Oncotarget

Research Papers:

Discovery and characterization of Isofistularin-3, a marine brominated alkaloid, as a new DNA demethylating agent inducing cell cycle arrest and sensitization to TRAIL in cancer cells

Cristina Florean, Michael Schnekenburger, Jin-Young Lee, Kyung Rok Kim, Aloran Mazumder, Sungmi Song, Jae-Myun Kim, Cindy Grandjenette, Jeoung-Gyun Kim, Ah-Young Yoon, Mario Dicato, Kyu-Won Kim, Christo Christov, Byung-Woo Han, Peter Proksch and Marc Diederich _

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Oncotarget. 2016; 7:24027-24049. https://doi.org/10.18632/oncotarget.8210

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Abstract

Cristina Florean1, Michael Schnekenburger1, Jin-Young Lee2, Kyung Rok Kim2, Aloran Mazumder2, Sungmi Song2, Jae-Myun Kim2, Cindy Grandjenette1, Jeoung-Gyun Kim3, Ah-Young Yoon3, Mario Dicato1, Kyu-Won Kim3, Christo Christov4, Byung-Woo Han2, Peter Proksch5, Marc Diederich2

1Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, Hôpital Kirchberg, Lëtzebuerg, Luxembourg

2Department of Pharmacy, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Gwanak-gu, Korea

3SNU-Harvard Neurovascular Protection Center, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Gwanak-gu, Korea

4Faculté de Médecine, Université de Lorraine, Nancy, France

5Institut für Pharmazeutische Biologie und Biotechnologie, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany

Correspondence to:

Marc Diederich, e-mail: marcdiederich@snu.ac.kr

Keywords: leukemia, DNMT inhibitor, TSG hypermethylation, cell cycle arrest, autophagy

Received: September 01, 2015     Accepted: March 02, 2016     Published: March 19, 2016

ABSTRACT

We characterized the brominated alkaloid Isofistularin-3 (Iso-3), from the marine sponge Aplysina aerophoba, as a new DNA methyltransferase (DNMT)1 inhibitor. Docking analysis confirmed our in vitro DNMT inhibition data and revealed binding of Iso-3 within the DNA binding site of DNMT1. Subsequent increased expression of tumor suppressor gene aryl hydrocarbon receptor (AHR) could be correlated to decreased methylation of CpG sites within the essential Sp1 regulatory region of its promoter. Iso-3 induced growth arrest of cancer cells in G0/G1 concomitant with increased p21 and p27 expression and reduced cyclin E1, PCNA and c-myc levels. Reduced proliferation was accompanied by morphological changes typical of autophagy revealed by fluorescent and transmission electron microscopy and validated by LC3I-II conversion. Furthermore, Iso-3 strongly synergized with tumor-necrosis-factor related apoptosis inducing ligand (TRAIL) in RAJI [combination index (CI) = 0.22] and U-937 cells (CI = 0.21) and increased TRAIL-induced apoptosis via a mechanism involving reduction of survivin expression but not of Bcl-2 family proteins nor X-linked inhibitor of apoptosis protein (XIAP). Iso-3 treatment decreased FLIPL expression and triggered activation of endoplasmatic reticulum (ER) stress with increased GRP78 expression, eventually inducing TRAIL receptor death receptor (DR)5 surface expression. Importantly, as a potential candidate for further anticancer drug development, Iso-3 reduced the viability, colony and in vivo tumor forming potential without affecting the viability of PBMCs from healthy donors or zebrafish development.


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