Cardenolides and its Sapogenins
Lanatoside C, a cardiac glycoside, acts through protein kinase Cδ to cause apoptosis of human hepatocellular carcinoma cells. PUMID/DOI：28387249 Sci Rep. 2017 Apr 7;7:46134. Recent studies have revealed that cardiac glycosides, such as digitalis and digoxin, have anticancer activity and may serve as lead compounds for the development of cancer treatments. The poor prognosis of hepatocellular carcinoma (HCC) patients reflects the development of resistance to current chemotherapeutic agents, highlighting the need for discovering new small-molecule therapeutics. Here, we found that Lanatoside C, an anti-arrhythmic agent extracted from Digitalis lanata, inhibited the growth of HCC cells and dramatically decreased tumor volume as well as delayed tumor growth without obvious body weight loss.We also found that the AKT/mTOR pathway was negatively regulated by Lanatoside C through PKCδ activation. In conclusion, we provide the first demonstration that the anticancer effects of Lanatoside C are mainly attributable to PKCδ activation. Antiviral activity of lanatoside C against dengue virus infection. PUMID/DOI：25251726 Antiviral Res. 2014 Nov;111:93-9 Our data revealed that Lanatoside C has an IC50 of 0.19μM for dengue virus infection in HuH-7 cells. Dose-dependent reduction in dengue viral RNA and viral proteins synthesis were also observed upon treatment with increasing concentrations of Lanatoside C. Time of addition study indicated that Lanatoside C inhibits the early processes of the dengue virus replication cycle. Furthermore, Lanatoside C can effectively inhibit all four serotypes of dengue virus, flavivirus Kunjin, alphavirus Chikungunya and Sindbis virus as well as the human enterovirus 71. These findings suggest that Lanatoside C possesses broad spectrum antiviral activity against several groups of positive-sense RNA viruses. Lanatoside C sensitizes glioblastoma cells to tumor necrosis factor-related apoptosis-inducing ligand and induces an alternative cell death pathway. PUMID/DOI：21757445 Neuro Oncol. 2011 Nov;13(11):1213-24. Human glioblastoma (GBM) cells are notorious for their resistance to apoptosis-inducing therapeutics. We have identified Lanatoside C as a sensitizer of GBM cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced cell death partly by upregulation of the death receptor 5. We show that Lanatoside C sensitizes GBM cells to TRAIL-induced apoptosis in a GBM xenograft model in vivo. Lanatoside C on its own serves as a therapeutic agent against GBM by activating a caspase-independent cell death pathway. Cells treated with Lanatoside C showed necrotic cell morphology with absence of caspase activation, low mitochondrial membrane potential, and early intracellular ATP depletion. In conclusion, Lanatoside C sensitizes GBM cells to TRAIL-induced cell death and mitigates apoptosis resistance of glioblastoma cells by inducing an alternative cell death pathway. To our knowledge, this is one of the first examples of use of caspase-independent cell death inducers to trigger tumor regression in vivo. Activation of such mechanism may be a useful strategy to counter resistance of cancer cells to apoptosis.
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It has been established that lanatoside C, a FDA-approved cardiac glycoside, reduces proliferation of cancer cell lines. The proliferation of fibroblasts is critical to the pathogenesis of pulmonary fibrosis (PF), a progressive and fatal fibrotic lung disease lacking effective treatment. In this study we have investigated the impact of lanatoside C on a bleomycin (BLM)-induced mouse model of PF and through the evaluation of fibroblast proliferation and activation in vitro. We evaluated explanted lung tissue by histological staining, western blot analysis, qRT-PCR and survival analysis, demonstrating that lanatoside C was able to protect mice against BLM-induced pulmonary fibrosis. The proliferation of cultured pulmonary fibroblasts isolated from BLM-induced PF mice was suppressed by lanatoside C, as hypothesized, through the induction of cell apoptosis and cell cycle arrest at the G2/M phase. The Akt signalling pathway was involved in this process. Interestingly, the production of α-SMA, fibronectin, and collagen I and III in response to TGF-β1 in healthy mouse fibroblasts was suppressed following lanatoside C administration by inhibition of TGF-β1/Smad signalling. In addition, TGF-β1-induced migration in lung fibroblasts was also impeded after lanatoside C treatment. Together, our data revealed that lanatoside C alleviated BLM-induced pulmonary fibrosis in mice via attenuation of growth and differentiation of fibroblasts, suggesting that it has potential as a candidate therapy for PF patients.
Akt; TGF-β1; differentiation; lanatoside C; proliferation; pulmonary fibrosis.
Lanatoside C protects mice against bleomycin-induced pulmonary fibrosis through suppression of fibroblast proliferation and differentiation
Yunjuan Nie 1, Dan Zhang 2, Zhewu Jin 1, Boyu Li 1, Xue Wang 1, Huilian Che 1, Yaqian You 1, Xiaohang Qian 1, Yang Zhang 3, Peng Zhao 1, Gaoshang Chai 1
Gastric cancer is the third common cause of cancer mortality in the world with poor prognosis and high recurrence due to lack of effective medicines. Our studies revealed that lanatoside C, a FDA-approved cardiac glycoside, had an anti-proliferation effect on different human cancer cell lines (MKN-45; SGC-7901; HN4; MCF-7; HepG2) and gastric cell lines MKN-45 and SGC-7901 were the most sensitive cell lines to lanatoside C. MKN-45 cells treated with lanatoside C showed cell cycle arrest at G2/M phase and inhibition of cell migration. Meanwhile, upregulation of cleaved caspase-9 and cleaved PARP and downregulation of Bcl-xl were accompanied with the loss of mitochondrial membrane potential (MMP) and induction of intracellular reactive oxygen species (ROS). Lanatoside C inhibited Wnt/β-catenin signaling with downregulation of c-Myc, while overexpression of c-Myc reversed the anti-tumor effect of lanatoside C, confirming that c-Myc is a key drug target of lanatoside C. Furthermore, we discovered that lanatoside C prompted c-Myc degradation in proteasome-ubiquitin pathway with attenuating the binding of USP28 to c-Myc. These findings indicate that lanatoside C targeted c-Myc ubiquitination to inhibit MKN-45 proliferation and support the potential value of lanatoside C as a chemotherapeutic candidate.
Gastric cancer; Lanatoside C; Ubiquitination; c-Myc; β-Catenin.
Lanatoside C inhibits cell proliferation and induces apoptosis through attenuating Wnt/β-catenin/c-Myc signaling pathway in human gastric cancer cell
Yudong Hu 1, Kaikai Yu 2, Gang Wang 3, Depeng Zhang 4, Chaoji Shi 5, Yunhe Ding 6, Duo Hong 7, Dan Zhang 8, Huiqiong He 9, Lei Sun 10, Jun-Nian Zheng 11, Shuyang Sun 12, Feng Qian 13
Purpose: This study investigated the effect of cedilanid on retinal neovascularization in a mouse model of oxygen-induced retinopathy.
Methods: Seven-day-old C57BL/6 mice were exposed to 75% ± 1% oxygen for 5 days and were then returned to room air to induce retinal neovascularization. Cedilanid (0.025-0.2 μg) was intravitreally injected into the left eye of each mouse on postnatal day 12 (P12) and P15. PBS was intravitreally injected into the right eye as a control. Retinal neovascularization was evaluated with isolectin GS-IB4 staining of the retinal blood vessels. The function of reestablishment blood vessels was evaluated with angiography with the injection of fluorescein isothiocyanate (FITC)-dextran followed by isolectin GS-IB4 staining. Real time (RT)-PCR and western blot were used to examine the mRNA and protein expression of hypoxia inducible factor 1 alpha (HIF-1α) and vascular endothelial growth factor (VEGF), respectively.
Results: Retinal neovascular areas and obliterative areas were statistically significantly smaller in the eyes injected with cedilanid (0.05 μg, 0.1 μg, and 0.2 μg) compared with the control eyes. The inhibitory effect of cedilanid was observed in a dose-dependent manner. In addition, the retinal neovascular areas and the obliterative areas in the eyes injected with 0.2 μg cedilanid on P12 were statistically significantly smaller than those in the eyes injected with the same dose of cedilanid on P15. Cedilanid promoted the circulative function of reestablished blood vessels in the obliterative areas. Cedilanid inhibited the expression of HIF-1α and VEGF in mice treated with hyperoxia.
Conclusions: Cedilanid inhibits retinal neovascularization in a mouse model of oxygen-induced retinopathy. Early treatment with cedilanid produces better inhibition of retinal neovascularization. Cedilanid may be a potential treatment of neovascular diseases.
Cedilanid inhibits retinal neovascularization in a mouse model of oxygen-induced retinopathy
Jing Shang Zhang 1, Jin Da Wang 1, Ying An 1, Ying Xiong 2, Jing Li 2, JostB Jonas 1 3, Liang Xu 1, Wei Zhang 1, Xiu Hua Wan 1
2017 Jun 16;