/patología , Inflamación/metabolismo , Lignanos/farmacología , Ratones Endogámicos C57BL , Osteogénesis/efectos de los fármacos , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Transducción de Señal/efectos de los fármacos , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
The ribosomal protein L22-like1 (RPL22L1) is a constituent of the 60 S ribosomal subunit whose function in lung adenocarcinoma (LUAD) remains ambiguous. This study aims to elucidate the role of RPL22L1 in LUAD through a thorough analysis and experimental validation. Our findings indicate that RPL22L1 exhibits abnormal expression patterns in various cancer types, including LUAD. Moreover, a statistically significant association was observed between elevated levels of RPL22L1 expression in LUAD patients and several clinical parameters, such as pathological stage (p = 0.0083) and gender (p = 0.0038). The high expression of RPL22L1 in LUAD demonstrated a significant association with poorer overall survival (OS) (p = 0.005), progression-free survival (PFS) (p = 0.027), and disease-specific survival (p = 0.015). The expression of RPL22L1 in LUAD (p = 0.005) was identified as an independent prognostic factor. Additionally, RPL22L1 expression in LUAD was found to be correlated with immune infiltration, immune checkpoint genes, TMB/MSI, and mRNAsi. Notably, the expression of RPL22L1 exhibited significant negative correlations with 1-BET-762, Trametinib, and WZ3105 in LUAD. The RPL22L1 gene exhibited up-regulation in multiple individual cells of LUAD, leading to a comparatively shorter PFS in the RPL22L1 variant group as opposed to the RPL22L1 variant-free group in LUAD. Significantly increased expression of RPL22L1 was noted in LUAD cell lines, where it was found to enhance the growth and metastasis of LUAD cells by suppressing the MDM2/P53 signaling pathway. Therefore, RPL22L1 may serve as a promising prognostic biomarker and therapeutic target for patients with LUAD.
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Adenocarcinoma del Pulmón , Biomarcadores de Tumor , Neoplasias Pulmonares , Proteínas Proto-Oncogénicas c-mdm2 , Proteínas Ribosómicas , Transducción de Señal , Proteína p53 Supresora de Tumor , Humanos , Proteínas Ribosómicas/genética , Proteínas Ribosómicas/metabolismo , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/metabolismo , Adenocarcinoma del Pulmón/patología , Adenocarcinoma del Pulmón/inmunología , Adenocarcinoma del Pulmón/mortalidad , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/genética , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genética , Pronóstico , Femenino , Masculino , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/mortalidad , Persona de Mediana Edad , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Animales , Proliferación Celular/genética , Ratones , AncianoRESUMEN
Chronic lymphocytic leukemia (CLL) is a genetically and clinically diverse hematological cancer affecting middle-aged and elderly individuals. Novel targeted therapy options are needed for patients who relapse following initial responses or who are intrinsically resistant to current treatments. There is a growing body of investigation currently underway on MDM2 inhibitors in clinical trials, reflecting the increasing interest in including these drugs in cancer treatment regimens. One of the developed compounds, idasanutlin (RG7388), has shown promise in early-stage clinical trials. It is a second-generation MDM2-p53-binding antagonist with enhanced potency, selectivity, and bioavailability. In addition to the TP53 status, which is an important determinant of the response, we have shown in our previous studies that the SF3B1 mutational status is also an independent predictive biomarker of the ex vivo CLL patient sample treatment response to RG7388. The objective of this study was to identify novel biomarkers associated with resistance to RG7388. Gene set enrichment analysis of differentially expressed genes (DEGs) between RG7388-sensitive and -resistant CLL samples showed that the increased p53 activity led to upregulation of pro-apoptosis pathway genes while DNA damage response pathway genes were additionally upregulated in resistant samples. Furthermore, differential expression of certain genes was detected, which could serve as the backbone for novel combination treatment approaches. This research provides preclinical data to guide the exploration of drug combination strategies with MDM2 inhibitors, leading to future clinical trials and associated biomarkers that may improve outcomes for CLL patients.
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Endoplasmic reticulum (ER) stress is a primary mechanism leading to cell apoptosis, making it of great research interests in cancer management. This study delves into the function of ribosomal protein L5 (RPL5) in ER stress within pancreatic cancer (PCa) cells and investigates its regulatory mechanisms. Bioinformatics predictions pinpointed RPL5 as an ER stress-related gene exhibiting diminished expression in PCa. Indeed, RPL5 was found to be poorly expressed in PCa tissues and cells, with this reduced expression correlating with an unfavorable prognosis. Moreover, RPL5 overexpression led to heightened levels of p-PERK, p-eIF2α, and CHOP, bolstering the proapoptotic effect of Tunicamycin, an ER stress activator, on PCa cells. Additionally, the RPL5 overexpression curbed cell proliferation, migration, and invasion. Tunicamycin enhanced the binding between RPL5 and murine double minute 2 (MDM2), thus suppressing MDM2-mediated ubiquitination and degradation of P53. Consequently, P53 augmentation intensified ER stress, which further enhanced the binding between RPL5 and MDM2 through PERK-dependent eIF2α phosphorylation, thereby establishing a positive feedback loop. Zinc finger and BTB domain containing 7A (ZBTB7A), conspicuously overexpressed in PCa samples, repressed RPL5 transcription, thereby reducing P53 expression. Silencing of ZBTB7A heightened ER stress and subdued the malignant attributes of PCa cells, effects counteracted upon RPL5 silencing. Analogous outcomes were recapitulated in vivo employing a xenograft tumor mouse model, where ZBTB7A silencing dampened the tumorigenic potential of PCa cells, an effect reversed by additional RPL5 silencing. In conclusion, this study suggests that ZBTB7A represses RPL5 transcription, thus impeding the RPL5-P53 feedback loop and mitigating ER-induced apoptosis in PCa cells.
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Apoptosis , Proliferación Celular , Estrés del Retículo Endoplásmico , Neoplasias Pancreáticas , Proteínas Ribosómicas , Factores de Transcripción , Proteína p53 Supresora de Tumor , Humanos , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/genética , Proteínas Ribosómicas/metabolismo , Proteínas Ribosómicas/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genética , Animales , Línea Celular Tumoral , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Ratones , Regulación Neoplásica de la Expresión Génica , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Retroalimentación Fisiológica , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/genética , Ratones Desnudos , Tunicamicina/farmacología , MasculinoRESUMEN
Biliary tract cancer (BTC) is a rare cancer with poor prognosis, characterized by considerable pathophysiological and molecular heterogeneity. While this makes it difficult to treat, it also provides targeted therapy opportunities. Current standard-of-care is chemotherapy ± immunotherapy, but several targeted agents have recently been approved. The current investigational landscape in BTC emphasizes the importance of biomarker testing at diagnosis. MDM2/MDMX are important negative regulators of the tumor suppressor p53 and provide an additional target in BTC (â¼5-8% of tumors are MDM2-amplified). Brigimadlin (BI 907828) is a highly potent MDM2-p53 antagonist that has shown antitumor activity in preclinical studies and promising results in early clinical trials; enrollment is ongoing in a potential registrational trial for patients with BTC.
[Box: see text].
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Neoplasias del Sistema Biliar , Terapia Molecular Dirigida , Humanos , Neoplasias del Sistema Biliar/tratamiento farmacológico , Neoplasias del Sistema Biliar/terapia , Terapia Molecular Dirigida/métodos , Biomarcadores de Tumor , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Antineoplásicos/uso terapéutico , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genética , Inmunoterapia/métodos , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas de Ciclo CelularRESUMEN
Background: In patients with advanced biliary tract cancer (BTC), first-line chemotherapy plus immunotherapy has improved outcomes; however, second-line options that reflect the disease's molecular heterogeneity are still needed. One emerging target is MDM2, amplified in ~5-8% of BTC cases. Methods: This is a subset analysis of two ongoing Phase Ia/Ib trials assessing patients treated with brigimadlin (BI 907828; a highly potent, oral MDM2-p53 antagonist) ± ezabenlimab (PD-1 inhibitor) ± BI 754111 (anti-LAG-3; n = 1). Results: Results from 12 patients with BTC are shown (monotherapy: n = 6/combination: n = 6). Six patients achieved partial response (monotherapy: n = 2/combination: n = 4), four had stable disease; responses were durable. Brigimadlin had a manageable safety profile. Seven patients had dose reductions due to adverse events, but no treatment-related adverse events led to treatment discontinuation. Conclusion: Brigimadlin demonstrated anti-tumor activity in patients with advanced MDM2-amplified BTC, and warrants further investigation.
Biliary tract carcinoma (BTC) is a cancer that affects the bile ducts which are part of the digestive system. Usually, the first treatment for advanced BTC (ie cannot be removed surgically and/or has spread) is chemotherapy in combination with immunotherapy. However, if chemotherapy does not work, or stops working, there are few treatment options available in second-line. Accordingly, intensive research is ongoing to try and find effective drugs. One potential medicine, called brigimadlin (or BI 907828), is a tablet that activates a molecule in tumor cells called p53. The normal function of p53 is to kill cells when they first start to become cancerous. However, if p53 is turned off by genetic mutations, or other mechanisms, then cancer can develop. Although p53 is rarely mutated in BTC tumors, it is inactivated by another molecule called MDM2 which is usually present at abnormally high levels in BTC. Brigimadlin prevents interaction between MDM2 and p53. This activates p53 and causes the cancer to die. Two clinical trials are currently assessing brigimadlin in a range of cancers, including BTC, with the aim of identifying a safe dose that can be examined in more detail in larger trials. So far, 12 patients with BTC have been treated. The patients' tumors significantly shrank in six of these patients and remained stable in a further four patients. Side effects were as expected and could be tolerated by pausing treatment or lowering the dose. These results show that brigimadlin should be tested further in patients with advanced BTC.
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OBJECTIVE: Several novel fluorinated chalcone derivatives were synthesized, and their in vitro anticervical cancer activity and mechanism of action were investigated using the parent nucleus of licorice chalcone as the lead compound backbone and MDM2-p53 as the target. METHODS: In this study, 16 novel chalcone derivatives (3a-3r) were designed and synthesized by molecular docking technology based on the licorice chalcone parent nucleus as the lead compound scaffold and the cancer apoptosis regulatory target MDM2-p53. The structures of these compounds were confirmed by 1H-NMR, 13C-NMR, and HR-ESI-MS. The inhibitory effects of the compounds on the proliferation of three human cervical cancer cell lines (SiHa, HeLa, and C-33A) and two normal cell lines (H8 and HaCaT) were determined by MTT assay, and the initialstructure-activity relationship was analyzed. Transwell and flow cytometry were used to evaluate the effects of target compounds on the inhibition of cancer cell migration and invasion, apoptosis induction, and cell cycle arrest. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot (WB) were used to detect the effects of candidate compounds on mRNA, p53, and Murine double minute 2 (MDM2) protein expression. The binding characteristics of the target compounds to the MDM2 protein target in the p53-MDM2 pathway were evaluated by molecular docking technology. RESULTS: The target compounds had considerable inhibitory activity on the proliferation of three cervical cancer cell lines. Among them, compound 3k (E)-3-(4-(dimethylamino)phenyl)-2-methyl-1-(3-(trifluoromethyl)phenyl) prop-2-en-1-one) showed the highest activity against HeLa cells (IC50=1.08 µmol/L), which was better than that of the lead compound Licochalcone B, and 3k showed lower toxicity to both normal cells. Compound 3k strongly inhibited the migration and invasion of HeLa cells and induced apoptosis and cell cycle arrest at the G0/G1 phase. Furthermore, compound 3k upregulated the expression of p53 and BAX and downregulated the expression of MDM2, MDMX, and BCL2. Moreover, molecular docking results showed that compound 3k could effectively bind to the MDM2 protein (binding energy: -9.0 kcal/mol). These results suggest that the compounds may activate the p53 signaling pathway by inhibiting MDM2 protein, which prevents cancer cell proliferation, migration, and invasion and induces apoptosis and cell cycle arrest in cancer cells. CONCLUSION: This study provides a new effective and low-toxicity drug candidate from licochalcone derivatives for treating cervical cancer.
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Antineoplásicos , Diseño de Fármacos , Proteínas Proto-Oncogénicas c-mdm2 , Proteína p53 Supresora de Tumor , Neoplasias del Cuello Uterino , Femenino , Humanos , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Chalcona/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Simulación del Acoplamiento Molecular , Estructura Molecular , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Relación Estructura-Actividad , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/antagonistas & inhibidores , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/metabolismoRESUMEN
OBJECTIVE To investigate the effects of aucubin （AU） on the proliferation and tumor growth of prostate cancer （PC） cells by regulating the protein kinase B （Akt）/murine double minute2 （MDM2）/p53 signaling pathway. METHODS Prostate cancer cell PC3 were separated into control group， 50 μmol/L AU group， 100 μmol/L AU group， SC79 （Akt activator） group （5 μmol/L）， and 100 μmol/L AU+SC79 group. The cell cloning and proliferation ability were investigated； the rate of cell apoptosis and the expressions of Akt/MDM2/p53 signaling pathway-related protein were detected. Meanwhile， xenograft tumor models of nude mice were constructed and separated into tumor group， AU group （80 mg/kg）， SC79 group （50 mg/kg）， and AU+SC79 group （80 mg/kg AU+50 mg/kg SC79）， with 10 mice in each group. They were given relevant medicine， once a day， for 21 d. After the last medication， tumor weight was determined， and the expressions of nucleus-associated antigen （Ki-67） and Akt/MDM2/p53 signaling pathway-related protein were detected in tumor tissue. RESULTS In the cell experiment， compared with control group， the cell clonal formation number， proliferation rate and phosphorylation levels of Akt and MDM2 protein in 50 μmol/L AU and 100 μmol/L AU groups were significantly decreased （P＜0.05）， while the cell apoptosis rate and p53 protein expression levels were significantly increased （P＜0.05）； however， the change trend of each index in SC79 group was opposite （P＜0.05）. Compared with 100 μmol/L AU group， the cell clonal formation number， proliferation rate and phosphorylation levels of Akt and MDM2 protein in 100 μmol/L AU+SC79 group were significantly increased （P＜0.05）， while cell apoptosis rate and p53 protein expression levels were significantly decreased （P＜0.05）； however， compared with SC79 group， the changing trend of indexes was the opposite （P＜0.05）. In the in vivo experiment， compared with the tumor group， the tumor mass and Ki-67 positive expression and the phosphorylation levels of Akt and MDM2 protein in nude mice of AU group were significantly decreased （P＜0.05）， and the expression level of p53 protein was significantly increased （P＜0.05）， but the changing trend of above indexes of nude mice in SC79 group were opposite （P＜0.05）. Compared with AU group， the tumor mass， Ki-67 positive expression and phosphorylation levels of Akt and MDM2 protein in tumor tissues of nude mice in AU+SC79 group were significantly increased （P＜0.05）， while the expression level of p53 protein was significantly decreased （P＜0.05）； however， compared with SC79 group， the changing trend of above indexes was opposite （P＜0.05）. CONCLUSIONS AU can inhibit PC cell proliferation and tumor growth by inhibiting Akt/MDM2/p53 signaling pathway.
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@#[摘 要] 目的：探究茯苓酸（PA）是否通过AKT/MDM2/p53通路影响结直肠癌HCT116细胞的恶性生物学行为。方法：常规培养HCT116细胞，并将其分为对照组、MK-2206（AKT抑制剂）组、PA低浓度（PA-L）组、PA高浓度（PA-H）组、PA-H+ SC79（AKT激活剂）组。CCK-8法、细胞克隆形成实验、流式细胞术、Transwell、qPCR法和WB法实验分别检测各组HCT116细胞的增殖活力，克隆形成能力，细胞凋亡，迁移、侵袭能力，E-cadherin、N-cadherin和vimentin mRNA表达以及AKT/MDM2/p53通路相关蛋白的表达。结果：PA可明显抑制HCT116细胞的增殖活力（P<0.05）、克隆形成能力（P<0.05）、迁移和侵袭能力（P<0.05），诱导其凋亡（P<0.05），抑制N-cadherin、vimentin mRNA的表达（P<0.05），促进E-cadherin mRNA的表达（P<0.05），抑制AKT、MDM2的磷酸化水平（P<0.05），促进p53蛋白的表达（P<0.05）；AKT抑制剂MK-2206可模拟PA的作用（均P<0.05），而其激活剂SC79则可逆转PA的作用（均P<0.05）。结论：PA通过调控AKT/MDM2/p53信号通路来抑制HCT116细胞的增殖、迁移和侵袭并诱导其凋亡。
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Well-differentiated and dedifferentiated liposarcomas (WDLPS and DDLPS) are rare tumors that arise from lipocytes in soft tissue. There is a high unmet need in patients with these liposarcomas given poor outcomes, particularly for DDLPS. WDLPS and DDLPS share important genetic and histological characteristics - most notably, the amplification of the 2 genes MDM2 and CDK4. Both genes are considered oncogenes because of their ability to shut down tumor suppressor pathways. There are multiple therapeutic approaches that aim to target MDM2 and CDK4 activity for the purpose of restoring intrinsic tumor suppressor cellular response and terminating oncogenesis. However, current understanding of the molecular mechanisms involved in WDLPS and DDLPS pathology is limited. In recent years, significant efforts have been made to refine and implement targeted therapy for this patient population. The use of patient-derived cell and tumor xenograft models has been an important tool for recapitulating WDLPS and DDLPS biology. These models also offer valuable insights for drug development and drug combination studies. Here we offer a review of the current understanding of WDLPS and DDLPS biology and its therapeutic implications.
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Liposarcoma , Proteína p53 Supresora de Tumor , Humanos , Quinasa 4 Dependiente de la Ciclina/metabolismo , Liposarcoma/tratamiento farmacológico , Liposarcoma/genética , Proteínas Proto-Oncogénicas c-mdm2/genética , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/uso terapéuticoRESUMEN
Licochalcone A (Lico A), a flavonoid found in licorice, possesses multiple pharmacological activities in modulating oxidative stress, glycemia, inflammation, and lipid metabolism. This study aimed to explore the potential mechanism of Lico A in mitigating ferroptosis associated with doxorubicin-induced cardiotoxicity (DIC). Initially, network pharmacology analysis was applied to identify the active components present in licorice and their targeted genes associated with DIC. Subsequently, to assess the role of Lico A in a DIC mouse model, electrocardiograms, myocardial injury markers, and myocardial histopathological changes were measured. Additionally, cell viability, reactive oxygen species (ROS), ferrous iron, glutathione/glutathione disulfide (GSH/GSSG), and malondialdehyde (MDA) were measured in the cell model as hallmarks of ferroptosis. Finally, the PI3K/AKT/MDM2/p53 signaling pathway and ferroptosis-related proteins were measured in vitro and in vivo. Bioinformatics results revealed that 8 major compounds of licorice, including Lico A, primarily regulated targets such as p53 and the PI3K/AKT signaling pathways in DIC. In the mouse model of DIC, Lico A significantly ameliorated serum biomarkers, histopathology, and electrocardiogram abnormalities. Pretreatment with Lico A enhanced the viability of H9C2 cells treated with doxorubicin. Furthermore, Lico A administration resulted in decreased levels of ROS, ferrous iron, and MDA and increased levels of GSH/GSSG. At the protein level, Lico A increased the phosphorylation of PI3K/AKT/MDM2, reduced p53 accumulation, and induced the upregulation of SLC7A11 and GPX4 expression. However, selective inhibition of PI3K/AKT and plasmid-based overexpression of p53 significantly abolished the anti-ferroptosis functions of Lico A. In conclusion, Lico A attenuates DIC by suppressing p53-mediated ferroptosis through activating PI3K/AKT/MDM2 signaling.
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Dibromosterculic acid [8-(1,2-dibromo-2-octylcyclopropyl)-octanoic acid], a new synthetic derivative was prepared by bromination of sterculic acid. This synthetic derivative showed strong fungicidal activity against two pathogenic fungal species namely Penicillium chrysogenum and Aspergillus niger with minimum inhibitory concentration (MIC) value of 0.007 mg/ml and good bactericidal activity against Bacillus subtilis and Xanthomonas sp. with MIC value of 0.015 mg/ml. Cytotoxic activity on both normal (MCF-10A) and cancerous (MDA-MB-468) cell lines revealed that the survivability percentage of normal cells was unaffected, whereas cancerous cells were decreased greatly by dibromosterculic acid with 50% survivability at 9 µg/ml concentration. Molecular-docking using AutoDock 4.2 with Bax exhibited strong pi-sigma interaction with PHE-93, pi-alkyl and alkyl interaction with TRP-139, ARG-89 and PHE-92 whereas MDM2 revealed strong hydrogen bond interaction with GLN-59 and pi-alkyl interaction with PHE-55. All experimental parameters suggested that this synthetic derivative would be valuable for target-specific drug development with nominal side effects.
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Cancer cells often depend on multiple pathways for their growth and survival, resulting in therapeutic resistance and the limited effectiveness of treatments. Combination therapy has emerged as a favorable approach to enhance treatment efficacy and minimize acquired resistance and harmful side effects. The murine double minute 2 (MDM2) protein regulates cellular proliferation and promotes cancer-related activities by negatively regulating the tumor suppressor protein p53. MDM2 aberrations have been reported in a variety of human cancers, making it an appealing target for cancer therapy. As a result, several small-molecule MDM2 inhibitors have been developed and are currently being investigated in clinical studies. Nevertheless, it has been shown that the inhibition of MDM2 alone is inadequate to achieve long-term suppression of tumor growth, thus prompting the need for further investigation into combination therapeutic strategies. In this review, possible clinical and preclinical MDM2 combination inhibitor regimens are thoroughly analyzed and discussed. It provides a rationale for combining MDM2 inhibitors with other therapeutic approaches in the management of cancer, taking into consideration ongoing clinical trials that evaluate the combination of MDM2 inhibitors. The review explores the current status of MDM2 inhibitors in combination with chemotherapy or targeted therapy, as well as promising approach of combining MDM2 inhibitors with immunotherapy. In addition, it investigates the function of PROTACs as MDM2 degraders in cancer treatment. A comprehensive examination of these combination regimens highlights the potential for advancing MDM2-inhibitor therapy and improving clinical outcomes for cancer patients and establishes the foundation for future research and development in this promising area of study.
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The interaction between the tumor suppressor protein p53 and its negative regulator, the MDM2 oncogenic protein, has gained significant attention in cancer drug discovery. In this study, 120 lignans reported from Ferula sinkiangensis and Justicia procumbens were assessed for docking simulations on the active pocket of the MDM2 crystal structure bound to Nutlin-3a. The docking analysis identified nine compounds with higher docking scores than the co-crystallized reference. Subsequent AMDET profiling revealed satisfactory pharmacokinetic and safety parameters for these natural products. Three compounds, namely, justin A, 6-hydroxy justicidin A, and 6'-hydroxy justicidin B, were selected for further investigation due to their strong binding affinities of -7.526 kcal/mol, -7.438 kcal/mol, and -7.240 kcal/mol, respectively, which surpassed the binding affinity of the reference inhibitor Nutlin-3a (-6.830 kcal/mol). To assess the stability and reliability of the binding of the candidate hits, a molecular dynamics simulation was performed over a duration of 100 ns. Remarkably, the thorough analysis demonstrated that all the hits exhibited stable molecular dynamics profiles. Based on their effective binding to MDM2, favorable pharmacokinetic properties, and molecular dynamics behavior, these compounds represent a promising starting point for further refinement. Nevertheless, it is essential to synthesize the suggested compounds and evaluate their activity through in vitro and in vivo experiments.
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Antineoplásicos , Lignanos , Plantas Medicinales , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Reproducibilidad de los Resultados , Proteína p53 Supresora de Tumor , Antineoplásicos/farmacología , Lignanos/farmacologíaRESUMEN
INTRODUCTION: Hexarelin exhibits significant protection against organ injury in models of ischemia/reperfusion (I/R)-induced injury (IRI). Nevertheless, the impact of Hexarelin on acute kidney injury (AKI) and its underlying mechanism remains unclear. In this study, we investigated the therapeutic potential of Hexarelin in I/R-induced AKI and elucidated its molecular mechanisms. METHODS: We assessed the protective effects of Hexarelin through both in vivo and in vitro experiments. In the I/R-induced AKI model, rats were pretreated with Hexarelin at 100 µg/kg/d for 7 days before being sacrificed 24 h post-IRI. Subsequently, kidney function, histology, and apoptosis were assessed. In vitro, hypoxia/reoxygenation (H/R)-induced HK-2 cell model was used to investigate the impact of Hexarelin on apoptosis in HK-2 cells. Then, we employed molecular docking using a pharmmapper server and autodock software to identify potential target proteins of Hexarelin. RESULTS: In this study, rats subjected to I/R developed severe kidney injury characterized by tubular necrosis, tubular dilatation, increased serum creatinine levels, and cell apoptosis. However, pretreatment with Hexarelin exhibited a protective effect by mitigating post-ischemic kidney pathological changes, improving renal function, and inhibiting apoptosis. This was achieved through the downregulation of conventional apoptosis-related genes, such as Caspase-3, Bax and Bad, and the upregulation of the anti-apoptotic protein Bcl-2. Consistent with the in vivo results, Hexarelin also reduced cell apoptosis in post-H/R HK-2 cells. Furthermore, our analysis using GSEA confirmed the essential role of the apoptosis pathway in I/R-induced AKI. Molecular docking revealed a strong binding affinity between Hexarelin and MDM2, suggesting the potential mechanism of Hexarelin's anti-apoptosis effect at least partially through its interaction with MDM2, a well-known negative regulator of apoptosis-related protein that of p53. To validate these findings, we evaluated the relative expression of MDM2 and p53 in I/R-induced AKI with or without Hexarelin pre-administration and observed a significant suppression of MDM2 and p53 by Hexarelin in both in vivo and in vitro experiments. CONCLUSION: Collectively, Hexarelin was identified as a promising medication in protecting apoptosis against I/R-induced AKI.
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Lesión Renal Aguda , Daño por Reperfusión , Animales , Ratas , Proteína p53 Supresora de Tumor/genética , Simulación del Acoplamiento Molecular , Lesión Renal Aguda/tratamiento farmacológico , Daño por Reperfusión/tratamiento farmacológico , IsquemiaRESUMEN
This study aims to explore the male reproductive toxicity of Benzo[b]fluoranthene (BbF) and related mechanisms. The results of computational toxicology analysis indicated male reproductive toxicity of BbF was related to apoptosis of Leydig cells and that Akt/p53 pathway might play a key role. In experiments, BbF induced testosterone decline, decreased concentration and motility of sperm and aggravated testicular pathological injury in mice. Besides, BbF led to apoptosis in Leydig cells, and decreased expressions of p-Akt and Bcl2, while improving the expressions of p53, Bax and Cleaved Caspase-3 in vivo and in vitro. Further, compared with BbF group, Akt activator SC79 significantly reduced cell apoptosis rate, improved cell viability, promoted the expressions of p-Akt and p-Mdm2, and reversed the above molecular expressions. Similarly, p53 inhibitor Pifithrin-α also significantly enhanced the cell vitality, alleviated the apoptosis of TM3 cells induced by BbF, and decreased the expressions of Bax and Cleaved Caspase-3, with the up-regulation of Bcl2. To sum up, by inhibiting Akt-Mdm2 signaling, BbF activated the p53-mediated mitochondrial apoptosis pathway, further inducing the apoptosis of Leydig cells, therefore resulting in testosterone decline and male reproductive damage. Besides, this study provided a valid mode integrating computational toxicology and experimental approaches in toxicity testing.