JNC-1043, a Novel Podophyllotoxin Derivative, Exerts Anticancer Drug and Radiosensitizer Effects in Colorectal Cancer Cellsopen access
- Authors
- Kwon, Jin-Hee; Lee, Na-Gyeong; Kang, A-Ram; Ahn, In-Ho; Choi, In-Young; Song, Jie-Young; Hwang, Sang-Gu; Um, Hong-Duck; Choi, Jong-Ryoo; Kim, Joon; Park, Jong Kuk
- Issue Date
- Oct-2022
- Publisher
- MDPI
- Keywords
- JNC-1043; radiosensitizer; topoisomerase inhibitor; ROS; apoptosis; colorectal cancer
- Citation
- MOLECULES, v.27, no.20
- Indexed
- SCIE
SCOPUS
- Journal Title
- MOLECULES
- Volume
- 27
- Number
- 20
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/146571
- DOI
- 10.3390/molecules27207008
- ISSN
- 1420-3049
- 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 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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