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Article ; Online: Marine Polyether Phycotoxin Palytoxin Induces Apoptotic Cell Death via Mcl-1 and Bcl-2 Downregulation.

Kim, Jaemyun / Ji, Seungwon / Lee, Jin-Young / Lorquin, Jean / Orlikova-Boyer, Barbora / Cerella, Claudia / Mazumder, Aloran / Muller, Florian / Dicato, Mario / Detournay, Olivier / Diederich, Marc

Marine drugs

2023 Volume 21, Issue 4

Abstract: Palytoxin is considered one of the most potent biotoxins. As palytoxin-induced cancer cell death mechanisms remain to be elucidated, we investigated this effect on various leukemia and solid tumor cell lines at low picomolar concentrations. As palytoxin ... ...

Abstract	Palytoxin is considered one of the most potent biotoxins. As palytoxin-induced cancer cell death mechanisms remain to be elucidated, we investigated this effect on various leukemia and solid tumor cell lines at low picomolar concentrations. As palytoxin did not affect the viability of peripheral blood mononuclear cells (PBMC) from healthy donors and did not create systemic toxicity in zebrafish, we confirmed excellent differential toxicity. Cell death was characterized by a multi-parametric approach involving the detection of nuclear condensation and caspase activation assays. zVAD-sensitive apoptotic cell death was concomitant with a dose-dependent downregulation of antiapoptotic Bcl-2 family proteins Mcl-1 and Bcl-xL. Proteasome inhibitor MG-132 prevented the proteolysis of Mcl-1, whereas the three major proteasomal enzymatic activities were upregulated by palytoxin. Palytoxin-induced dephosphorylation of Bcl-2 further exacerbated the proapoptotic effect of Mcl-1 and Bcl-xL degradation in a range of leukemia cell lines. As okadaic acid rescued cell death triggered by palytoxin, protein phosphatase (PP)2A was involved in Bcl-2 dephosphorylation and induction of apoptosis by palytoxin. At a translational level, palytoxin abrogated the colony formation capacity of leukemia cell types. Moreover, palytoxin abrogated tumor formation in a zebrafish xenograft assay at concentrations between 10 and 30 pM. Altogether, we provide evidence of the role of palytoxin as a very potent and promising anti-leukemic agent, acting at low picomolar concentrations in cellulo and in vivo.
MeSH term(s)	Animals ; Humans ; Leukocytes, Mononuclear/metabolism ; Zebrafish/metabolism ; Down-Regulation ; Myeloid Cell Leukemia Sequence 1 Protein ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Apoptosis ; Apoptosis Regulatory Proteins/metabolism ; Cell Line, Tumor ; Leukemia ; bcl-X Protein/metabolism ; bcl-X Protein/pharmacology
Chemical Substances	palytoxin (OQ17NC0MOV) ; Myeloid Cell Leukemia Sequence 1 Protein ; Proto-Oncogene Proteins c-bcl-2 ; Apoptosis Regulatory Proteins ; bcl-X Protein
Language	English
Publishing date	2023-04-06
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2175190-0
ISSN	1660-3397 ; 1660-3397
ISSN (online)	1660-3397
ISSN	1660-3397
DOI	10.3390/md21040233
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Article ; Online: Metabolism 2014--alterations of metabolic pathways as therapeutic targets.

Ji, Seungwon / Kim, Jaemyun / Orlikova, Barbora / Diederich, Marc

Biochemical pharmacology

2014 Volume 92, Issue 1, Page(s) 1–2

MeSH term(s)	Cell Proliferation/physiology ; Energy Metabolism/physiology ; Gene Expression Regulation, Neoplastic ; Genes, Tumor Suppressor/physiology ; Humans ; Neoplasms/metabolism ; Oncogenes/physiology
Language	English
Publishing date	2014-11-01
Publishing country	England
Document type	Editorial
ZDB-ID	208787-x
ISSN	1873-2968 ; 0006-2952
ISSN (online)	1873-2968
ISSN	0006-2952
DOI	10.1016/j.bcp.2014.09.003
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Article ; Online: Signal Transducers and Activators of Transcription (STAT) Regulatory Networks in Marine Organisms: From Physiological Observations towards Marine Drug Discovery.

Lee, Jin-Young / Orlikova, Barbora / Diederich, Marc

Marine drugs

2015 Volume 13, Issue 8, Page(s) 4967–4984

Abstract: Part of our ocean's richness comes from its extensive history of supporting life, resulting in a highly diverse ecological system. To date, over 250,000 species of marine organisms have been identified, but it is speculated that the actual number of ... ...

Abstract	Part of our ocean's richness comes from its extensive history of supporting life, resulting in a highly diverse ecological system. To date, over 250,000 species of marine organisms have been identified, but it is speculated that the actual number of marine species exceeds one million, including several hundreds of millions of species of marine microorganisms. Past studies suggest that approximately 70% of all deep-sea microorganisms, gorgonians, and sea sponges produce secondary metabolites with anti-cancer activities. Recently, novel FDA-approved drugs derived from marine sponges have been shown to reduce metastatic breast cancer, malignant lymphoma, and Hodgkin's disease. Despite the fact that many marine natural products have been shown to possess a good inhibition potential against most of the cancer-related cell signaling pathways, only a few marine natural products have been shown to target JAK/STAT signaling. In the present paper, we describe the JAK/STAT signaling pathways found in marine organisms, before elaborating on the recent advances in the field of STAT inhibition by marine natural products and the potential application in anti-cancer drug discovery.
MeSH term(s)	Animals ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Aquatic Organisms/genetics ; Biological Products/pharmacology ; Biological Products/therapeutic use ; Drug Discovery/methods ; Gene Regulatory Networks/genetics ; Humans ; Signal Transduction/genetics ; Transcription, Genetic/genetics
Chemical Substances	Antineoplastic Agents ; Biological Products
Language	English
Publishing date	2015-08-07
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2175190-0
ISSN	1660-3397 ; 1660-3397
ISSN (online)	1660-3397
ISSN	1660-3397
DOI	10.3390/md13084967
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Article: Non-edible plants as an attractive source of compounds with chemopreventive potential.

Ji, Seungwon / Orlikova, Barbora / Diederich, Marc

Journal of cancer prevention

2014 Volume 19, Issue 1, Page(s) 1–6

Abstract: Cancer remains a lethal disease, and many scientists are currently trying to develop more effective therapies. Natural compounds are potential sources of anti-cancer therapies and are obtained from diverse sources including marine organisms, ... ...

Abstract	Cancer remains a lethal disease, and many scientists are currently trying to develop more effective therapies. Natural compounds are potential sources of anti-cancer therapies and are obtained from diverse sources including marine organisms, microorganisms and plants. In this paper, we evaluated natural compounds from non-edible plant sources, which is a neglected area of research despite the promising future of these compounds. In addition, we assessed the function and mechanism of action of these compounds in relation to cancer chemoprevention.
Language	English
Publishing date	2014-10-07
Publishing country	Korea (South)
Document type	Journal Article ; Review
ZDB-ID	3019805-7
ISSN	2288-3657 ; 2288-3649
ISSN (online)	2288-3657
ISSN	2288-3649
DOI	10.15430/jcp.2014.19.1.1
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Article ; Online: Petromurin C Induces Protective Autophagy and Apoptosis in FLT3-ITD-Positive AML: Synergy with Gilteritinib.

Ha, You Na / Song, Sungmi / Orlikova-Boyer, Barbora / Cerella, Claudia / Christov, Christo / Kijjoa, Anake / Diederich, Marc

Marine drugs

2020 Volume 18, Issue 1

Abstract: Treatment of acute myeloid leukemia (AML) remains inefficient due to drug resistance and relapse, particularly in patients with FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD). Marine-derived natural products have recently been used ... ...

Abstract	Treatment of acute myeloid leukemia (AML) remains inefficient due to drug resistance and relapse, particularly in patients with FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD). Marine-derived natural products have recently been used for drug development against AML. We show in this study that petromurin C, which was isolated from the culture extract of the marine-derived fungus
MeSH term(s)	Aniline Compounds/administration & dosage ; Aniline Compounds/pharmacology ; Animals ; Antineoplastic Combined Chemotherapy Protocols/pharmacology ; Apoptosis/drug effects ; Aquatic Organisms/chemistry ; Autophagy/drug effects ; Biological Products/administration & dosage ; Biological Products/pharmacology ; Cell Line, Tumor ; Down-Regulation/drug effects ; Drug Resistance, Neoplasm ; Drug Synergism ; Humans ; Leukemia, Myeloid, Acute/drug therapy ; Leukemia, Myeloid, Acute/genetics ; Leukemia, Myeloid, Acute/metabolism ; Leukemia, Myeloid, Acute/pathology ; Pyrazines/administration & dosage ; Pyrazines/pharmacology ; Signal Transduction/drug effects ; U937 Cells ; Zebrafish ; fms-Like Tyrosine Kinase 3/genetics ; fms-Like Tyrosine Kinase 3/metabolism
Chemical Substances	Aniline Compounds ; Biological Products ; Pyrazines ; gilteritinib ; FLT3 protein, human (EC 2.7.10.1) ; fms-Like Tyrosine Kinase 3 (EC 2.7.10.1)
Language	English
Publishing date	2020-01-16
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2175190-0
ISSN	1660-3397 ; 1660-3397
ISSN (online)	1660-3397
ISSN	1660-3397
DOI	10.3390/md18010057
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Article: 1,000 Ways to die: natural compounds modulate non-canonical cell death pathways in cancer cells

Orlikova, Barbora / Dicato, Mario / Diederich, Marc

Phytochemistry reviews. 2014 Mar., v. 13, no. 1

2014

Abstract: Over the past decades, apoptosis emerged as a leading strategy to eliminate cancer cells. Nowadays, it becomes progressively clear that apoptosis is not the only programmed cell death mechanism implicated in the elimination of malignant cells. This ... ...

Abstract	Over the past decades, apoptosis emerged as a leading strategy to eliminate cancer cells. Nowadays, it becomes progressively clear that apoptosis is not the only programmed cell death mechanism implicated in the elimination of malignant cells. This review will discuss non-apoptotic cell death modalities and will focus on natural compounds acting as inducers of these recently described processes. We will describe the major molecular characteristics of each individual death mechanism and we will detail the effects of natural and naturally-derived compounds on these cellular mechanisms.
Keywords	apoptosis ; biochemical mechanisms ; neoplasms ; structure-activity relationships
Language	English
Dates of publication	2014-03
Size	p. 277-293.
Publishing place	Springer-Verlag
Document type	Article
ZDB-ID	2065661-0
ISSN	1572-980X ; 1568-7767
ISSN (online)	1572-980X
ISSN	1568-7767
DOI	10.1007/s11101-013-9318-0
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Signal Transducers and Activators of Transcription (STAT) Regulatory Networks in Marine Organisms

Jin-Young Lee / Barbora Orlikova / Marc Diederich

Marine Drugs, Vol 13, Iss 8, Pp 4967-

From Physiological Observations towards Marine Drug Discovery

2015 Volume 4984

Abstract: Part of our ocean’s richness comes from its extensive history of supporting life, resulting in a highly diverse ecological system. To date, over 250,000 species of marine organisms have been identified, but it is speculated that the actual number of ... ...

Abstract	Part of our ocean’s richness comes from its extensive history of supporting life, resulting in a highly diverse ecological system. To date, over 250,000 species of marine organisms have been identified, but it is speculated that the actual number of marine species exceeds one million, including several hundreds of millions of species of marine microorganisms. Past studies suggest that approximately 70% of all deep-sea microorganisms, gorgonians, and sea sponges produce secondary metabolites with anti-cancer activities. Recently, novel FDA-approved drugs derived from marine sponges have been shown to reduce metastatic breast cancer, malignant lymphoma, and Hodgkin’s disease. Despite the fact that many marine natural products have been shown to possess a good inhibition potential against most of the cancer-related cell signaling pathways, only a few marine natural products have been shown to target JAK/STAT signaling. In the present paper, we describe the JAK/STAT signaling pathways found in marine organisms, before elaborating on the recent advances in the field of STAT inhibition by marine natural products and the potential application in anti-cancer drug discovery.
Keywords	anti-cancer ; drug discovery ; JAK/STAT signaling ; Biology (General) ; QH301-705.5
Subject code	333
Language	English
Publishing date	2015-08-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Petromurin C Induces Protective Autophagy and Apoptosis in FLT3-ITD-Positive AML

You Na Ha / Sungmi Song / Barbora Orlikova-Boyer / Claudia Cerella / Christo Christov / Anake Kijjoa / Marc Diederich

Marine Drugs, Vol 18, Iss 1, p

Synergy with Gilteritinib

2020 Volume 57

Abstract	Treatment of acute myeloid leukemia (AML) remains inefficient due to drug resistance and relapse, particularly in patients with FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD). Marine-derived natural products have recently been used for drug development against AML. We show in this study that petromurin C, which was isolated from the culture extract of the marine-derived fungus Aspergillus candidus KUFA0062, isolated from the marine sponge Epipolasis sp., induces early autophagy followed by apoptotic cell death via activation of the intrinsic cell death pathway concomitant with mitochondrial stress and downregulation of Mcl-1 in FLT3-ITD mutated MV4-11 cells. Moreover, petromurin C synergized with the clinically-used FLT3 inhibitor gilteritinib at sub-toxic concentrations. Altogether, our results provide preliminary indications that petromurin C provides anti-leukemic effects alone or in combination with gilteritinib.
Keywords	acute myeloid leukemia ; aspergillus candidus ; epipolasis sp ; cell death ; mitochondrial stress ; combination treatment ; Biology (General) ; QH301-705.5
Subject code	610
Language	English
Publishing date	2020-01-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Anti-Leukemic Properties of Aplysinopsin Derivative EE-84 Alone and Combined to BH3 Mimetic A-1210477.

Song, Sungmi / Kim, Sua / El-Sawy, Eslam R / Cerella, Claudia / Orlikova-Boyer, Barbora / Kirsch, Gilbert / Christov, Christo / Dicato, Mario / Diederich, Marc

Marine drugs

2021 Volume 19, Issue 6

Abstract: Aplysinopsins are a class of marine indole alkaloids that exhibit a wide range of biological activities. Although both the indole and N-benzyl moieties of aplysinopsins are known to possess antiproliferative activity against cancer cells, their mechanism ...

Abstract	Aplysinopsins are a class of marine indole alkaloids that exhibit a wide range of biological activities. Although both the indole and N-benzyl moieties of aplysinopsins are known to possess antiproliferative activity against cancer cells, their mechanism of action remains unclear. Through in vitro and in vivo proliferation and viability screening of newly synthesized aplysinopsin analogs on myelogenous leukemia cell lines and zebrafish toxicity tests, as well as analysis of differential toxicity in noncancerous RPMI 1788 cells and PBMCs, we identified EE-84 as a promising novel drug candidate against chronic myeloid leukemia. This indole derivative demonstrated drug-likeness in agreement with Lipinski's rule of five. Furthermore, EE-84 induced a senescent-like phenotype in K562 cells in line with its cytostatic effect. EE-84-treated K562 cells underwent morphological changes in line with mitochondrial dysfunction concomitant with autophagy and ER stress induction. Finally, we demonstrated the synergistic cytotoxic effect of EE-84 with a BH3 mimetic, the Mcl-1 inhibitor A-1210477, against imatinib-sensitive and resistant K562 cells, highlighting the inhibition of antiapoptotic Bcl-2 proteins as a promising novel senolytic approach against chronic myeloid leukemia.
MeSH term(s)	Animals ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/toxicity ; Apoptosis/drug effects ; Autophagy/drug effects ; Cell Cycle/drug effects ; Cell Death/drug effects ; Cell Line ; Cytotoxins/chemistry ; Cytotoxins/pharmacology ; Cytotoxins/toxicity ; Drug Synergism ; Endoplasmic Reticulum Stress/drug effects ; Humans ; Indoles/chemistry ; Indoles/pharmacology ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology ; Myeloid Cell Leukemia Sequence 1 Protein/antagonists & inhibitors ; Sulfonamides/chemistry ; Sulfonamides/pharmacology ; Tryptophan/analogs & derivatives ; Tryptophan/chemistry ; Tryptophan/pharmacology ; Tryptophan/toxicity ; Zebrafish
Chemical Substances	A-1210477 ; Antineoplastic Agents ; Cytotoxins ; Indoles ; MCL1 protein, human ; Myeloid Cell Leukemia Sequence 1 Protein ; Sulfonamides ; aplysinopsin (63153-56-0) ; Tryptophan (8DUH1N11BX)
Language	English
Publishing date	2021-05-21
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2175190-0
ISSN	1660-3397 ; 1660-3397
ISSN (online)	1660-3397
ISSN	1660-3397
DOI	10.3390/md19060285
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Article: Petromurin C Induces Protective Autophagy and Apoptosis in FLT3-ITD-Positive AML: Synergy with Gilteritinib

Ha, You Na / Song, Sungmi / Orlikova-Boyer, Barbora / Cerella, Claudia / Christov, Christo / Kijjoa, Anake / Diederich, Marc

Marine drugs. 2020 Jan. 16, v. 18, no. 1

2020

Abstract	Treatment of acute myeloid leukemia (AML) remains inefficient due to drug resistance and relapse, particularly in patients with FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD). Marine-derived natural products have recently been used for drug development against AML. We show in this study that petromurin C, which was isolated from the culture extract of the marine-derived fungus Aspergillus candidus KUFA0062, isolated from the marine sponge Epipolasis sp., induces early autophagy followed by apoptotic cell death via activation of the intrinsic cell death pathway concomitant with mitochondrial stress and downregulation of Mcl-1 in FLT3-ITD mutated MV4-11 cells. Moreover, petromurin C synergized with the clinically-used FLT3 inhibitor gilteritinib at sub-toxic concentrations. Altogether, our results provide preliminary indications that petromurin C provides anti-leukemic effects alone or in combination with gilteritinib.
Keywords	Aspergillus candidus ; Porifera ; apoptosis ; autophagy ; drug development ; drug resistance ; enzymes ; fungi ; mitochondria ; myeloid leukemia ; patients ; relapse ; tyrosine
Language	English
Dates of publication	2020-0116
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2175190-0
ISSN	1660-3397
ISSN	1660-3397
DOI	10.3390/md18010057
Database	NAL-Catalogue (AGRICOLA)

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