Radiosensitization by Marine Sponge Agelas sp. Extracts in Hepatocellular Carcinoma Cells with Autophagy Induction

Changhoon Choi,Hyi-Seung Lee,Hee Chul Park,Arang Son,Yeon-Ju Lee

doi:10.1038/s41598-018-24745-w

Abstract

Although radiation therapy is an effective treatment modality in many cancers, there is an urgent need to develop therapeutic drugs capable of overcoming radioresistance or minimizing normal tissue toxicity. A wide variety of marine-derived bioactive compounds have been screened for anti-cancer drug discovery, but little is known regarding radiation therapy applications. In this study, six different extracts of marine sponges collected from the Micronesian sea were screened for anti-cancer and radiosensitizing activity. Two extracts derived from Agelas sponges collected off the coast of Kosrae and Chuuk, the Federated States of Micronesia significantly decreased clonogenic survival of hepatocellular carcinoma (HCC) cells after exposure to ionizing radiation (IR). The Agelas extracts augmented IR-induced apoptosis and accumulation of reactive oxygen species (ROS). Endoplasmic reticulum (ER) stress was increased via unfolded protein response stimulation, which induced autophagy. N-acetylcysteine, a ROS scavenger, diminished ER stress and autophagy induction effects. This result indicated that Agelas extracts may sensitize HCC cells to IR via ROS overproduction in vitro. Our findings suggest that the Agelas sp. may have potential utility in radiosensitizer development.

Highlights

Radiation therapy is a powerful treatment modality that is applied for approximately 50% of cancer patients
We selected six methanol extracts of marine sponges collected from the Micronesian ocean and identified marine-derived bioactivity with potential application for radiation therapy
Extracts with mild cytotoxic activity were prepared from Agelas sp. (#1 and #2) and Coscinoderma sp. (#5)

Summary

Introduction

Radiation therapy is a powerful treatment modality that is applied for approximately 50% of cancer patients. Much effort has been devoted to developing radiosensitizers, chemical compounds that potentiate the anti-cancer effect of radiation therapy, to increase local tumour control[9,10,11]. Hypoxia-targeted agents are another mainstay of radiosensitizers that alleviate resistance to radiation therapy[9]. Molecular-targeted agents have been shown to provide a synergistic effect with radiation therapy[11]. Comprehensive genomic studies have provided clues for molecular targeted therapeutics or new treatment strategies, but little success has been reported[14]. Applications of marine bioactive compounds have not been reported regarding radiation therapy. We obtained the extracts of marine species collected from the Micronesian ocean and evaluated the HCC cytotoxicity and radiation sensitization activity. We reported for the first time that marine sponges of the Agelas sp. may be a source of natural compounds with radiosensitizing activity

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Results

Conclusion