Therapeutic Potential of (-)-Agelamide D, a Diterpene Alkaloid from the Marine Sponge Agelas sp., as a Natural Radiosensitizer in Hepatocellular Carcinoma Models SCIE SCOPUS

Cited 3 time in WEB OF SCIENCE Cited 3 time in Scopus
Title
Therapeutic Potential of (-)-Agelamide D, a Diterpene Alkaloid from the Marine Sponge Agelas sp., as a Natural Radiosensitizer in Hepatocellular Carcinoma Models
Author(s)
Choi, Changhoon; Cho, Yeonwoo; Son, Arang; Shin, Sung-Won; Lee, Yeon Ju; Park, Hee Chul
KIOST Author(s)
Lee, Yeon Ju(이연주)
Publication Year
2020-09
Abstract
Radiation therapy (RT) is an effective local treatment for unresectable hepatocellular carcinoma (HCC), but there are currently no predictive biomarkers to guide treatment decision for RT or adjuvant systemic drugs to be combined with RT for HCC patients. Previously, we reported that extracts of the marine sponge Agelas sp. may contain a natural radiosensitizer for HCC treatment. In this study, we isolated (-)-agelamide D from Agelas extract and investigated the mechanism underlying its radiosensitization. (-)-Agelamide D enhanced radiation sensitivity of Hep3B cells with decreased clonogenic survival and increased apoptotic cell death. Furthermore, (-)-agelamide D increased the expression of protein kinase RNA-like endoplasmic reticulum kinase/inositol-requiring enzyme 1 alpha/activating transcription factor 4 (PERK/eIF2 alpha/ATF4), a key pathway of the unfolded protein response (UPR) in multiple HCC cell lines, and augmented radiation-induced UPR signaling. In vivo xenograft experiments confirmed that (-)-agelamide D enhanced tumor growth inhibition by radiation without systemic toxicity. Immunohistochemistry results showed that (-)-agelamide D further increased radiation-induced ATF4 expression and apoptotic cell death, which was consistent with our in vitro finding. Collectively, our results provide preclinical evidence that the use of UPR inducers such as (-)-agelamide D may enhance the efficacy of RT in HCC management.
ISSN
1660-3397
URI
https://sciwatch.kiost.ac.kr/handle/2020.kiost/37594
DOI
10.3390/md18100500
Bibliographic Citation
MARINE DRUGS, v.18, no.10, 2020
Publisher
MDPI
Subject
UNFOLDED PROTEIN RESPONSE; RADIOTHERAPY; RESISTANCE; GLIOBLASTOMA; INHIBITION; ACTIVATION; ROTAMERS; PATHWAY; ATF6
Keywords
(− )-agelamide D; radiation therapy; hepatocellular carcinoma; unfolded protein response (UPR); activating transcription factor 4 (ATF4)
Type
Article
Language
English
Document Type
Article
Publisher
MDPI
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