Luteolin Shifts Oxaliplatin-Induced Cell Cycle Arrest at G₀/G₁ to Apoptosis in HCT116 Human Colorectal Carcinoma Cells.

Chan Jang,Nayoung Moon,Jisun Oh,Jong-Sang Kim

doi:10.3390/nu11040770

Chan Jang, Nayoung Moon + Show 2 more

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https://doi.org/10.3390/nu11040770

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Journal: Nutrients	Publication Date: Apr 2, 2019
Citations: 26	License type: CC BY 4.0

Affiliation: Kyungpook National University

Abstract

Certain antioxidative flavonoids are known to activate nuclear factor E2-related factor 2 (Nrf2), a transcription factor that regulates cellular antioxidants and detoxifying response and is reportedly highly activated in many types of cancers. Few studies on the potential undesired effects of flavonoid intake during chemotherapy have been conducted, yet Nrf2 activators could favor cancer cell survival by attenuating chemotherapeutic efficiency. This study aimed to examine if luteolin, an Nrf2 activator, hinders chemotherapeutic activity of oxaliplatin, a potent anticancer agent for colorectal cancer, in HCT116 cells. Luteolin treatment strongly increased the transcriptional activity of the antioxidant response element in HCT116 cells and induced the protein expression of heme oxygenase-1, which were indicative of its Nrf2-inducing potential. Intriguingly, 25 μM luteolin reduced cell viability through apoptotic induction, which was intensified in p53-expressing cells while 1 μM oxaliplatin caused cell cycle arrest at G0/G1-phase via the p53/p21-dependent mechanism. Moreover, luteolin treatment was found to reduce oxaliplatin-treated p53-null cell viability and colony counts further, thereby demonstrating an additional effect of luteolin in the killing of human colorectal tumor HCT116 cells not expressing functional p53 protein. The findings suggest that luteolin can induce p53-mediated apoptosis regardless of oxaliplatin treatment and may eliminate oxaliplatin-resistant p53-null colorectal cells.

Highlights

The cellular redox status exists in a dynamic balance between production and elimination of reactive oxygen species (ROS) [1,2,3]
Oxaliplatin at concentrations of ≥0.5 μM reduced the viability of p53+/+ HCT116 cells to approximately 90%, whereas p53−/− HCT116 cells needed ≥2 μM oxaliplatin to achieve the same effect, indicating that p53+/+ HCT116 cells were more susceptible to oxaliplatin than p53−/−
We showed for the first time that luteolin, a naturally occurring nuclear factor E2-related factor 2 (Nrf2) activator, can enhance the chemotherapeutic effect of oxaliplatin in HCT116 human colorectal cancer cells, potentially by shifting oxaliplatin-induced cell cycle arrest to apoptosis

Summary

Introduction

The cellular redox status exists in a dynamic balance between production and elimination of reactive oxygen species (ROS) [1,2,3]. A cell undergoing aerobic metabolism is essentially exposed to ROS, the redox balance can be controlled by the cellular antioxidant defense response. When ROS production exceeds antioxidant capability, oxidative stress is generated. The cellular defense against the oxidative stress is mainly achieved by activation of the nuclear factor E2-related factor 2/antioxidant response element (Nrf2/ARE). Most chemopreventive compounds including dietary phytochemicals have been reported to remove intracellular ROS by increasing the expression of genes involved in the antioxidant defense system, which, in turn, is activated by Nrf, a transcription factor liberated from

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