The Cytotoxicity of Doxorubicin Can Be Accelerated by a Combination of Hyperthermia and 5-Aminolevulinic Acid.

Hiromi Kurokawa,Hirofumi Matsui

doi:10.3390/antiox10101531

Hiromi Kurokawa, Hirofumi Matsui

Open Access

https://doi.org/10.3390/antiox10101531

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Journal: Antioxidants	Publication Date: Sep 27, 2021
Citations: 2	License type: CC BY 4.0

Affiliation: University of Tsukuba

Abstract

Chemotherapy is cytotoxic to various cancer cells and as well as normal cells. Thus, treatments that demonstrate selective cytotoxicity for cancer cells are desired. The combination of chemotherapy and other cancer therapies can show synergic cytotoxicity, which may be a clue to the nature of the involved cancer cellar-specific damage. We previously reported a phenomenon whereby mitochondrial reactive oxygen species (mitROS) regulate the expression transporters involved in anticancer drug transport and mitROS production is increased by hyperthermia. Moreover, the uptake of 5-aminolevulinic acid (ALA) was enhanced by the increase in mitROS production. In this study, we investigated whether the combination of hyperthermia and ALA can enhance the cytotoxicity of doxorubicin. MitROS production and ALA-derived porphyrin accumulation by hyperthermia (HT) were increased in a murine breast cancer cell line. The expression of solute carrier 15A1 (SLC15A1) upregulated and an ATP-binding cassette subfamily G member 2 (ABCG2) downregulated by HT. Since SLC15A1 is an accumulating transporter for ALA, while ABCG2 is a porphyrin efflux transporter, porphyrin accumulation was enhanced. ABCG2 is also a doxorubicin efflux transporter. Thus, ALA treatment accelerates the intracellular concentration of porphyrin, which acts as a competitive inhibitor of doxorubicin. Indeed, the amount of intracellular doxorubicin was increased by a combination of HT and ALA. The cytotoxicity of doxorubicin was also enhanced. This enhancement was observed in the human breast cancer cell line while it was not seen in normal cells. The combination of HT and ALA treatment can enhance the cancer-specific cytotoxicity of doxorubicin.

Highlights

Hyperthermia (HT) is a cancer treatment strategy based on the different heat sensitivities of normal and cancer tissues [1]
We previously reported that ATP-binding cassette subfamily G member 2 (ABCG2) expression is decreased transiently by pretreatment HT via increased production of mitochondrial reactive oxygen species [20]
The results of the MitoSOX assay showed that HT increased the fluorescence intensity of MitoSOX and intracellular mitochondrial reactive oxygen species (mitROS) production was increased by HT (Figure 2A,B)

Summary

Introduction

Hyperthermia (HT) is a cancer treatment strategy based on the different heat sensitivities of normal and cancer tissues [1]. Heterogeneity in the distribution of vasculature and blood flow increases the heat stress in cancer tissues [3]. Recent studies have reported that HT includes six components: blocking cell survival, inducing cellular stress response, modulating immune response, evading DNA repair, changing tumor microenvironment, and sensitization to radiation and chemotherapy [4]. Because the effect of HT alone is not sufficient for cancer treatment, it is used in combination with conventional therapies [5]. The effects of gemcitabine and cisplatin, as well as of gemcitabine and 5-fluorouracil combination chemotherapies, were reported to be enhanced when used together with HT treatment [8,9]

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