Subamolide A Induces Mitotic Catastrophe Accompanied by Apoptosis in Human Lung Cancer Cells

Jen‐Yu Hung ,Ching-Wen Wen,Chung‐Yi Chen ,Ming‐Shyan Huang ,Ya‐Ling Hsu ,En‐Shyh Lin ,Po‐Lin Kuo

doi:10.1155/2013/828143

Abstract

This study investigated the anticancer effects of subamolide A (Sub-A), isolated from Cinnamomum subavenium, on human nonsmall cell lung cancer cell lines A549 and NCI-H460. Treatment of cancer cells with Sub-A resulted in decreased cell viability of both lung cancer cell lines. Sub-A induced lung cancer cell death by triggering mitotic catastrophe with apoptosis. It triggered oxidant stress, indicated by increased cellular reactive oxygen species (ROS) production and decreased glutathione level. The elevated ROS triggered the activation of ataxia-telangiectasia mutation (ATM), which further enhanced the ATF3 upregulation and subsequently enhanced p53 function by phosphorylation at Serine 15 and Serine 392. The antioxidant, EUK8, significantly decreased mitotic catastrophe by inhibiting ATM activation, ATF3 expression, and p53 phosphorylation. The reduction of ATM and ATF3 expression by shRNA decreased Sub-A-mediated p53 phosphorylation and mitotic catastrophe. Sub-A also caused a dramatic 70% reduction in tumor size in an animal model. Taken together, cell death of lung cancer cells in response to Sub-A is dependent on ROS generation, which triggers mitotic catastrophe followed by apoptosis. Therefore, Sub-A may be a novel anticancer agent for the treatment of nonsmall cell lung cancer.

Highlights

Lung cancer has been one of the most common causes of death throughout the world for several decades [1, 2]
To examine the selection of subamolide A (Sub-A) cytotoxicity, we evaluated the effect of Sub-A in normal fibroblast cell line, IMR-90
The results showed that treatment of IMR-90 cells with Sub-A failed to affect the cell viability (Figure 1(d))

Summary

Introduction

Lung cancer has been one of the most common causes of death throughout the world for several decades [1, 2]. Mitotic catastrophe is defined as a type of cell death caused by aberrant mitosis [4, 5]. Mitotic catastrophe is defined as an aberrant form of mitosis associated with concurrent multinucleated giant cells that are temporarily viable but lose the ability to proliferate and eventually die by apoptosis or necrosis [6, 7]. Mitotic catastrophe can be induced by chemical stress, DNA damage, and chemotherapeutic agents like paclitaxel, doxorubicin, and nocodazole. Deficiencies in DNA damage response and cell cycle checkpoints of cancer cells make them more susceptible to the trigger of mitotic catastrophe by anticancer drugs [8,9,10]. Novel strategies targeting the activation of mitotic catastrophe is being developed in preclinical and clinical studies [11]

Methods

Results

Conclusion