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 1α/activating transcription factor 4 (PERK/eIF2α/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.
Highlights
Radiation therapy (RT) using ionizing radiation remains the mainstay treatment for solid tumors.new therapeutic radiosensitizers that can potentially enhance tumor cell killing duringRT are needed to improve treatment outcomes
1A/1B light chain 3B (LC3B) were used as indicators to screen for radiosensitizing activity; activating transcription factor 4 (ATF4) is a master transcription factor in the unfolded protein response (UPR), and LC3B is a key autophagy-related protein in Hep3B cells
This fraction was separated into seven subfractions through MPLC using an octadecyl-silica (ODS) column, and each fraction was examined for its effect on the expression of ATF4 and LC3B
Summary
Radiation therapy (RT) using ionizing radiation remains the mainstay treatment for solid tumors. Plant natural products that are capable of inhibiting or retarding the initiation of cancer by interacting with various cellular proteins have been considered as attractive candidate radiosensitizers [7] Compounds such as resveratrol [8], genistein [9], curcumin [10], and quercetin [11] have been proven to enhance the tumoricidal effect of radiotherapy in preclinical settings, their mechanism may vary. Based on these promising results, clinical studies have been conducted. Subsequent studies have focused on the identification of active pharmaceutical ingredients contained in the Agelas sponges (Figure S1), which led to the discovery of a potent natural radiosensitizer reported
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