4.6 Article

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

期刊

MOLECULES
卷 27, 期 20, 页码 -

出版社

MDPI
DOI: 10.3390/molecules27207008

关键词

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

资金

  1. Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Science, ICT [505382022, 505312022]
  2. Basic Science Research Program through the NRF [NRF-2021R1F1A1055981, NRF-2020M2D9A2094153]

向作者/读者索取更多资源

The objective of this study was to investigate the potential anticancer and radiosensitizing effects of JNC-1043 in colorectal cancer cells. The results demonstrated that JNC-1043 inhibited cell proliferation, enhanced cell death and apoptosis, and increased mitochondrial ROS production when combined with gamma-ionizing radiation. These findings suggest that JNC-1043 acts as a radiosensitizer and exerts its anticancer effects by promoting apoptosis through mitochondrial ROS.
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 beta-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 gamma-ionizing radiation (IR) enhanced cell death. Treatment with JNC-1043 or IR alone induced cell death by 50 similar to 60%, whereas the combination of JNC-1043 and IR increased this cell death by more than 20 similar to 30%. Annexin V-propidium iodide assays showed that the combination of JNC-1043 and IR increased apoptosis by more 30 similar to 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.

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