JNC-1043, a Novel Podophyllotoxin Derivative, Exerts Anticancer Drug and Radiosensitizer Effects in Colorectal Cancer Cells

Jin Hee Kwon, Na Gyeong Lee, A. Ram Kang, In Ho Ahn, In Young Choi, Jie Young Song, Sang Gu Hwang, Hong Duck Um, Jong Ryoo Choi, Joon Kim, Jong Kuk Park

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    5 Citations (Scopus)

    Abstract

    The objective of this study was to determine whether (5S)-5-(4-benzyloxy-3,5-dimethoxy-phenyl)-5,9-dihydro-8H-furo [3’,4’:6,7] naphtho [2,3-d] [1,3]dioxol-6-one (JNC-1043), which is a novel chemical derivative of β-apopicropodophyllin, acts as a novel potential anticancer reagent and radiosensitizer in colorectal cancer (CRC) cells. Firstly, we used MTT assays to assess whether JNC-1043 could inhibit the cell proliferation of HCT116 and DLD-1 cells. The IC50 values of these cell lines were calculated as 114.5 and 157 nM, respectively, at 72 h of treatment. Using doses approximating the IC50 values, we tested whether JNC-1043 had a radiosensitizing effect in the CRC cell lines. Clonogenic assays revealed that the dose-enhancement ratios (DER) of HCT116 and DLD-1 cells were 1.53 and 1.25, respectively. Cell-counting assays showed that the combination of JNC-1043 and γ-ionizing radiation (IR) enhanced cell death. Treatment with JNC-1043 or IR alone induced cell death by 50~60%, whereas the combination of JNC-1043 and IR increased this cell death by more than 20~30%. Annexin V-propidium iodide assays showed that the combination of JNC-1043 and IR increased apoptosis by more 30~40% compared to that induced by JNC-1043 or IR alone. DCFDA- and MitoSOX-based assays revealed that mitochondrial ROS production was enhanced by the combination of JNC-1043 and IR. Finally, we found that suppression of ROS by N-acetylcysteine (NAC) blocked the apoptotic cell death induced by the combination of JNC-1043 and IR. The xenograft model also indicated that the combination of JNC-1043 and IR increased apoptotic cell death in tumor mass. These results collectively suggest that JNC-1043 acts as a radiosensitizer and exerts anticancer effects against CRC cells by promoting apoptosis mediated by mitochondrial ROS.

    Original languageEnglish
    Article number7008
    JournalMolecules
    Volume27
    Issue number20
    DOIs
    Publication statusPublished - 2022 Oct

    Bibliographical note

    Funding Information:
    This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT (505382022 and 505312022), and by the Basic Science Research Program through the NRF (NRF-2021R1F1A1055981 and NRF-2020M2D9A2094153).

    Publisher Copyright:
    © 2022 by the authors.

    Keywords

    • JNC-1043
    • ROS
    • apoptosis
    • colorectal cancer
    • radiosensitizer
    • topoisomerase inhibitor

    ASJC Scopus subject areas

    • Analytical Chemistry
    • Chemistry (miscellaneous)
    • Molecular Medicine
    • Pharmaceutical Science
    • Drug Discovery
    • Physical and Theoretical Chemistry
    • Organic Chemistry

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