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

Dhanasekhar Reddy¹, Preetam Ghosh², Ranjith Kumavath¹

¹Department of Genomic Science, School of Biological Sciences, Central University of Kerala, Kasaragod, India.

Frontiers in Oncology

|February 4, 2020

Abstract:

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.

Insights

Strophanthidin, a natural cardiac glycoside, shows potent anticancer activity against breast, lung, and liver cancer cells. It induces cell cycle arrest and apoptosis by targeting multiple signaling pathways, suggesting its potential as a novel cancer therapeutic.

Area of Science:

Oncology
Pharmacology
Molecular Biology

Background:

Lung and breast cancers are leading causes of cancer deaths globally.
Cancer drug resistance and recurrence limit therapeutic efficacy.
Cardiac glycosides (CGs) are emerging as potent anticancer agents targeting multiple cellular pathways.

Purpose of the Study:

To investigate the anticancer potential of strophanthidin, a natural CG.
To evaluate strophanthidin's effects on human breast (MCF-7), lung (A549), and liver cancer (HepG2) cells.
To elucidate the molecular mechanisms underlying strophanthidin's cytotoxic effects.

Main Methods:

Cell viability assays in MCF-7, A549, and HepG2 cell lines.
DNA damage assessment following strophanthidin treatment.
Cell cycle analysis and Western blotting to determine protein expression changes.
In silico molecular docking studies to predict protein interactions.

Main Results:

Strophanthidin exhibited dose-dependent cytotoxicity in all tested cancer cell lines.
The compound induced DNA damage and G2/M cell cycle arrest.
Strophanthidin inhibited key proteins in MAPK, PI3K/AKT/mTOR, and Wnt/β-catenin signaling pathways.
In silico analysis confirmed strophanthidin's interaction with multiple target proteins.

Conclusions:

Strophanthidin demonstrates significant anticancer activity through apoptosis and cell cycle arrest.
The natural compound effectively modulates critical cancer-related signaling pathways.
Strophanthidin shows promise as a potential novel anticancer drug candidate.

Read full analysis

Keywords:

G2/M phase Na+/K+-ATPase apoptosis autophagy cardiac glycoside strophanthidin

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