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Lee, Haesol,Lee, Dahae,Kang, Ki Sung,Song, Ji Hoon,Choi, You-Kyoung MDPI AG 2018 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.19 No.3
<P>Cisplatin is a well-known anticancer drug frequently used for treating solid tumors, including ovarian, testicular, bladder, and cervical tumors. However, usage of cisplatin has been limited because of its adverse effects, particularly nephrotoxicity. Therefore, the present study sought to investigate the protective effect of formononetin against cisplatin-induced cytotoxicity in LLC-PK1 pig kidney epithelial cells as well as the anticancer effect of cisplatin in three different human cervical cancer cell lines, including HeLa, SiHa, and CaSKi cells. We first demonstrated that formononetin strongly prevented cisplatin-induced LLC-PK1 cell death. Although formononetin had no anticancer effect, it did not interrupt the anticancer effect of cisplatin in human cervical carcinoma cell lines. Furthermore, the treatment with formononetin reduced reactive oxygen species (ROS) accumulation and chromatin condensation. The percentage of Annexin V-positive cells also increased following cisplatin treatment. Finally, formononetin-inhibited c-Jun N-terminal kinase (JNK) phosphorylation, cleavage of caspase-8 and caspase-3, and the ratio of Bax to Bcl-2 increased with cisplatin. Taken together, these findings suggest that formononetin may be a possible option to prevent nephrotoxicity induced by cisplatin during treatment for cervical cancer.</P>
Lee, Dahae,Lee, Dong-Soo,Jung, Kiwon,Hwang, Gwi Seo,Lee, Hye Lim,Yamabe, Noriko,Lee, Hae-Jeong,Eom, Dae-Woon,Kim, Ki Hyun,Kang, Ki Sung The Korean Society of Ginseng 2018 Journal of Ginseng Research Vol.42 No.1
Background: The aim of the present study was to evaluate the potential protective effects of six ginsenosides (Rb1, Rb2, Rc, Rd, Rg1, and Rg3) isolated from Panax ginseng against tacrolimus (FK506)-induced apoptosis in renal proximal tubular LLC-PK1 cells. Methods: LLC-PK1 cells were treated with FK506 and ginsenosides, and cell viability was measured. Protein expressions of mitogen-activated protein kinases, caspase-3, and kidney injury molecule-1 (KIM-1) were evaluated by Western blotting analyses. The number of apoptotic cells was measured using an image-based cytometric assay. Results: Reduction in cell viability by $60{\mu}M$ FK506 was ameliorated significantly by cotreatment with ginsenosides Rg1 and Rb1. The phosphorylation of p38, extracellular signal-regulated kinases, and KIM-1, and cleavage of caspase-3, increased markedly in LLC-PK1 cells treated with FK506 and significantly decreased after cotreatment with ginsenoside Rb1. The number of apoptotic cells decreased by 6.0% after cotreatment with ginsenoside Rb1 ($10{\mu}M$ and $50{\mu}M$). Conclusion: The antiapoptotic effects of ginsenoside Rb1 on FK506-induced apoptosis were mediated by the inhibition of mitogen-activated protein kinases and caspase activation.
MTA1 is a novel regulator of autophagy that induces tamoxifen resistance in breast cancer cells
Lee, Min-Ho,Koh, Dahae,Na, Hyelin,Ka, Na-Lee,Kim, Seungsu,Kim, Hyeon-Ji,Hong, Sungyoul,Shin, Young Kee,Seong, Je Kyung,Lee, Mi-Ock TaylorFrancis 2018 AUTOPHAGY Vol.14 No.5
<P><B>ABSTRACT</B></P><P>Tamoxifen is commonly used to treat patients with ESR/ER-positive breast cancer, but its therapeutic benefit is limited by the development of resistance. Recently, alterations in macroautophagy/autophagy function were demonstrated to be a potential mechanism for tamoxifen resistance. Although MTA1 (metastasis-associated 1) has been implicated in breast tumorigenesis and metastasis, its role in endocrine resistance has not been studied. Here, we report that the level of MTA1 expression was upregulated in the tamoxifen resistant breast cancer cell lines MCF7/TAMR and T47D/TR, and knockdown of MTA1 sensitized the cells to 4-hydroxytamoxifen (4OHT). Moreover, knockdown of MTA1 significantly decreased the enhanced autophagy flux in the tamoxifen resistant cell lines. To confirm the role of MTA1 in the development of tamoxifen resistance, we established a cell line, MCF7/MTA1, which stably expressed MTA1. Compared with parental MCF7, MCF7/MTA1 cells were more resistant to 4OHT-induced growth inhibition in vitro and in vivo, and showed increased autophagy flux and higher numbers of autophagosomes. Knockdown of ATG7 or cotreatment with hydroxychloroquine, an autophagy inhibitor, restored sensitivity to 4OHT in both the MCF7/MTA1 and tamoxifen resistant cells. In addition, AMP-activated protein kinase (AMPK) was activated, probably because of an increased AMP:ATP ratio and decreased expression of mitochondrial electron transport complex components. Finally, publicly available breast cancer patient datasets indicate that MTA1 levels correlate with poor prognosis and development of recurrence in patients with breast cancer treated with tamoxifen. Overall, our findings demonstrated that MTA1 induces AMPK activation and subsequent autophagy that could contribute to tamoxifen resistance in breast cancer.</P>
Lee, Seulah,Park, Jun Yeon,Lee, Dahae,Seok, Soonja,Kwon, Yeon Jung,Jang, Tae Su,Kang, Ki Sung,Kim, Ki Hyun Elsevier 2017 Bioorganic & medicinal chemistry letters Vol.27 No.17
<P><B>Abstract</B></P> <P> <I>Calvatia</I> species, also known as puffball mushrooms, are common sources of food worldwide. <I>Calvatia nipponica</I> (Agaricaceae) is one of the most rare species in the <I>Calvatia</I> genus. It was first validated in 2008. Due to its scarcity, <I>C. nipponica</I> has never been chemically investigated. Its recent discovery in Korea allowed to conduct this study, and using bioactivity-guided fractionation for antiangiogenic activity, chemical investigation of the MeOH extract of the fruiting bodies of <I>C. nipponica</I> led to the isolation of five alkaloids (<B>1</B>–<B>5</B>) and two phenolic compounds (<B>6</B>–<B>7</B>). This is the first study to report the chemical investigation of <I>C. nipponica</I>, and compound <B>1</B> was previously reported as chemically synthesized only until our report of its isolation and identification from natural sources. The structure of <B>1</B> was determined by spectroscopic analysis by 1D and 2D NMR spectra and HR-MS. All compounds (<B>1</B>–<B>7</B>) were tested for inhibition of angiogenesis using human umbilical vein endothelial cells (HUVECs). Compounds <B>2</B>, <B>4</B> and <B>5</B> significantly inhibited the promotion of angiogenesis in HUVECs. Compound <B>5</B> showed the most potent inhibition via downregulation of VEGF, p38 and ERK signaling pathways. These results suggested that the rare mushroom <I>C. nipponica</I> might be beneficial in antiangiogenesis therapy for cancer treatment.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
Dahae Lee,Ranhee Kim,So-Ri Son,Ji-Young Kim,Sungyoul Choi,Ki Sung Kang,Dae Sik Jang The Korean Society of Ginseng 2023 Journal of Ginseng Research Vol.47 No.2
Background: Here, we aimed to assess the inhibitory effect of a new compound from Panax ginseng on the migration of human ovarian cancer cells and tube formation of human umbilical vein endothelial cells (HUVECs). Methods: A new compound, ginsenglactone A (1), was isolated from ginseng roots, together with seven known compounds (2-8). Spectroscopic data were used to elucidate the chemical structure of 1. The tubular structure formation in HUVECs was assessed by Mayer's hematoxylin staining. The migration of A2780 cells was evaluated using the scratch wound healing assay. Results: HUVECs treated with 1 had the statistically significant decrease in tubular structure formation compared to the HUVECs treated with compounds 2-8. This effect was enhanced by co-treatment with inhibitors for phosphatidylinositol 3-kinase (PI3K) (LY294002) and extracellular signal-regulated kinase (ERK) (U0126). Treatment with 1 decreased the expression of phosphorylation of ERK, PI3K, vascular endothelial growth factor receptor2 (VEGFR2), Akt, and mammalian target of rapamycin (mTOR). In addition, the ability of A2780 cells to cover the scratched area were also decreased. This effect was enhanced by co-treatment with U0126. Lastly, treatment with 1 decreased the phosphorylation of ERK, matrix metalloproteinase-9 (MMP-9), and MMP-2. Conclusion: These results suggest that ginsenglactone A is a potential inhibitor of HUVEC tubular structure formation and A2780 cellular migration, which may be helpful for understanding its anticancer mechanism.
Protective effect of Korean Red Ginseng against FK506-induced damage in LLC-PK1 cells
Lee, Dahae,Kang, Ki Sung,Yu, Jae Sik,Woo, Jung-Yoon,Hwang, Gwi Seo,Eom, Dae-Woon,Baek, Seung-Hoon,Lee, Hye Lim,Kim, Ki Hyun,Yamabe, Noriko The Korean Society of Ginseng 2017 Journal of Ginseng Research Vol.41 No.3
Background: Compound FK506 is an immunosuppressant agent that is frequently used to prevent rejection of solid organs upon transplant. However, nephrotoxicity due to apoptosis and inflammatory response mediated by FK506 limit its usefulness. In this study, the protective effect of Korean Red Ginseng (KRG) against FK506-induced damage in LLC-PK1 pig kidney epithelial cells was investigated. Methods: LLC-PK1 cells were exposed to FK506 with KRG and cell viability was measured. Western blotting and RT-PCR analyses evaluated protein expression of MAPKs, caspase-3, and KIM-1. TLR-4 gene expression was assessed. Caspase-3 activities were also determined. The number of apoptotic cells was measured using an image-based cytometric assay. Results: The reduction in LLC-PK1 cell viability by $60{\mu}M$ FK506 was recovered by KRG cotreatment in a dose-dependent manner. The phosphorylation of p38, p44/42 MAPKs (ERK), KIM-1, cleaved caspase-3, and TLR-4 mRNA expression was increased markedly in LLC-PK1 cells treated with $60{\mu}M$ FK506. However, with the exception of p-ERK, elevated levels of p-p38, KIM-1, cleaved caspase-3, and TLR-4 mRNA expression were significantly decreased after cotreatment with KRG. Activity level of caspase-3 was also attenuated by KRG cotreatment. Moreover, image-based cytometric assay showed that apoptotic cell death was increased by $60{\mu}M$ FK506 treatment, whereas it was decreased after cotreatment with KRG. Conclusion: Taken together, these results suggest that the molecular mechanism of KRG in the FK506-induced nephrotoxicity may lead to the development of an adjuvant for the inhibition of adverse effect FK506 in the kidney.
Protective effect of Korean Red Ginseng against FK506-induced damage in LLC-PK1 cells
Dahae Lee,Ki Sung Kang,Jae Sik Yu,Jung-Yoon Woo,Gwi Seo Hwang,Dae-Woon Eom,Seung-Hoon Baek,Hye Lim Lee,Ki Hyun Kim,Noriko Yamabe 고려인삼학회 2017 Journal of Ginseng Research Vol.41 No.3
Background: Compound FK506 is an immunosuppressant agent that is frequently used to prevent rejection of solid organs upon transplant. However, nephrotoxicity due to apoptosis and inflammatory response mediated by FK506 limit its usefulness. In this study, the protective effect of Korean Red Ginseng (KRG) against FK506-induced damage in LLC-PK1 pig kidney epithelial cells was investigated. Methods: LLC-PK1 cells were exposed to FK506 with KRG and cell viability was measured. Western blotting and RT-PCR analyses evaluated protein expression of MAPKs, caspase-3, and KIM-1. TLR-4 gene expression was assessed. Caspase-3 activities were also determined. The number of apoptotic cells was measured using an image-based cytometric assay. Results: The reduction in LLC-PK1 cell viability by 60mM FK506 was recovered by KRG cotreatment in a dose-dependent manner. The phosphorylation of p38, p44/42 MAPKs (ERK), KIM-1, cleaved caspase-3, and TLR-4 mRNA expression was increased markedly in LLC-PK1 cells treated with 60mM FK506. However, with the exception of p-ERK, elevated levels of p-p38, KIM-1, cleaved caspase-3, and TLR-4 mRNA expression were significantly decreased after cotreatment with KRG. Activity level of caspase-3 was also attenuated by KRG cotreatment. Moreover, image-based cytometric assay showed that apoptotic cell death was increased by 60mM FK506 treatment, whereas it was decreased after cotreatment with KRG. Conclusion: Taken together, these results suggest that the molecular mechanism of KRG in the FK506-induced nephrotoxicity may lead to the development of an adjuvant for the inhibition of adverse effect FK506 in the kidney.