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De, Umasankar,Son, Ji Yeon,Sachan, Richa,Park, Yu Jin,Kang, Dongwan,Yoon, Kyungsil,Lee, Byung Mu,Kim, In Su,Moon, Hyung Ryong,Kim, Hyung Sik MDPI 2018 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.19 No.9
<P>We previously discovered a novel sirtuin (SIRT) inhibitor, MHY2256, that exerts anticancer activity through p53 acetylation in MCF-7 human breast cancer cells. We investigated the anticancer activity of MHY2256 against hormone-related cancer, an endometrial cancer with a poor prognosis. The IC<SUB>50</SUB> values of MHY2256 were shown to be much lower than those of salermide, a well-known SIRT inhibitor. Furthermore, MHY2256 significantly reduced the protein expression and activities of SIRT1, 2, and 3, with similar effects to salermide. Particularly, MHY2256 markedly inhibited tumor growth in a tumor xenograft mouse model of Ishikawa cancer cells. During the experimental period, there was no significant change in the body weight of mice treated with MHY2256. A detailed analysis of the sensitization mechanisms of Ishikawa cells revealed that late apoptosis was largely increased by MHY2256. Additionally, MHY2256 increased G1 arrest and reduced the number of cell cyclic-related proteins, suggesting that apoptosis by MHY2256 was achieved by cellular arrest. Particularly, p21 was greatly increased by MHY225656, suggesting that cell cycle arrest by p21 is a major factor in MHY2256 sensitization in Ishikawa cells. We also detected a significant increase in acetylated p53, a target protein of SIRT1, in Ishikawa cells after MHY2256 treatment. In a mouse xenograft model, MHY2256 significantly reduced tumor growth and weight without apparent side effects. These results suggest that MHY2256 exerts its anticancer activity through p53 acetylation in endometrial cancer and can be used for targeting hormone-related cancers.</P>
( Umasankar De ),( Soma Kundu ),( Nabanita Patra ),( Mee Young Ahn ),( Ji Hae Ahn ),( Ji Yeon Son ),( Jung Hyun Yoon ),( Hyung Ryoung Moon ),( Byung Mu Lee ),( Hyung Sik Kim ) 한국응용약물학회 2015 Biomolecules & Therapeutics(구 응용약물학회지) Vol.23 No.5
Histone deacetylase (HDAC) inhibitors are considered novel agents for cancer chemotherapy. We previously investigated MHY219, a new HDAC inhibitor, and its potent anticancer activity in human prostate cancer cells. In the present study, we evaluated MHY219 molecular mechanisms involved in the regulation of prostate cancer cell migration. Similar to suberanilohydroxamic acid (SAHA), MHY219 inhibited HDAC1 enzyme activity in a dose-dependent manner. MHY219 cytotoxicity was higher in LNCaP (IC50=0.67 μM) than in DU145 cells (IC50=1.10 μM) and PC3 cells (IC50=5.60 μM) after 48 h of treatment. MHY219 significantly inhibited the HDAC1 protein levels in LNCaP and DU145 cells at high concentrations. However, inhibitory effects of MHY219 on HDAC proteins levels varied based on the cell type. MHY219 significantly inhibited LNCaP and DU145 cells migration by downregulation of matrix metalloprotease-1 (MMP-1) and MMP-2 and induction of tissue inhibitor of metalloproteinases-1 (TIMP-1). These results suggest that MHY219 may potentially be used as an anticancer agent to block cancer cell migration through the repression of MMP-1 and MMP-2, which is related to the reduction of HDAC1.
De, Umasankar,Son, Ji Yeon,Jeon, Yukyoung,Ha, Song-Yi,Park, Yu Jin,Yoon, Sungpil,Ha, Ki-Tae,Choi, Wahn Soo,Lee, Byung Mu,Kim, In Su,Kwak, Jong Hwan,Kim, Hyung Sik Elsevier 2019 Food and chemical toxicology Vol.123 No.-
<P><B>Abstract</B></P> <P>Plumbagin (5-hydroxy-2-methyl-1,4-naphthaquinone) has displayed antitumor activity <I>in vitro</I> and in animal models; however, the underlying molecular mechanisms have not been fully explored. The aim of this study was to investigate the anticancer effects of plumbagin isolated from <I>Nepenthes alata</I> against MCF-7 breast cancer cells. We examined the cytotoxicity, cell cycle regulation, apoptotic cell death, and generation of intracellular reactive oxygen species (ROS) in MCF-7 cells. Plumbagin exhibited potent cytotoxicity in MCF-7 cells (wild-type p53) compared to that in SK-OV-3 (null-type) human epithelial ovarian cancer cells. Specifically, plumbagin upregulated the expression of p21<SUP>CIP1/WAF1</SUP> in MCF-7 cells, causing cell cycle arrest in the G2/M phase through inhibition of cyclin B1 levels. Plumbagin also significantly increased the ratio of Bax/Bcl-2 and release of cytochrome c, resulting in apoptotic cell death in MCF-7 cells. Furthermore, plumbagin dramatically increased the intracellular ROS level, whereas pretreatment with the ROS scavenger N-acetyl cysteine protected against plumbagin-induced cytotoxicity, suggesting that ROS formation plays a pivotal role in antitumor activity in MCF-7 cells. In mice bearing MCF-7 cell xenografts, plumbagin significantly reduced tumor growth and weight without apparent side effects. We therefore concluded that plumbagin exerts anticancer activity against MCF-7 cells through the generation of intracellular ROS, resulting in the induction of apoptosis via a p53-dependent pathway. This study thus identifies a new anticancer mechanism of plumbagin against p53-dependent breast cancer cells and suggests a novel strategy for overcoming of breast cancer therapy.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Plumbagin, first isolated from <I>N. alata</I>, exhibits anticancer activity in human breast cancer MCF-7 cells. </LI> <LI> ROS generation contributes to the cytotoxicity of plumbagin against MCF7 cells. </LI> <LI> Plumbagin act as a lead molecule for new anticancer drug against breast cancer patients. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
De, Umasankar,Kundu, Soma,Patra, Nabanita,Ahn, Mee Young,Ahn, Ji Hae,Son, Ji Yeon,Yoon, Jung Hyun,Moon, Hyung Ryoung,Lee, Byung Mu,Kim, Hyung Sik The Korean Society of Applied Pharmacology 2015 Biomolecules & Therapeutics(구 응용약물학회지) Vol.23 No.5
Histone deacetylase (HDAC) inhibitors are considered novel agents for cancer chemotherapy. We previously investigated MHY219, a new HDAC inhibitor, and its potent anticancer activity in human prostate cancer cells. In the present study, we evaluated MHY219 molecular mechanisms involved in the regulation of prostate cancer cell migration. Similar to suberanilohydroxamic acid (SAHA), MHY219 inhibited HDAC1 enzyme activity in a dose-dependent manner. MHY219 cytotoxicity was higher in LNCaP ($IC_{50}=0.67{\mu}M$) than in DU145 cells ($IC_{50}=1.10{\mu}M$) and PC3 cells ($IC_{50}=5.60{\mu}M$) after 48 h of treatment. MHY219 significantly inhibited the HDAC1 protein levels in LNCaP and DU145 cells at high concentrations. However, inhibitory effects of MHY219 on HDAC proteins levels varied based on the cell type. MHY219 significantly inhibited LNCaP and DU145 cells migration by down-regulation of matrix metalloprotease-1 (MMP-1) and MMP-2 and induction of tissue inhibitor of metalloproteinases-1 (TIMP-1). These results suggest that MHY219 may potentially be used as an anticancer agent to block cancer cell migration through the repression of MMP-1 and MMP-2, which is related to the reduction of HDAC1.
Roh, Taehyun,De, Umasankar,Lim, Seong Kwang,Kim, Min Kook,Choi, Seul Min,Lim, Duck Soo,Yoon, Sungpil,Kacew, Sam,Kim, Hyung Sik,Lee, Byung-Mu Elsevier 2018 Food and chemical toxicology Vol.114 No.-
<P><B>Abstract</B></P> <P>The detoxifying effect of pyridoxine against acetaminophen (APAP)-induced hepatotoxicity was investigated. HepG2 cells were co-treated with APAP and pyridoxine to compare with betaine or methionine for 24 h. LDH, ALT and AST activities were measured to determine direct cells damage <I>in vitro</I> and in vivo. Lipid peroxidation, antioxidant enzymes activity, and glutathione level were measured. Cytochrome c releaseand procaspase-3, cleaved caspase-3, Bcl-2, or Bax protein levels were measured to determine APAP-induced apoptotic cell death. Pyridoxine treatment significantly increased cell viability and decreased leakage of LDH activity against APAP-induced hepatotoxicity in HepG2 cells. ALT and AST activities were dose-dependently reduced by pyridoxine treatment compared to APAP-treated group. Significant increases in activities of GST and GPx were observed after co-treatment with APAP and pyridoxine. Although APAP-induced Nrf2 and HO-1 expression levels were gradually reduced in HepG2 cells by pyridoxine treatment, induction of antioxidant enzymes activities were dose-dependently increased. These protected effects of pyridoxine against APAP-induced hepatoxicity were closely associated with suppression of APAP-induced oxidative stress and apoptotic cell death in HepG2 cells. These data indicated that the protective action of pyridoxine against hepatic cell injuries was involved in the direct antioxidant activity which provides a pivotal mechanism for its potential hepatoprotective action.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Pyridoxine decreased LDH, ALT and AST activities against APAP-induced hepatotoxicity <I>in vitro</I> and in vivo. </LI> <LI> Increases in antioxidant enzymes (GST and GPx) and GSH levels were observed after co-treatment with APAP and pyridoxine. </LI> <LI> Cytochrome c and procaspase-3, Bcl-2, or Bax protein levels were measured to determine APAP-induced apoptotic cell death. </LI> <LI> The protective action of pyridoxine against hepatic cell injuries was involved in the direct antioxidant activity. </LI> <LI> Pyridoxine showed protective activity via HO-1 induction serving as a key player in APAP-induced cell survival pathway. </LI> </UL> </P>
Patra, Nabanita,De, Umasankar,Kang, Jin-Ah,Kim, Ji Mim,Ahn, Mee Young,Lee, Jaewon,Jung, Jee H.,Chung, Hae Young,Moon, Hyung Ryong,Kim, Hyung Sik Elsevier 2011 european journal of pharmacology Vol.658 No.2
<P><B>Abstract</B></P><P>Here, we reported the synthesis of a novel topoisomerase II inhibitor, MHY336, which that has strong topoisomerase-mediated anticancer activity but fewer side effects than other topoisomerase II inhibitors. The catalytic activity of MHY336 on the topoisomerase II enzyme was the same as that of the etoposide. In a cell-free system, MHY336 exhibited a potent activity on scavenging of reactive oxygen species against 3-morpholinosydnonimine hydrochloride (SIN-1)-induced oxidative stress. An <I>in vitro</I> cell-based assay demonstrated that MHY336 significantly inhibited the proliferation of three prostate cancer cell lines, LNCaP, PC-3, and DU145 cells. Notably, the cytotoxicity of MHY336 was more potent in LNCaP cells (IC<SUB>50</SUB>=1.39μM) than in DU145 (IC<SUB>50</SUB>=2.94μM) and PC3 cells (IC<SUB>50</SUB>=3.72μM). Furthermore, MHY336 treatment induced similar levels of cytotoxicity compared to doxorubicin treatment (IC<SUB>50</SUB>=1.55μM) in LNCap cells. Also, MHY336 significantly down-regulated topoisomerase II alpha expression and up-regulated p53 expression in LNCaP cells (wild-type p53), whereas it up-regulated the topoisomerase II alpha protein in both DU145 and PC3 cells (p53 mutated or deleted). MHY336 induced G2/M or S phase arrest in LNCaP cells through a well-documented topoisomerase II-dependent mechanism. Further studies using Annexin V-FITC binding assay, DAPI staining, and Western blot analyses illustrated that MHY336 markedly induced apoptotic cell death via the mitochondria-mediated intrinsic pathway in LNCaP cells. These results suggest that MHY336 is an attractive chemotherapeutic agent because of its topoisomerase II-mediated anti-tumour activity in human prostate cancer.</P>
Shin, Youngmi,Han, Sangil,De, Umasankar,Park, Jihye,Sharma, Satyasheel,Mishra, Neeraj Kumar,Lee, Eui-Kyung,Lee, Youngil,Kim, Hyung Sik,Kim, In Su American Chemical Society 2014 Journal of organic chemistry Vol.79 No.19
<P>A ketone-assisted ruthenium-catalyzed selective amination of xanthones and chromones C–H bonds with sulfonyl azides is described. The reactions proceed efficiently with a broad range of substrates with excellent functional group compatibility. This protocol provides direct access to 1-aminoxanthones, 5-aminochromones, and 5-aminoflavonoid derivatives known to exhibit potent anticancer activity.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/joceah/2014/joceah.2014.79.issue-19/jo501709f/production/images/medium/jo-2014-01709f_0012.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/jo501709f'>ACS Electronic Supporting Info</A></P>
Tripathy, Suman Kumar,De, Umasankar,Dehury, Niranjan,Pal, Satyanarayan,Kim, Hyung Sik,Patra, Srikanta The Royal Society of Chemistry 2014 Dalton Transactions Vol.43 No.39
<P>Phpy bridged homodinuclear Ru–Ru (<B>1</B>) and heterodinuclear Ir–Ru complexes (<B>2</B>) have been developed. Complex <B>2</B> induces autophagy towards the cisplatin resistant human breast cancer (MCF7) cell line, whereas <B>1</B> is inactive.</P> <P>Graphic Abstract</P><P>Heterodinuclear Ir–Ru (<B>2</B>) with polypyridyl based phpy ligand shows autophagy induced cell death, whereas homodinuclear Ru–Ru (<B>1</B>) is inactive. <IMG SRC='http://pubs.rsc.org/services/images/RSCpubs.ePlatform.Service.FreeContent.ImageService.svc/ImageService/image/GA?id=c4dt01033g'> </P>
Tripathy, Suman Kumar,De, Umasankar,Dehury, Niranjan,Laha, Paltan,Panda, Manas Kumar,Kim, Hyung Sik,Patra, Srikanta The Royal Society of Chemistry 2016 Dalton Transactions Vol.45 No.38
<P>Six mononuclear Ir complexes (1-6) using polypyridyl-pyrazine based ligands (L-1 and L-2) and {[cp*IrCl-(mu-Cl)](2) and [(ppy)(2)Ir(mu-Cl)](2)} precursors have been synthesised and characterised. Complexes 1-5 have shown potent anticancer activity against various human cancer cell lines (MCF-7, LNCap, Ishikawa, DU145, PC3 and SKOV3) while complex 6 is found to be inactive. Flow cytometry studies have established that cellular accumulation of the complexes lies in the order 2 > 1 > 5 > 4 > 3 > 6 which is in accordance with their observed cytotoxicity. No changes in the expression of the proteins like PARP, caspase 9 and beclin-1, Atg12 discard apoptosis and autophagy, respectively. Overexpression of CHOP, activation of MAPKs (P38, JNK, and ERK) and massive cytoplasmic vacuolisation collectively suggest a paraptotic mode of cell death induced by proteasomal dysfunction as well as endoplasmic reticulum and mitochondrial stress. An intimate relationship between p53, ROS production and extent of cell death has also been established using p53 wild, null and mutant type cancer cells.</P>
Sharma, Satyasheel,Oh, Yongguk,Mishra, Neeraj Kumar,De, Umasankar,Jo, Hyeim,Sachan, Richa,Kim, Hyung Sik,Jung, Young Hoon,Kim, In Su American Chemical Society 2017 Journal of organic chemistry Vol.82 No.7
<P>The rhodium(III)-catalyzed redox-neutral coupling reaction of N-acyl ketimines generated in situ from 3-hydro-xyisoindolinones with various activated olefins is described. This approach leads to the synthesis of bioactive spiroisoindolinone derivatives in moderate to high yields. In the case of internal olefins such as maleimides, maleates, fumarates, and cinnamates, spiroindanes were obtained by the [3 + 2] annulations reaction. In sharp contrast, acrylates and quinones displayed the beta-H elimination followed, by Prins-type cyclization furnishing spiroindenes. The synthetic compounds were evaluated for in vitro anticancer activity against androgen-sensitive human prostate adenocarcinoma cells (LNCaP), human prostate adenocarcinoma cells (DU145), human endometrial adenocarcinoma cells (Ichikawa), human breast cancer cell (MCF-7), and triple negative human breast cancer cells (MDA-MB-231). Notably, quinone-containing spiroindenes displayed potent anticancer activity about 2- to 3-fold stronger than that of anticancer agent doxorubicin.</P>