Raddeanin A

Raddeanin A is an oleanane-type triterpenoid saponin with oral activity. Raddeanin A inhibits SRC, mTOR, JNK, VEGFR2, NLRP3 inflammasome, Wnt/β-catenin, Wee1, PI3K/AKT signaling pathway, MAPK/ERK signaling pathway, AR-FL, AR-Vs, and downregulates the expression of p-PI3K and p-AKT. Raddeanin A inhibits osteoclast formation, bone resorption, osteolysis, cancer cell invasion, migration, proliferation, angiogenesis and epithelial-mesenchymal transition, while induces apoptosis, cell cycle arrest, ROS production, immunogenic cell death and dendritic cell maturation. Raddeanin A improves blood-retinal barrier function, alleviates inflammation, regulates the tumor microenvironment, and enhances the activity of anti-PD-1 antibody. Raddeanin A is applicable to the research of breast cancer-associated osteolysis, human osteosarcoma, colorectal cancer, glioblastoma, Alzheimer's disease, cholangiocarcinoma, melanoma, non-small cell lung cancer, castration-resistant prostate cancer and multiple myeloma^{[1][2][3][4][5][6][7][8][9][10][11]}. In Vitro:Raddeanin A (0.2-0.8 μM; 3-7 days) potently inhibits RANKL-induced osteoclast formation in BMMs, with a 72-hour cytotoxicity IC₅₀ of 2.91 μM, and suppresses osteoclast survival in a concentration-dependent manner^[1].
Raddeanin A (0.4 μM; 5-7 days) downregulates key osteoclastogenic markers CTSK and NFATc1 at both the gene and protein levels in RANKL-stimulated BMMs^[1].
Raddeanin A (0.2-0.8 μM; 7-21 days), at concentrations up to 0.8 μM, does not inhibit osteoblast differentiation in MC3T3-E1 cells, and at 0.2 μM enhances mineralization and increases SPARC gene expression^[1].
Raddeanin A (6.25-50 μM; 24-96 h) inhibits viability, proliferation, and invasion of MDA-MB-231 breast cancer cells, and induces apoptosis, with a 96-hour cytotoxicity IC₅₀ of 15.77 μM^[1].
Raddeanin A (3 μM; 6-12 h) inhibits AKT/mTOR signaling in MDA-MB-231 cells by reducing p-AKT and mTOR protein levels^[1].
Raddeanin A (0.2-50 μM; 24-48 h) dose- and time-dependently inhibits the viability of human osteosarcoma MG-63, HOS, U-2 OS, Saos-2, and 143B cells, with MG-63 and HOS cells showing the highest sensitivity (IC₅₀ values of 1.60 μM and 2.57 μM at 48 h, respectively)^[2].
Raddeanin A (1-4 μM; 24 h) dose-dependently modulates mitochondrial apoptotic pathway proteins (reducing Bcl-2/Bax ratio, increasing cleaved caspase-3 and cleaved PARP) in human osteosarcoma MG-63 and HOS cells^[2].
Raddeanin A (1-4 μM; 12 h) dose-dependently inhibits IκBα phosphorylation in human osteosarcoma MG-63 and HOS cells after 12 h of treatment^[2].
Raddeanin A (1-4 μM; 2 μM, 6 h) dose-dependently suppresses p65 nuclear translocation in human osteosarcoma MG-63 and HOS cells, with 2 μM treatment for 6 h visibly reducing nuclear p65 localization^[2].
Raddeanin A (100-800 nM; 48 h) dose-dependently reduces the viability of U87, U251, T98G, and LN299 human glioblastoma cells, with greater potency in U87 and U251 cells^[4].
Raddeanin A (100-200 nM; 48 h) dose-dependently reduces the mRNA and protein expression of β-catenin and EMT-related biomarkers (N-cadherin, vimentin, snail) in U87 and U251 human glioblastoma cells^[4].
Raddeanin A (100 nM) inhibits viability, migration, invasion, and EMT biomarker expression in β-catenin-overexpressing U87 and U251 human glioblastoma cells, but these effects are reversed by β-catenin overexpression^[4].
Raddeanin A (0.125-0.5 μM; 24 h) inhibits Aβ1-42-induced activation of the NLRP3 inflammasome and secretion of inflammatory cytokines in MIO-M1 cells^[5].
Raddeanin A (0-160 μg/mL; 24 h) reduces cell viability in a dose-dependent manner in RBE, LIPF155C, LIPF178C, and LICCF cholangiocarcinoma cell lines (EC₅₀: 50.95-64.76 μg/mL; LC₅₀: 34.65-49.47 μg/mL) with lower toxicity to normal HIBEpiC biliary epithelial cells^[6].
Raddeanin A (1-5 μM; 20 h) dose-dependently increases HMGB1-Gluc activity, a marker of immunogenic cell death, in B16 and MC38 cells^[7].
Raddeanin A (1-5 μM; 6-8 h) dose-dependently increases mitochondrial ROS production in MC38 cells^[7].
Raddeanin A (1-4 μM; 24 h) dose-dependently inhibits the migration and invasion of H1299, A549, and PC-9 NSCLC cells after 24 h of treatment^[8].
Raddeanin A (1-4 μM; 24 h) modulates EMT-related protein expression and specifically inhibits CDK6 expression and Rb phosphorylation in H1299, A549, and PC-9 NSCLC cells after 24 h of treatment^[8].
Raddeanin A (1-4 μM; 24 h) dose-dependently induces G1 phase cell cycle arrest in H1299, A549, and PC-9 NSCLC cells after 24 h of treatment^[8].
Raddeanin A (1-16 μM; 12 h) potently inhibits proliferation of human colorectal cancer HCT116 cells in a dose-dependent manner, with a 12 h IC₅₀ of 2.61 μM^[9].
Raddeanin A (2-4 μM; 12 h) dose-dependently downregulates the mRNA expression of apoptosis-related genes (caspase-3, PARP) and cell cycle-related genes (cyclinD1, cyclinE) in human colorectal cancer HCT116 cells^[9].
Raddeanin A (2-4 μM; 12 h) modulates protein expression in human colorectal cancer HCT116 cells by increasing pro-apoptotic proteins, decreasing anti-apoptotic and cell cycle-related proteins, and suppressing the PI3K/AKT signaling pathway via reduced p-PI3K and p-AKT expression^[9].
Raddeanin A (1.5-6 μM; 12-72 h) dose- and/or time-dependently inhibits the growth of AR-positive 22Rv1, C4-2, C4-2B, and LNCaP95 CRPC cells, with no effect on AR-null PC-3 and DU145 prostate cancer cells^[10].
Raddeanin A (3 μM; 6-24 h) time-dependently downregulates mRNA levels of AR target genes PSA (in C4-2 and LNCaP95 cells) and UBE2C (in LNCaP95 cells)^[10].
Raddeanin A (0.125-8 μM; 24-48 h) inhibits the proliferation of MM.1S, MM.1R, and RPMI 8226 multiple myeloma cells in a time-dependent and concentration-dependent manner, with IC₅₀ values ranging from 1.058 μM (MM.1S, 48 h) to 6.091 μM (RPMI 8226, 24 h)^[11]. In Vivo:Raddeanin A (50-100 μg/kg; daily; 14 days) significantly inhibits Ti-particle-induced calvarial osteolysis in male C57BL/6 mice by reducing osteoclast formation and bone resorption, as evidenced by increased BV/TV, decreased porosity, and fewer TRAP- and CTSK-positive osteoclasts^[1].
Raddeanin A (100 μg/kg; i.p.; every other day; 28 days) significantly inhibits breast cancer-induced osteolysis in female BALB/c nu/nu mice by preserving bone structure and increasing tumor cell apoptosis, as evidenced by higher BV/TV, reduced Tb. Sp, intact bone cortex, and increased TUNEL-positive cells^[1].
Raddeanin A (1.25-5 mg/kg; i.p.; every other day; 20 consecutive days) dose-dependently inhibits the growth of HOS osteosarcoma xenografts in nude mice, while inducing tumor cell apoptosis and demonstrating low systemic toxicity^[2].
Raddeanin A (0.4 μM; continuous immersion; 30 h) inhibits zebrafish intersegmental vessel formation by 67.64%^[3].
Raddeanin A (5 mg/kg; i.p.; once every 2 days; 11 injections) reduces HCT-15 colorectal xenograft tumor volume and weight, increases tumor apoptosis and necrosis, and decreases intratumoral microvessel density without obvious toxicity^[3].
Raddeanin A (100 mg/kg; i.p.; daily) inhibits glioblastoma tumor growth, reduces tumor vessel density, downregulates β-catenin-mediated EMT and angiogenesis, and increases survival rate to ~80% at day 30 in an intracranial U87 xenograft mouse model^[4].
Raddeanin A (10 mg/kg; p.o.; daily; 9 weeks) protects the blood-retinal barrier and improves Alzheimer's disease-related retinopathy in 3×Tg-AD mice by inhibiting NLRP3-mediated inflammation, suppressing Wnt/β-catenin pathway-mediated apoptosis, and restoring retinal structural and vascular integrity^[5].
Raddeanin A (1-4 mg/kg; i.p., i.t.; four times at indicated time points) inhibits MC38 colon adenocarcinoma growth in a DC and CD8⁺ T cell-dependent manner in C57BL/6J mice, and induces 60% tumor-free survival in a tumor rechallenge model^[7].
Raddeanin A (4 mg/kg; i.t.; four times at indicated time points)'s antitumor activity against MC38 colon adenocarcinoma in C57BL/6J mice is dependent on CD8⁺ T cells and DCs, and combining it with anti-PD-1 antibody enhances therapeutic efficacy by reprogramming the tumor immune microenvironment^[7].
Raddeanin A (0.5-1.0 mg/kg; i.p.; once every 2 days; 7 total doses over 30 days) exerts dose-dependent anti-NSCLC efficacy in BALB/c nude mouse xenografts, with the 1.0 mg/kg dose significantly reducing tumor volume and weight while showing no detectable organ toxicity^[8].
Raddeanin A (4 mg/kg; injected; 2 weeks) significantly inhibits colorectal cancer xenograft tumor growth in BALB/c nude mice, reduces tumor volume and weight, induces tumor cell apoptosis at a rate of 43.6%, modulates apoptosis- and cell cycle-related proteins, and regulates the PI3K/AKT signaling pathway without causing liver toxicity^[9].