Lanatoside C inhibits cell proliferation and induces apoptosis through attenuating Wnt/β-catenin/c-Myc signaling pathway in human gastric cancer cell

Hu, Yudong; Yu, Kaikai; Wang, Gang; Zhang, Depeng; Shi, Chaoji; Ding, Yue; Hong, Duo; Zhang, Dan; He, Huiqiong; Sun, Lei; Zheng, Junnian; Sun, Shuyang; Qian, Feng

doi:10.1016/j.bcp.2018.02.023

Cited by 69 publications

(53 citation statements)

References 51 publications

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“…Owing to this feature, two CGs—namely lanatoside c and digoxin—have been used extensively in the treatment of several cardiac conditions, including different types of arrhythmia and contractility disorders. However, recent studies demonstrate that several CGs exhibit potent anticancer capacities to multiple cancers through different mechanisms, such as the Wnt/β‐catenin/c‐Myc/EGFR/RAS/ERK signaling pathway, p21, NF‐κB, AP‐1, topoisomerase, and HIF‐1, some of which are dependent on the Na + /K + ion pump …”

Section: Introductionmentioning

confidence: 99%

Cardiac glycoside sensitized hepatocellular carcinoma cells to TRAIL via ROS generation, p38MAPK, mitochondrial transition, and autophagy mediation

Rasheduzzaman

Yin

Park

2019

Molecular Carcinogenesis

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A major concern in the clinical application of tumor necrosis factor related apoptosis‐inducing ligand (TRAIL) in tumors is the development of resistance. Therefore, agents that can potentially restore TRAIL sensitivity are important therapeutic targets for cancer treatment. Herein, we evaluated lanatoside c and digoxin, both of which are widely used cardiac glycosides (CGs), for their ability to sensitize human hepatocellular carcinoma cells (Huh‐7 and HepG2) through TRAIL‐induced apoptosis. CGs functionalize TRAIL as shown by its effect on intracellular reactive oxygen species (ROS) generation, which damages mitochondrial integrity and thereby confers intrinsic apoptotic caspase cascade during combined treatment. Caspase activation is dependent on ROS as shown by the ability of CGs to generate ROS and the ROS‐N‐acetylcysteine (NAC) relationship, which inhibits apoptosis during cotreatment by preventing the formation of caspase‐8 and ‐3. Furthermore, CGs triggered p38MAPK phosphorylation and NAC pre‐exposure blocked p38MAPK phosphorylation, which demonstrated that p38MAPK was dependent upon ROS generation. Additionally, CGs were found to be potent inducers of AMPK‐mediated protective autophagy as pharmacological and genetic autophagy inhibition reached the higher threshold of TRAIL‐mediated apoptosis. Finally, CGs downregulated the expression of the antiapoptotic protein Bcl‐2 and increased the translocation of proapoptotic protein cytochrome c, thereby inducing apoptosis. Collectively, these results indicate that CGs potentiate the enhanced cytotoxic capacity to TRAIL through ROS generation, p38MAPK phosphorylation, cell survival protein downregulation, and protective autophagy inhibition.

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Section: Introductionmentioning

confidence: 99%

Cardiac glycoside sensitized hepatocellular carcinoma cells to TRAIL via ROS generation, p38MAPK, mitochondrial transition, and autophagy mediation

Rasheduzzaman

Yin

Park

2019

Molecular Carcinogenesis

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“…Lanatoside C was initially approved as a cardiac glycoside for the efficient treatment of arrhythmias and heart failure. However, recent studies demonstrating involvement in anti‐cancer functions and mechanistic studies have focused principally on its anti‐proliferation, apoptosis‐promoting and migration‐suppressing properties . It is well‐established that the overproduction of excessive quantities of ECM proteins and the formation of fibrous scars in pulmonary fibrosis are driven mainly by pulmonary fibroblast proliferation and their differentiation into myofibroblasts .…”

Section: Discussionmentioning

confidence: 99%

“…However, recent studies demonstrating involvement in anti-cancer functions and mechanistic studies have focused principally on its antiproliferation, apoptosis-promoting and migration-suppressing properties. 15,26 It is well-established that the overproduction of excessive quantities of ECM proteins and the formation of fibrous scars in pulmonary fibrosis are driven mainly by pulmonary fibroblast proliferation and their differentiation into myofibroblasts. 27,28 In the pathological conditions of PF, activated fibroblasts resist apoptosis and exhibit excessive proliferation and differentiation.…”

Section: Discussionmentioning

confidence: 99%

“…Lanatoside C, a cardiac glycoside approved by the US Food and Drug Administration (FDA), is widely used in the treatment of heart failure and cardiac arrhythmia . Recent studies have reported that its therapeutic effect on cancer occurs via induction of apoptosis and suppression of cellular proliferation . Characteristics of pulmonary fibrosis exhibit a degree of overlap with cancer during the process of fibrosis.…”

Section: Introductionmentioning

confidence: 99%

“…14 Recent studies have reported that its therapeutic effect on cancer occurs via induction of apoptosis and suppression of cellular proliferation. 15,16 Characteristics of pulmonary fibrosis exhibit a degree of overlap with cancer during the process of fibrosis. Fibroblasts in PF are capable of proliferation and invasion of the alveolar basement membrane.…”

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confidence: 99%

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Lanatoside C protects mice against bleomycin‐induced pulmonary fibrosis through suppression of fibroblast proliferation and differentiation

Nie

Zhang

Jin

et al. 2019

Clin Exp Pharma Physio

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Summary 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.

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Assessment of Thiosemicarbazone‐Containing Compounds as Potential Antileukemia Agents against P‐gp Overexpressing Drug Resistant K562/A02 Cells

Guan

Jiang

et al. 2021

Chemistry & Biodiversity

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P‐Glycoprotein (P‐gp) overexpression is considered to be the leading cause of multidrug resistance (MDR) and failure of chemotherapy for leukemia. In this study, seventeen thiosemicarbazone‐containing compounds were prepared and evaluated as potential antileukemia agents against drug resistant K562/A02 cell overexpressing P‐gp. Among them, N‐hydroxy‐6‐({(2E)‐2‐[(3‐nitrophenyl)methylidene]hydrazinecarbothioyl}amino)hexanamide could significantly inhibit K562/A02 cells proliferation with an IC50 value of 0.96 μM. Interestingly, N‐hydroxy‐6‐({(2E)‐2‐[(3‐nitrophenyl)methylidene]hydrazinecarbothioyl}amino)hexanamide could dose‐dependently increase ROS levels of drug resistant K562/A02 cells, thus displaying a potential collateral sensitivity (CS)‐inducing effect and selectively killing K562/A02 cells. Furthermore, N‐hydroxy‐6‐({(2E)‐2‐[(3‐nitrophenyl)methylidene]hydrazinecarbothioyl}amino)hexanamide possessed potent inhibitory effect on HDAC1 and HDAC6, and could promote K562/A02 cells apoptosis via dose‐dependently increasing Bax expression, reducing Bcl‐2 protein level, and inducing the cleavage of PARP and caspase3. These present findings suggest that N‐hydroxy‐6‐({(2E)‐2‐[(3‐nitrophenyl)methylidene]hydrazinecarbothioyl}amino)hexanamide might be a promising lead to discover novel antileukemia agents against P‐gp overexpressing leukemic cells.

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Lanatoside C inhibits cell proliferation and induces apoptosis through attenuating Wnt/β-catenin/c-Myc signaling pathway in human gastric cancer cell

Cited by 69 publications

References 51 publications

Cardiac glycoside sensitized hepatocellular carcinoma cells to TRAIL via ROS generation, p38MAPK, mitochondrial transition, and autophagy mediation

Cardiac glycoside sensitized hepatocellular carcinoma cells to TRAIL via ROS generation, p38MAPK, mitochondrial transition, and autophagy mediation

Lanatoside C protects mice against bleomycin‐induced pulmonary fibrosis through suppression of fibroblast proliferation and differentiation

Assessment of Thiosemicarbazone‐Containing Compounds as Potential Antileukemia Agents against P‐gp Overexpressing Drug Resistant K562/A02 Cells

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