Transcutaneous Application of Carbon Dioxide (CO2) Enhances Chemosensitivity by Reducing Hypoxic Conditions in Human Malignant Fibrous Histiocytoma

Yasuo Onishi,Teruya Kawamoto

doi:10.4172/1948-5956.1000136

Abstract

Background: Tumor hypoxia is a common feature of various human malignancies. Hypoxia contributes to tumor progression, and is a major cause of tumor resistance to chemotherapy. Hypoxia-inducible factor (HIF)-1 is a key transcription factor in hypoxic responses, and regulates the transcription of genes that are involved in crucial aspects of cancer biology, including angiogenesis, cell survival, and invasion. We previously demonstrated that transcutaneous application of carbon dioxide (CO2) induced oxygenation in the treated tissue in vivo, therefore, we hypothesized that transcutaneous CO2 exposure could enhance the chemosensitivity by reducing hypoxia in a tumor tissue. The aim of this study was to examine the effect of oxygenation by transcutaneous application of CO2 on the therapeutic efficacy of doxorubicin (DOX) to treat human malignant fibrous histiocytoma (MFH) in vivo. Methods: In this study, we utilized a murine model of human MFH, and mice were randomly divided into four groups: control, CO2, DOX and combination (CO2 + DOX) treatment groups to examine the effect of transcutaneous application of CO2 on the hypoxic condition, and to assess the therapeutic effect of combination therapy using transcutaneous CO2and DOX treatment in vivo. Results: Transcutaneous application of CO2 treatment decreased HIF-1α expression in human MFH tumor tissues, suggesting that our transcutaneous CO2 treatment reduced the hypoxic conditions. Furthermore, transcutaneous CO2 treatment alone had an antitumoral effect, and increased the chemotherapeutic effect of DOX on MFH tumor growth in vivo, with no observable effects on body weight. Conclusions: Our findings in this study strongly indicate that our transcutaneous CO2 system has antitumor effects and can enhance the chemosensitivity of tumor cells by reducing the local hypoxic conditions.

Highlights

Musculoskeletal malignancies, high-grade sarcomas such as malignant fibrous histiocytoma (MFH), are clinically aggressive and demonstrate high metastatic behavior in various organs
Reduced hypoxic conditions enhanced the chemotherapeutic effect of DOX on human MFH cells in vitro
After 48 h of incubation, protein expression of Hypoxia-inducible factor (HIF)-1α was strongly increased in cells under hypoxic conditions (1% O2), whereas the expression was decreased in cells cultured under reoxygenated conditions (1% O2 and 20% O2) (Figure 2A)

Summary

Introduction

Musculoskeletal malignancies, high-grade sarcomas such as malignant fibrous histiocytoma (MFH), are clinically aggressive and demonstrate high metastatic behavior in various organs. Despite the higher response rate achieved in several studies, no multidrug regimen has demonstrated any advantage in terms of overall survival when compared with the single-agent, DOX [4]. There is evidence for a dose-response side effect of DOX treatment for soft tissue sarcoma. New strategies to enhance the therapeutic effect of DOX to treat high-grade sarcomas are needed. We previously demonstrated that transcutaneous application of carbon dioxide (CO2) induced oxygenation in the treated tissue in vivo, we hypothesized that transcutaneous CO2 exposure could enhance the chemosensitivity by reducing hypoxia in a tumor tissue. The aim of this study was to examine the effect of oxygenation by transcutaneous application of CO2 on the therapeutic efficacy of doxorubicin (DOX) to treat human malignant fibrous histiocytoma (MFH) in vivo

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