Ribociclib Derivative RB-BC Induces Apoptosis in Breast Cancer through p53 Pathway Activation
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PROVIDER: PRJNA1250294 | ENA |
REPOSITORIES: ENA
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Project description:Breast cancer persists as the most prevalent malignancy and principal contributor to cancer-associated mortality among women worldwide, exhibiting marked disease heterogeneity and therapeutic resistance. Consequently, the development of novel therapeutic agents remains imperative. Ribociclib, a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, has emerged as a focus in adjuvant breast cancer research due to its mechanism of cell cycle arrest induction.Building upon this rationale, we designed and synthesized a novel ribociclib derivative RB-BC, systematically investigating its anti-neoplastic efficacy and molecular mechanisms in breast cancer through integrated in vitro and in vivo experimental systems. The compound's anti-proliferative effects were quantitatively assessed via MTT assays , EdU incorporation assays , and colony formation assays .Functional characterization through cell adhesion assays, scratch wound healing assays, and Transwell invasion assays demonstrated RB-BC’s dose-dependent suppression of tumor migration and invasion. Mechanistic analyses via RNA sequencing and Western blotting revealed that its anti-tumor activity primarily stems from p53 pathway activation, inducing caspase-3-mediated apoptosis in breast cancer cells. Machine learning algorithms identified p53-associated genetic signatures, and subsequent bioinformatics analyses elucidated their significant correlation with immune cell infiltration dynamics in the tumor microenvironment (TME).Moreover, RB-BC effectively suppressed tumor growth in vivo and significantly disrupted angiogenesis in the chick chorioallantoic membrane (CAM) assay. In summary, the ribociclib-derived compound RB-BC demonstrates compelling potential as a candidate therapeutic agent for breast cancer.
2025-04-15 | GSE294486 | GEO
Project description:Breast cancer remains the most prevalent malignancy among women globally, with its incidence continuing to rise and ranking as the leading cause of cancer-related mortality in females. Ribociclib, a cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor, suppresses tumor cell proliferation by blocking the transition from the G1 to S phase. This study investigates the molecular mechanisms and therapeutic efficacy of RB-1 (7-cyclopentyl-N-ethyl-N-methyl-2-((3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide), a novel Ribociclib derivative, in inhibiting breast cancer progression. The effects of RB-1 on breast cancer cell viability were evaluated via MTT assay. In vitro and in vivo experiments demonstrated that RB-1 significantly inhibited cell proliferation, colony formation, and the proportion of EdU-positive cells in multiple breast cancer cell lines (e.g., MDA-MB-231 and SKBR3). The chicken chorioallantoic membrane (CAM) assay revealed that RB-1 treatment markedly suppressed tumor angiogenesis, outperforming Ribociclib. Mechanistic studies indicated that RB-1 regulates the p53 signaling pathway and cell cycle-related targets (e.g., E2F targets, mitotic spindle assembly), specifically inhibiting CDK4/6-mediated cell cycle progression. Furthermore, machine learning analysis identified Hyaluronan-Mediated Motility Receptor (HMMR) as a diagnostic and prognostic biomarker for breast cancer, with its expression significantly correlating with tumor-infiltrating immune cells. This study highlights the anti-cancer potential of RB-1 and elucidates its molecular mechanisms, offering a promising therapeutic candidate and novel targets for breast cancer treatment.
2025-04-12 | GSE294375 | GEO
Project description:Ribociclib derivative Rib-CA suppresses breast cancer progression by inducing p53-dependent apoptosis
| PRJNA1248440 | ENA
Project description:Breast cancer remains the most prevalent malignancy among women worldwide. Although ribociclib, a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, has demonstrated significant antitumor activity in breast cancer therapy, its clinical application is limited by hematological toxicity, cardiotoxicity, and patient tolerance. In this study, we synthesized a novel ribociclib derivative, YW-LF, and systematically evaluated its antitumor activity and underlying mechanisms. Through a series of in vitro assays—including MTT, colony formation, EdU incorporation, transwell migration, and invasion experiments—as well as in vivo evaluation using a chick chorioallantoic membrane (CAM) model, we demonstrated that YW-LF significantly inhibited breast cancer cell proliferation, migration, and invasion, while effectively suppressing tumor growth and angiogenesis. Compared to the positive control ribociclib, YW-LF exhibited superior antitumor efficacy. Transcriptomic profiling revealed that YW-LF suppressed tumor progression by activating the p53 signaling pathway and apoptosis-related pathways. Western blot analysis further validated the dysregulation of key proteins, providing protein-level evidence for its mechanism of action. Additionally, machine learning-based bioinformatics analysis identified three core genes (ADRB1, ATOH8, and CCNE2) with potential clinical significance in breast cancer diagnosis and treatment. Immune infiltration analysis highlighted the strong correlation of these genes with specific immune cell subsets within the tumor microenvironment, underscoring their critical roles in modulating breast cancer immunobiology. Collectively, this study elucidates the therapeutic potential of YW-LF, a ribociclib derivative, in breast cancer treatment and delineates its multifaceted mechanisms, offering a promising strategy to overcome the limitations of current CDK4/6 inhibitors.
2025-04-11 | GSE294223 | GEO
Project description:Novel Ribociclib Derivative RB-1 Exhibits Anti-breast Cancer Actions by Regulating p53 and Cell Cycle Pathways
| PRJNA1249285 | ENA
Project description:Triple-negative breast cancer (TNBC) is a subtype of breast cancer (BC) characterized by deletion of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (Her-2). It accounts for 10.0% to 20.8% of all pathological types of BC, has specific biological behavior and clinicopathological features, and has a worse prognosis than other types. TNBC usually has a high mortality and recurrence rate, and a poor prognosis after surgery, radiation, chemotherapy, and endocrine therapy. There are no conventional and effective treatments to control its progression. Therefore, we designed and developed a derivative based on Abemaciclib, named LA-CB1. To investigate the influence of LA-CB1 on biological function of TNBC. We use the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test (MTT) to detect the viability of breast cancer cells. Evaluation of drug effects on cell migration and invasion by Transwell assays. Cell clone formation assay detects cell proliferation ability after drug addition. Subsequently, we determined the clinical significance and functional role of LA-CB1 through chick embryo experiments. Then, transcriptome sequencing technology (RNA-Seq) and bioinformatics methods were used to study the main pathway of LA-CB1 action on MDA-MB-231 cells. Western Blot assay verified the effect of LA-CB1 on the expression of CDK4/6-CyclinD1-Rb-E2F pathway protein. The compound LA-CB1 can inhibit the proliferation, colony formation, migration and invasion of TNBC cells. Effect of compound LA-CB1 on apoptosis and cell cycle detected by flow cytometry. The expression levels of CDK4, CDK6, CyclinD1, E2F1 and p-Rb proteins were positively correlated with LA-CB1 concentration. In summary, LA-CB1 showed a good anti-tumor cell proliferation effect, showing potential anti-TNBC drug candidate properties. This study provides new ideas and possibilities for TNBC treatment.
2024-10-11 | GSE276256 | GEO
Project description:We report transcriptional response to ribociclib treatment in resistant and sensitive CAMA-1 cells using RNA sequencing. Acquired ribociclib resistant cells were generated by treating CAMA-1 cells over a period of 5 month. Cells were then treated with ribociclib or DMSO control and processed for RNA sequencing.
2020-06-22 | GSE143944 | GEO
Project description:RNA sequencing and bioinformatics analysis revealed 2628 differentially expressed genes, with functional enrichment indicating strong associations with the p53 pathway, apoptosis, and G2/M checkpoint regulation
2025-04-09 | GSE294138 | GEO
Project description:Inhibiting protein-protein interactions via designed peptides is a suitable strategy to block the function of important proteins in cells. The Elongin BC heterodimer (ELOB/C) is involved in transcription elongation and protein turnover. It interacts with target proteins via a so-called BC-box to modulate their functions. ELOB and ELOC are commonly upregulated in cancer and are essential for cancer cell growth, making them attractive drug targets. However, currently, no strategy has been established to inhibit the function of ELOB/C in cells. Here, we show that peptides that mimic the high-affinity BC-box of EPOP can block the interaction of ELOB/C with its target proteins, both in vitro and in the cellular environment. Cancer cells treated with BC-box peptides, but not with the mutated control, show decreased cell viability, altered cell cycle and increased apoptosis, demonstrating a biological impact by inhibiting ELOB/C in vivo. Together our work suggests that targeting the BC-box binding pocket of ELOB/C is a feasible strategy to impair the function of the ELOB/C heterodimer and to inhibit cancer cell growth.
2023-06-27 | PXD038414 | Pride
Project description:Inhibition of protein-protein interactions (PPIs) via designed peptides is an effective strategy to perturb their biological functions. The Elongin BC heterodimer (ELOB/C) binds to a BC-box motif and is essential for cancer cell growth. Here, we report a peptide that mimics the high-affinity BC-box of the PRC2-associated protein EPOP. This peptide tightly binds to the ELOB/C dimer (kD = 0.46 ± 0.02 nM) and blocks the association of ELOB/C with its interaction partners, both in vitro and in the cellular environment. Cancer cells treated with our peptide inhibitor showed decreased cell viability, increased apoptosis, and perturbed gene expression. Therefore, our work proposes that blocking the BC-box-binding pocket of ELOB/C is a feasible strategy to impair its function and inhibit cancer cell growth. Our peptide inhibitor promises novel mechanistic insights into the biological function of the ELOB/C dimer and offers a starting point for therapeutics linked to ELOB/C dysfunction.
2023-06-24 | GSE213767 | GEO