Distinct Modulatory Effects of Fever-Range Hyperthermia on the Response of Breast Cancer Cells and Macrophages to Mistletoe (Viscum album L.) Extract.

Henryk M Kozłowski,Sylwia Wrotek,Małgorzata Pawlikowska,Justyna Sobocińska,Artur Dzialuk,Tomasz Jędrzejewski

doi:10.3390/ph14060551

Abstract

Heat utility as a critical component of fever is often ignored, although the symptom is observed in many medical conditions. Mistletoe extract (ME) is an adjunctive medication prescribed to cancer patients. The increase in body temperature is frequently observed in patients following ME administration. Nevertheless, the impact of this fever on the effectiveness of therapy is unknown. Therefore, we aimed to investigate the effect of fever-range temperatures on ME-treated breast cancer cells and macrophages. The cells were simultaneously stimulated with ME and subjected to fever-range hyperthermia (FRH; 39 °C or 41 °C). After co-treatment, the cell viability, generation of reactive oxygen species (ROS), cell cycle distribution, and production of pro-inflammatory factors (interleukin (IL)-1β, IL-6, and cyclooxygenase (COX)-2) were evaluated. The results showed that the exposure of ME-treated breast cancer cells to FRH at 39 °C resulted in a slight decrease in their viability, whereas FRH of 41 °C enhanced this effect. Only FRH of 41 °C induced minor changes in ROS level in ME-treated breast cancer cell lines. In ME-treated macrophages, FRH stimulated cell proliferation. The cell cycle distribution analysis showed a difference between cells cultured at 39 °C and 41 °C in all examined cell lines. Moreover, hyperthermia at 41 °C completely inhibited the ME-induced increase in IL-1β and IL-6 expression in MCF-7 breast cancer cells, whereas this effect was not observed in 4T1 breast cancer cells. In contrast, in ME-treated macrophages, FRH of 41 °C strongly up-regulated expression of the pro-inflammatory factors. We conclude that fever is an important component of ME therapy that differentially affects cancer and immune cells.

Highlights

Introduction iationsBreast cancer is the most common cancer and the primary cause of mortality due to cancer in females around the world
We found that the exposure of MCF-7 cells cultured at 37 ◦ C to Mistletoe extract (ME) alone decreased their viability compared to not-treated cells (p < 0.01), whereas the exposure of ME-treated MCF-7 cells to heat at 41 ◦ C enhances this reduction in cell viability (p < 0.001)
Having observed that both not-treated and treated with ME MCF-7 cells cultured at 41 ◦ C display a decrease in cell viability (Figure 1A), we wanted to determine whether this effect is associated with an increase in reactive oxygen species (ROS) production

Summary

Introduction

Breast cancer is the most common cancer and the primary cause of mortality due to cancer in females around the world. In spite of many improvements in the use of hormonal and adjuvant cytotoxic therapies for breast cancer patients, the reduction in mortality is still not satisfactory [1]. Mistletoe extract (ME) is the most frequently prescribed therapy as an adjunct to standard treatment regimens for various malignancies in Europe [2,3]. It is widely used based on its ability to reduce emotional stress. It is an immunostimulant, and its anticancer properties have been confirmed in experimental studies as well as clinical trials [3,4].

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