Epicatechin stimulates mitochondrial activity and selectively sensitizes cancer cells to radiation.

Gabriele Multhoff,Hosam A Elbaz,Jenney Liu,Maik Hüttemann,Steven P Zielske,Deborah A Antwih,Icksoo Lee

doi:10.1371/journal.pone.0088322

Gabriele Multhoff, Hosam A Elbaz + Show 5 more

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https://doi.org/10.1371/journal.pone.0088322

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Abstract

Radiotherapy is the treatment of choice for solid tumors including pancreatic cancer, but the effectiveness of treatment is limited by radiation resistance. Resistance to chemotherapy or radiotherapy is associated with reduced mitochondrial respiration and drugs that stimulate mitochondrial respiration may decrease radiation resistance. The objectives of this study were to evaluate the potential of (-)-epicatechin to stimulate mitochondrial respiration in cancer cells and to selectively sensitize cancer cells to radiation. We investigated the natural compound (-)-epicatechin for effects on mitochondrial respiration and radiation resistance of pancreatic and glioblastoma cancer cells using a Clark type oxygen electrode, clonogenic survival assays, and Western blot analyses. (-)-Epicatechin stimulated mitochondrial respiration and oxygen consumption in Panc-1 cells. Human normal fibroblasts were not affected. (-)-Epicatechin sensitized Panc-1, U87, and MIA PaCa-2 cells with an average radiation enhancement factor (REF) of 1.7, 1.5, and 1.2, respectively. (-)-Epicatechin did not sensitize normal fibroblast cells to ionizing radiation with a REF of 0.9, suggesting cancer cell selectivity. (-)-Epicatechin enhanced Chk2 phosphorylation and p21 induction when combined with radiation in cancer, but not normal, cells. Taken together, (-)-epicatechin radiosensitized cancer cells, but not normal cells, and may be a promising candidate for pancreatic cancer treatment when combined with radiation.

Highlights

Radiotherapy is ideal for many solid tumors because of its localized cytotoxic effect
Flavonoids were shown to sensitize cancer cells to chemotherapy and radiotherapy, but more often have been shown to exhibit radioprotective effects on normal tissues [8,9,10,11]. (-)-Epicatechin is a monomeric flavanol that is a natural compound found in many fruits and vegetables, in particular in cocoa and green tea [6,12], and it exhibits several beneficial effects to human health [13]
Combination with ionizing radiation stimulated Chk2 phosphorylation, p21 expression, and increased apoptosis, in cancer cells. These results suggest that (-)-epicatechin exhibits the potential to improve the therapeutic outcome for cancer patients by augmenting conventional radiotherapy

Summary

Introduction

Radiotherapy is ideal for many solid tumors because of its localized cytotoxic effect. The Warburg effect, in which mitochondrial respiration is suppressed even in the presence of oxygen, and aerobic glycolysis is stimulated, is believed to mediate resistance to chemotherapy and radiotherapy in solid tumors [2,3]. Treatment with ionizing radiation stimulates mitochondrial respiration and increases reactive oxygen species (ROS) production in cancer cells [4]. We here show that (-)-epicatechin stimulated cytochrome c oxidase (COX) activity and mitochondrial respiration in pancreatic cancer cells. Combination with ionizing radiation stimulated Chk (checkpoint kinase 2) phosphorylation, p21 expression, and increased apoptosis, in cancer cells. These results suggest that (-)-epicatechin exhibits the potential to improve the therapeutic outcome for cancer patients by augmenting conventional radiotherapy

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