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Sachan, Richa,Kundu, Amit,Jeon, Yukyoung,Choi, Wahn Soo,Yoon, Kyungsil,Kim, In Su,Kwak, Jong Hwan,Kim, Hyung Sik Elsevier 2018 Phytomedicine Vol.51 No.-
<P><B>Abstract</B></P> <P><B>Background</B></P> <P>Afrocyclamin A, an oleanane-type triterpene saponin, was isolated from <I>Androsace umbellata</I> which used as a traditional herbal medicine.</P> <P><B>Purpose</B></P> <P>This study aimed to explore the anticancer activity of afrocyclamin A on human prostate cancer cells <I>in vitro</I> as well as <I>in vivo</I>.</P> <P><B>Methods</B></P> <P>Cytotoxicity, cell cycle distribution, apoptosis, and autophagic cell death were measured following exposure to afrocyclamin A. <I>In vivo</I> antitumor activity of afrocyclamin A was assessed in a xenograft model. The protein levels of p-Akt, p-mTOR, Bax, Bcl-2, caspase-3, and caspase-9 were quantified using western blot analysis.</P> <P><B>Results</B></P> <P>In DU145 cells, afrocyclamin A increased cytotoxicity, caused changes in cell morphology, and induced sub-G0/G1 phase indicating increased apoptosis. Afrocyclamin A robustly induced autophagic cell death as demonstrated by the conversion of LC3B-I to LC3B-II, and the formation of autophagic vacuoles as revealed by western blot analysis and fluorescence staining, respectively. Afrocyclamin A also inhibited the phosphorylation of PI3K, Akt, and mTOR, suggesting their role in afrocyclamin A induced cell death. In addition, afrocyclamin A inhibited cell migration and invasion in concentration and time-dependent manners. In an <I>in vivo</I> xenograft model, afrocyclamin A inhibited the growth of DU145 cells.</P> <P><B>Conclusion</B></P> <P>Afrocyclamin A has anticancer activity via the PI3K/Akt/mTOR pathway, which leads to cell death.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
( Sachan Richa ),( Prasanta Dey ),( Chaeun Park ),( Jungho Yang ),( Ji Yeon Son ),( Jae Hyeon Park ),( Su Hyun Lee ),( Mee-young Ahn ),( In Su Kim ),( Hyung Ryong Moon ),( Hyung Sik Kim ) 한국응용약물학회 2020 Biomolecules & Therapeutics(구 응용약물학회지) Vol.28 No.2
Histone deacetylase (HDAC) inhibitors represent a novel class of anticancer agents, which can be used to inhibit cell proliferation and induce apoptosis in several types of cancer cells. In this study, we investigated the anticancer activity of MHY4381, a newly synthesized HDAC inhibitor, against human prostate cancer cell lines and compared its efficacy with that of suberoylanilide hydroxamic acid (SAHA), a well-known HDAC inhibitor. We assessed cell viability, apoptosis, cell cycle regulation, and other biological effects in the prostate cancer cells. We also evaluated a possible mechanism of MHY4381 on the apoptotic cell death pathway. The IC<sub>50</sub> value of MHY4381 was lower in DU145 cells (IC<sub>50</sub>=0.31 µM) than in LNCaP (IC<sub>50</sub>=0.85 µM) and PC-3 cells (IC<sub>50</sub>=5.23 µM). In addition, the IC<sub>50</sub> values of MHY4381 measured in this assay were significantly lower than those of SAHA against prostate cancer cell lines. MHY4381 increased the levels of acetylated histones H3 and H4 and reduced the expression of HDAC proteins in the prostate cancer cell lines. MHY4381 increased G2/M phase arrest in DU145 cells, and G1 arrest in LNCaP cells. It also activated reactive oxygen species (ROS) generation, which induced apoptosis in the DU145 and LNCaP cells by increasing the ratio of Bax/Bcl-2 and releasing cytochrome c into the cytoplasm. Our results indicated that MHY4381 preferentially results in antitumor effects in DU145 and LNCaP cells via mitochondria-mediated apoptosis and ROS-facilitated cell death pathway, and therefore can be used as a promising prostate cancer therapeutic.
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>
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>
Jeon, Mijin,Mishra, Neeraj Kumar,De, Umasankar,Sharma, Satyasheel,Oh, Yongguk,Choi, Miji,Jo, Hyeim,Sachan, Richa,Kim, Hyung Sik,Kim, In Su American Chemical Society 2016 Journal of organic chemistry Vol.81 No.20
<P>The rhodium(III)-catalyzed direct C-H functionalization of various indolines with 1,4,2-dioxazol-5-ones as new amidating agents is described. This transformation provides efficient preparation of C7-amidated indolines known to display potent anticancer activity. The synthetic compounds were evaluated for in vitro anticancer activity against human prostate adenocarcinoma cells (LNCaP), human endometrial adenocarcinoma cells (Ishikawa), and human ovarian carcinoma cells (SKOV3). Compound 4f was found to be highly cytotoxic, with activity competitive with that of anticancer agent doxorubicin.</P>