Cardiac glycoside cerberin exerts anticancer activity through PI3K/AKT/mTOR signal transduction inhibition

Hossan, Shahadat; Chan, Zi Yang; Collins, Hilary M.; Shipton, Fiona Natalia; Butler, Mark S.; Rahmatullah, Mohammed; Lee, Jong Bong; Gershkovich, Pavel; Kagan, Leonid; Khoo, Teng-Jin; Wiart, Christophe; Bradshaw, Tracey D.

doi:10.1016/j.canlet.2019.03.034

Cited by 39 publications

(24 citation statements)

References 52 publications

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“…In the current study, we have found a significant downregulation of mTOR, PI3K, p62, and Beclin 1, which can effectively cause autophagy and could further induce apoptosis due to nutritional deficiency upon the stress created by strophanthidin. A similar result was observed by Hossan et al (15), suggesting that CGs such as cerberin act through PI3K/AKT/mTOR signaling to inhibit autophagy and to induce apoptosis in cancer cells. Our results in the current study not only enrich the anticancer potentiality of strophanthidin but also give novel insights into the mechanism of the cytotoxic effect on PI3K/AKT/mTOR signaling for improved cancer treatment.…”

Section: O21supporting

confidence: 85%

“…CGs have been recognized as the oldest drugs and used for centuries to treat congestive heart diseases. Epidemiological reports recommended that cancer patients under treatment with digitalis showed less mortality rates compared to others, which reintroduced the attention toward the antiproliferative activities of CGs (14,15). In the past 10 years, several in vitro and in vivo studies have been conducted, and many of the CGs or its derivatives are in clinical trials for cancer treatments (16).…”

Section: Discussionmentioning

confidence: 99%

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Strophanthidin Attenuates MAPK, PI3K/AKT/mTOR, and Wnt/β-Catenin Signaling Pathways in Human Cancers

2020

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Lung cancer is the most prevalent in cancer-related deaths, while breast carcinoma is the second most dominant cancer in women, accounting for the most number of deaths worldwide. Cancers are heterogeneous diseases that consist of several subtypes based on the presence or absence of hormone receptors and human epidermal growth factor receptor 2. Several drugs have been developed targeting cancer biomarkers; nonetheless, their efficiency are not adequate due to the high reemergence rate of cancers and fundamental or acquired resistance toward such drugs, which leads to partial therapeutic possibilities. Recent studies on cardiac glycosides (CGs) positioned them as potent cytotoxic agents that target multiple pathways to initiate apoptosis and autophagic cell death in many cancers. In the present study, our aim is to identify the anticancer activity of a naturally available CG (strophanthidin) in human breast (MCF-7), lung (A549), and liver cancer (HepG2) cells. Our results demonstrate a dose-dependent cytotoxic effect of strophanthidin in MCF-7, A549, and HepG2 cells, which was further supported by DNA damage on drug treatment. Strophanthidin arrested the cell cycle at the G2/M phase; this effect was further validated by checking the inhibited expressions of checkpoint and cyclin-dependent kinases in strophanthidin-induced cells. Moreover, strophanthidin inhibited the expression of several key proteins such as MEK1, PI3K, AKT, mTOR, Gsk3α, and β-catenin from MAPK, PI3K/AKT/mTOR, and Wnt/β-catenin signaling. The current study adequately exhibits the role of strophanthidin in modulating the expression of various key proteins involved in cell cycle arrest, apoptosis, and autophagic cell death. Our in silico studies revealed that strophanthidin can interact with several key proteins from various pathways. Taken together, this study demonstrates the viability of strophanthidin as a promising anticancer agent, which may serve as a new anticancer drug.

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Section: O21supporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Strophanthidin Attenuates MAPK, PI3K/AKT/mTOR, and Wnt/β-Catenin Signaling Pathways in Human Cancers

2020

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“…Akt/mTOR, Stat3, and NF-κB signalling pathways play an important role in cell proliferation and migration. [29][30][31] ALO treatment caused a marked decrease in the activation of the Akt/mTOR/P70S6K and Stat3 signalling pathways. Furthermore, IκBα phosphorylation was also considerably reduced ( Figure 4).…”

Section: Discussionmentioning

confidence: 96%

<p>Aloin Inhibits the Proliferation and Migration of Gastric Cancer Cells by Regulating NOX2–ROS-Mediated Pro-Survival Signal Pathways</p>

Wang¹,

Tang²,

Wang³

et al. 2020

DDDT

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Background: Aloin has been reported to have many pharmacological effects including antiinflammatory, anti-oxidant and anti-tumour activities. However, the precise molecular mechanisms underlying the anti-tumour properties of aloin are yet to be elucidated. Methods: HGC-27 and BGC-823 gastric cancer cells were treated with aloin. EdU and colony formation assays were used to detect the proliferation ability of cells. The migration of cells was detected using wound healing and transwell assays. Western blotting was used to detect the levels of cyclinD1, cyclin E1, MMPs, N-cadherin, E-cadherin and NOX2. The phosphorylation of Akt, mTOR, P70S6K, S6, Src, stat3 and IκBα were also detected by Western blotting. Flow cytometry was used to detect the cell cycle distribution.The location of p65 in cells was determined by using a confocal microscopy assay. The total amounts of ROS present in cells were measured using an ROS assay kit. Results: Here, we found that aloin inhibited the proliferation and migration of HGC-27 and BGC-823 gastric cancer cells using a combination of EdU, colony formation, wound healing and transwell assays. Further investigations revealed that aloin decreased the protein expression levels of cyclin D1, N-cadherin, and the matrix metalloproteinases (MMP)-2 and MMP-9; increased E-cadherin expression in a dose-dependent manner; inhibited reactive oxygen species (ROS) generation; and mediated the activation of Akt-mTOR, signal transducer and activator of transcription-3 (Stat3), and NF-κB signalling pathways. Our results also indicated that aloin is able to attenuate the expression levels of the two regulatory proteins of nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2), p47 phox and p22 phox , but had no effect on the level of gp91 phox. N-acetylcysteine treatment of gastric cancer cells inhibited ROS production and Akt-mTOR, Stat3, and IκBα phosphorylation. Taken together, our data suggest that aloin inhibits the proliferation and migration of gastric cancer cells by downregulating NOX2-ROS-mediated activation of the Akt-mTOR, Stat3, and NF-κB signalling pathways. Conclusion: Our findings suggest a potential role for aloin in the prevention of gastric cancer cell proliferation and migration and provide novel insights into the anti-cancer properties of aloin.

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“…Inhibitors of mTOR and PI3K through various stress conditions by chemotherapeutic drugs lead to the activation of AKT, which directly inhibits mTOR through several regulators. We have checked the role of Lanatoside C in PI3K/AKT/mTOR pathway to identify its role in autophagy, as recent reports suggested that CGs (Cerberin) cause apoptosis and autophagy inhibition through PI3K/AKT/mTOR signaling [67]. We have identified the dysregulation of AKT, mTOR, p62, LC3, and Beclin 1, which has led to the initiation of cell death by Lanatoside C in breast, lung, and liver cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Lanatoside C Induces G2/M Cell Cycle Arrest and Suppresses Cancer Cell Growth by Attenuating MAPK, Wnt, JAK-STAT, and PI3K/AKT/mTOR Signaling Pathways

et al. 2019

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Cardiac glycosides (CGs) are a diverse family of naturally derived compounds having a steroid and glycone moiety in their structures. CG molecules inhibit the α-subunit of ubiquitous transmembrane protein Na+/K+-ATPase and are clinically approved for the treatment of cardiovascular diseases. Recently, the CGs were found to exhibit selective cytotoxic effects against cancer cells, raising interest in their use as anti-cancer molecules. In this current study, we explored the underlying mechanism responsible for the anti-cancer activity of Lanatoside C against breast (MCF-7), lung (A549), and liver (HepG2) cancer cell lines. Using Real-time PCR, western blot, and immunofluorescence studies, we observed that (i) Lanatoside C inhibited cell proliferation and induced apoptosis in cell-specific and dose-dependent manner only in cancer cell lines; (ii) Lanatoside C exerts its anti-cancer activity by arresting the G2/M phase of cell cycle by blocking MAPK/Wnt/PAM signaling pathways; (iii) it induces apoptosis by inducing DNA damage and inhibiting PI3K/AKT/mTOR signaling pathways; and finally, (iv) molecular docking analysis shows significant evidence on the binding sites of Lanatoside C with various key signaling proteins ranging from cell survival to cell death. Our studies provide a novel molecular insight of anti-cancer activities of Lanatoside C in human cancer cells.

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Cardiac glycoside cerberin exerts anticancer activity through PI3K/AKT/mTOR signal transduction inhibition

Cited by 39 publications

References 52 publications

Strophanthidin Attenuates MAPK, PI3K/AKT/mTOR, and Wnt/β-Catenin Signaling Pathways in Human Cancers

Strophanthidin Attenuates MAPK, PI3K/AKT/mTOR, and Wnt/β-Catenin Signaling Pathways in Human Cancers

<p>Aloin Inhibits the Proliferation and Migration of Gastric Cancer Cells by Regulating NOX2–ROS-Mediated Pro-Survival Signal Pathways</p>

Lanatoside C Induces G2/M Cell Cycle Arrest and Suppresses Cancer Cell Growth by Attenuating MAPK, Wnt, JAK-STAT, and PI3K/AKT/mTOR Signaling Pathways

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