Introduction: Triple-Negative Breast Cancer (TNBC) has limited targeted therapeutic options. SIK1 is a tumor-suppressive kinase in breast cancer, but pharmacological SIK1 activators remain poorly defined. Although recent anticancer patents have disclosed SIK modulators and RIPK1/necroptosis-targeting agents, most SIK-related inventions focus on kinase inhibition rather than therapeutic SIK1 activation. Methods: We performed structure-based virtual screening of 23,006 traditional Chinese medicine- derived compounds against human SIK1 and validated anisodine binding and activity using molecular docking, CETSA, DARTS, immunoblotting, kinase assays, rescue experiments, RIPK1 mutagenesis, and xenograft models. Female BALB/c nude mice (4 weeks old) were used for the xenograft experiments. Results: Anisodine directly bound the SIK1 ligand-binding pocket, with S247 required for anisodine- mediated SIK1 activation. Anisodine increased pSIK1-T182 and SIK1 substrate phosphorylation, suppressed TNBC clonogenic growth and invasion, and reduced xenograft tumor growth. Pharmacological rescue showed that Necrostatin-1, but not inhibitors of apoptosis, ferroptosis, or copper chelation, reversed anisodine-induced cytotoxicity. Mechanistically, SIK1 interacted with RIPK1 and directly phosphorylated RIPK1 at Ser316, thereby activating the RIPK1(S316)-RIPK3-MLKL necroptosis cascade. RIPK1-S316A attenuated, whereas RIPK1- S316D enhanced, necroptotic signaling and tumor suppression. Discussion: These findings position anisodine as a mechanistically defined SIK1 activator and distinguish this strategy from existing SIK inhibitor-centered patent landscapes. The SIK1-RIPK1(S316) axis also provides a druggable framework that links kinase activation to regulated necroptosis in TNBC. Conclusion: This study identifies anisodine as a small-molecule SIK1 activator and defines a SIK1-RIPK1(S316) signaling axis that induces necroptosis in TNBC, supporting a patentrelevant therapeutic concept for kinase-directed and regulated-cell-death-based anticancer drug discovery.
Introduction: Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype associated with poor prognosis and limited targeted treatment options. Natural multicomponent formulations have emerged as promising complementary therapeutic approaches because of their ability to modulate multiple cancer-related pathways. To evaluate the antitumour efficacy and systemic effects of a carvacrol-enriched multi-component oil formulation (CMCO) in a xenograft mouse model of TNBC. Methods: CMCO was characterized using Gas Chromatography-Mass Spectrometry (GC-MS). BALB/c nude mice bearing MDA-MB-231 xenograft tumours were treated with CMCO orally (40 mg/kg) or by combined oral and topical administration for 40 days. Tumour progression was assessed histopathologically. Liver and kidney function tests, hematological parameters, and immune profiles were evaluated. Molecular mechanisms were investigated using real-time quantitative polymerase chain reaction targeting genes associated with apoptosis, autophagy, oxidative stress, and vesicular transport. Results: GC-MS analysis identified 30 phytochemical constituents, with carvacrol as the predominant compound. CMCO treatment reduced tumour cell density, improved stromal organization, and induced focal necrosis, particularly in the combined treatment group. Compared with cisplatin-treated animals, CMCO-treated mice exhibited a more favorable biochemical profile without evidence of hepatorenal toxicity. Gene expression analysis demonstrated upregulation of VPS29 and STK4 and modulation of CASP8, suggesting effects on apoptosis- and autophagy- related pathways. Discussion: Recent patent activity involving carvacrol-rich formulations, monoterpene-based phytotherapeutics, and essential oil-derived bioactive compositions highlights growing translational and commercial interest in natural-product-based therapeutic strategies. The present findings provide preclinical evidence supporting the potential applicability of standardized multicomponent phytotherapeutic formulations in TNBC management. Conclusion: CMCO demonstrated significant antitumour activity while maintaining a favorable safety profile in a TNBC xenograft model. These findings support further preclinical and clinical investigation of CMCO as a complementary therapeutic candidate for TNBC and contribute to the growing body of evidence supporting the development of natural-product-based anticancer formulations.
Introduction: Kushenol E is a prenylated flavonoid derived from Sophora flavescens. Although preliminary studies have suggested that Kushenol E possesses anticancer activity, its effects and molecular mechanisms in Colorectal Cancer (CRC) remain largely unexplored. Therefore, this study investigated the therapeutical effects of Kushenol E and its underlying molecular mechanisms against CRC. Methods: HT-29 cells, colorectal organoids, and an AOM/DSS-induced colorectal tumor model in mice were used. Cellular biomarkers related to growth, damage, programmed cell death, mitochondrial membrane integrity, and activation of the p38, ERK, and AKT signal cascades were measured. In vivo, survival rate, body weight, disease activity index, colon length, tumor volume, H&E staining, TUNEL assays, immunohistochemistry, and ELISA were assessed. Results: Kushenol E inhibited HT-29 cell proliferation, induced apoptosis, increased the expression of mitochondrial apoptosis-related proteins Bax and Caspase-3, and reduced Bcl-2 expression. Kushenol E also reduced phospho-ERK and phospho-AKT levels while increasing phospho-p38. In CRC organoids, Kushenol E significantly reduced organoid diameter on day 3 (p < 0.01) and decreased organoid viability (p < 0.01). In AOM/DSS-treated mice, Kushenol E showed increased TUNEL positivity and Bax and caspase-3 expression, together with reduced Ki67 and PCNA expression. Moreover, ELISA analysis showed that Kushenol E reduced serum levels of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β) and lowered the tumorassociated biomarker CEA. Discussion: Kushenol E inhibited CRC cell and organoid growth and attenuated AOM/DSSinduced colorectal tumorigenesis. These effects are associated with mitochondrial apoptosis and alterations in p38/ERK/AKT signaling, and are accompanied by reduced inflammatory cytokine and CEA levels in vivo. Conclusion: Kushenol E has shown excellent antitumor activity against CRC and warrants further mechanistic, pharmacological, and safety evaluation.
Introduction: Plant-derived alkaloids have attracted growing attention in Colorectal Cancer (CRC) research because of their diverse biological activities and ability to regulate multiple oncogenic pathways. CRC remains a major cause of cancer-related mortality worldwide despite advances in diagnosis and therapy. Methods: This review summarizes experimental and translational studies investigating the anticancer effects of plant-derived alkaloids in CRC, with emphasis on molecular mechanisms, cancer stem cell signaling, pharmacokinetic limitations, and recent patent-related developments. Results: Experimental studies have demonstrated that several alkaloids, including berberine, matrine, evodiamine, and palmatine, inhibit CRC progression through the induction of apoptosis, suppression of proliferation, inhibition of epithelial-mesenchymal transition, and modulation of inflammatory and oxidative stress-associated pathways. These compounds also influence signaling pathways frequently dysregulated in CRC, including Wnt/β-catenin, PI3K/Akt/mTOR, MAPK, NF-κB, and JAK/STAT signaling. Recent patents have focused on alkaloid-based formulations, nanotechnology-driven delivery systems, and combination strategies designed to improve therapeutic efficacy and bioavailability. Discussion: Although preclinical findings remain promising, most alkaloids investigated in CRC research continue to face limitations, including poor bioavailability, insufficient pharmacokinetic characterization, and limited clinical validation. Conclusion: Plant-derived alkaloids remain promising candidates for CRC therapy and chemoprevention. Further translational studies, pharmacological optimization, and clinically relevant investigations will be necessary to clarify their therapeutic applicability in CRC.
INTRODUCTION:Glypican-1 (GPC1), a heparan sulfate proteoglycan found on the cell surface, has been associated with carcinogenesis and chemoresistance in several malignancies. However, its function in rhabdomyosarcoma remains poorly understood. METHODS:GPC1 protein expression was evaluated in rhabdomyosarcoma tissue microarrays using immunohistochemistry and quantified using the Allred scoring system. Transcriptomic analysis was performed using the GSE108022 dataset, and protein-protein interaction networks were analyzed using STRING. Structural features were assessed using AlphaFold, and drug sensitivity associations were explored using CTRP data. RESULTS:GPC1 protein expression was detected in 61.5% (64/104) of rhabdomyosarcoma cases, while 75% of normal skeletal muscle samples were negative. A significant association was observed between GPC1 expression and tumor subtype (p = 0.002, Cramér's V = 0.403), as well as sex (p = 0.025, Cra-mér's V = 0.219). Transcriptomic analysis showed significantly higher GPC1 expression in rhabdomyosarcoma compared to normal muscle (p < 0.001). Protein interaction analysis revealed enrichment in pathways related to cell adhesion, growth factor signaling, and extracellular matrix organization. Drug-sensitivity analysis indicated that higher GPC1 expression was associated with resistance to PI3K and HDAC inhibitors and increased sensitivity to vincristine, topotecan, and alisertib. DISCUSSION:GPC1 is aberrantly expressed in rhabdomyosarcoma, influencing neoplastic signaling and treatment responses, and new patents emphasize its potential for therapeutic targeting and diagnostic purposes Conclusion: GPC1 is aberrantly overexpressed, readily accessible to ligands or other molecules, and is a functionally significant biomarker in rhabdomyosarcoma, with emerging potential for diagnostic purposes and targeted therapy development.
