Petromurin C induces protective autophagy and apoptosis in FLT3-ITD-positive AML: Synergy with gilteritinib

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

doi:10.3390/md18010057

Petromurin C induces protective autophagy and apoptosis in FLT3-ITD-positive AML: Synergy with gilteritinib

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › Research › peer-review

8 Citations (Scopus)

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.

Original language	English
Article number	57
Journal	Marine Drugs
Volume	18
Issue number	1
DOIs	https://doi.org/10.3390/md18010057
Publication status	Published - 16 Jan 2020
Externally published	Yes

Keywords

Acute myeloid leukemia
Aspergillus candidus
Cell death
Combination treatment
Epipolasis sp
Mitochondrial stress

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10.3390/md18010057

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title = "Petromurin C induces protective autophagy and apoptosis in FLT3-ITD-positive AML: Synergy with gilteritinib",

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.",

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author = "Ha, {You Na} and Sungmi Song and Barbora Orlikova-Boyer and Claudia Cerella and Christo Christov and Anake Kijjoa and Marc Diederich",

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T1 - Petromurin C induces protective autophagy and apoptosis in FLT3-ITD-positive AML

T2 - Synergy with gilteritinib

AU - Ha, You Na

AU - Song, Sungmi

AU - Orlikova-Boyer, Barbora

AU - Cerella, Claudia

AU - Christov, Christo

AU - Kijjoa, Anake

AU - Diederich, Marc

N1 - Publisher Copyright: © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

PY - 2020/1/16

Y1 - 2020/1/16

N2 - 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.

AB - 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.

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KW - Aspergillus candidus

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KW - Combination treatment

KW - Epipolasis sp

KW - Mitochondrial stress

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Petromurin C induces protective autophagy and apoptosis in FLT3-ITD-positive AML: Synergy with gilteritinib

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