Ginsenoside Rp1, A Ginsenoside Derivative, Augments Anti-Cancer Effects of Actinomycin D via Downregulation of an AKT-SIRT1 Pathway
Novel strategies for overcoming multidrug resistance are urgently needed to improve chemotherapy success and reduce side effects. Ginsenosides, the main active components of <i>Panax ginseng</i>, display anti-cancer properties and reverse drug resistance; however, the biological pathways...
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MDPI AG
2020-03-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/12/3/605 |
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| author | Un-Jung Yun In Hye Lee Jae-Seon Lee Jaegal Shim Yong-Nyun Kim |
| author_facet | Un-Jung Yun In Hye Lee Jae-Seon Lee Jaegal Shim Yong-Nyun Kim |
| author_sort | Un-Jung Yun |
| collection | DOAJ |
| description | Novel strategies for overcoming multidrug resistance are urgently needed to improve chemotherapy success and reduce side effects. Ginsenosides, the main active components of <i>Panax ginseng</i>, display anti-cancer properties and reverse drug resistance; however, the biological pathways mediating this phenomenon remain incompletely understood. This study aimed to evaluate the anti-cancer effects of ginsenoside Rp1, actinomycin D (ActD), and their co-administration in drug-resistant cells and murine xenograft model of colon cancer, and explore the underlying mechanisms. ActD increased expression and activity of SIRT1 in drug-resistant LS513 colon cancer, OVCAR8-DXR ovarian cancer, and A549-DXR lung cancer cells, but not in ActD-sensitive SW620 colon cancer cells. Inhibition of SIRT1, either pharmacologically, with EX527 or through siRNA, stimulated p53 acetylation and apoptosis in LS513 cells when treated with ActD. ActD also increased AKT activation in drug-resistant cells. Inhibition of AKT abrogated ActD-induced upregulation of SIRT1, suggesting that the AKT-SIRT1 pathway is important in ActD resistance. Rp1 inhibited both ActD-induced AKT activation and SIRT1 upregulation and re-sensitized the cells to ActD. Synergistic antitumor effects of Rp1 with ActD were also observed in vivo. Our results suggest that combining Rp1 with chemotherapeutic agents could circumvent drug resistance and improve treatment efficacy. |
| first_indexed | 2024-03-12T18:15:03Z |
| format | Article |
| id | doaj.art-3b09ad98acde4e87a1b1552b0866ac31 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T18:15:03Z |
| publishDate | 2020-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-3b09ad98acde4e87a1b1552b0866ac312023-08-02T09:09:30ZengMDPI AGCancers2072-66942020-03-0112360510.3390/cancers12030605cancers12030605Ginsenoside Rp1, A Ginsenoside Derivative, Augments Anti-Cancer Effects of Actinomycin D via Downregulation of an AKT-SIRT1 PathwayUn-Jung Yun0In Hye Lee1Jae-Seon Lee2Jaegal Shim3Yong-Nyun Kim4Division of Translational Science, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si 10408, KoreaDepartment of Life Science, Ewha Womans University, Seoul 03760, KoreaDepartment of Molecular Medicine, College of Medicine, Inha University, Incheon 22212, KoreaDivision of Translational Science, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si 10408, KoreaDivision of Translational Science, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si 10408, KoreaNovel strategies for overcoming multidrug resistance are urgently needed to improve chemotherapy success and reduce side effects. Ginsenosides, the main active components of <i>Panax ginseng</i>, display anti-cancer properties and reverse drug resistance; however, the biological pathways mediating this phenomenon remain incompletely understood. This study aimed to evaluate the anti-cancer effects of ginsenoside Rp1, actinomycin D (ActD), and their co-administration in drug-resistant cells and murine xenograft model of colon cancer, and explore the underlying mechanisms. ActD increased expression and activity of SIRT1 in drug-resistant LS513 colon cancer, OVCAR8-DXR ovarian cancer, and A549-DXR lung cancer cells, but not in ActD-sensitive SW620 colon cancer cells. Inhibition of SIRT1, either pharmacologically, with EX527 or through siRNA, stimulated p53 acetylation and apoptosis in LS513 cells when treated with ActD. ActD also increased AKT activation in drug-resistant cells. Inhibition of AKT abrogated ActD-induced upregulation of SIRT1, suggesting that the AKT-SIRT1 pathway is important in ActD resistance. Rp1 inhibited both ActD-induced AKT activation and SIRT1 upregulation and re-sensitized the cells to ActD. Synergistic antitumor effects of Rp1 with ActD were also observed in vivo. Our results suggest that combining Rp1 with chemotherapeutic agents could circumvent drug resistance and improve treatment efficacy.https://www.mdpi.com/2072-6694/12/3/605actinomycin daktcombination therapycolon cancerginsenoside rp1multidrug resistancesirt1 |
| spellingShingle | Un-Jung Yun In Hye Lee Jae-Seon Lee Jaegal Shim Yong-Nyun Kim Ginsenoside Rp1, A Ginsenoside Derivative, Augments Anti-Cancer Effects of Actinomycin D via Downregulation of an AKT-SIRT1 Pathway Cancers actinomycin d akt combination therapy colon cancer ginsenoside rp1 multidrug resistance sirt1 |
| title | Ginsenoside Rp1, A Ginsenoside Derivative, Augments Anti-Cancer Effects of Actinomycin D via Downregulation of an AKT-SIRT1 Pathway |
| title_full | Ginsenoside Rp1, A Ginsenoside Derivative, Augments Anti-Cancer Effects of Actinomycin D via Downregulation of an AKT-SIRT1 Pathway |
| title_fullStr | Ginsenoside Rp1, A Ginsenoside Derivative, Augments Anti-Cancer Effects of Actinomycin D via Downregulation of an AKT-SIRT1 Pathway |
| title_full_unstemmed | Ginsenoside Rp1, A Ginsenoside Derivative, Augments Anti-Cancer Effects of Actinomycin D via Downregulation of an AKT-SIRT1 Pathway |
| title_short | Ginsenoside Rp1, A Ginsenoside Derivative, Augments Anti-Cancer Effects of Actinomycin D via Downregulation of an AKT-SIRT1 Pathway |
| title_sort | ginsenoside rp1 a ginsenoside derivative augments anti cancer effects of actinomycin d via downregulation of an akt sirt1 pathway |
| topic | actinomycin d akt combination therapy colon cancer ginsenoside rp1 multidrug resistance sirt1 |
| url | https://www.mdpi.com/2072-6694/12/3/605 |
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