ATG5 Promotes Death Signaling in Response to the Cyclic Depsipeptides Coibamide A and Apratoxin A

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.

Section: Discussionsupporting

confidence: 92%

Petromurin C Induces Protective Autophagy and Apoptosis in FLT3-ITD-Positive AML: Synergy with Gilteritinib

Song

Orlikova-Boyer

et al. 2020

“…The effect of the induced autophagy on HUVEC cell viability is still to be investigated in the future. Using the mouse embryonic fibroblasts (MEFs) model two years later, the same group has shown that ATG5 is required for the cytotoxic activity of these depsipeptides, suggesting induction of cytotoxic autophagy [ 45 ]. Additionally, it was postulated that induced autophagy is not triggered by acute ER stress [ 45 ].…”

Section: Marine Compounds With a Validated Autophagy-modulatory Efmentioning

confidence: 99%

Blue-Print Autophagy in 2020: A Critical Review

Dyshlovoy

2020

Autophagy is an elegant and complex biological process that has recently attracted much attention from the scientific community. The compounds which are capable of control and modulation of this process have a promising potential as therapeutics for a number of pathological conditions, including cancer and neurodegenerative disorders. At the same time, due to the relatively young age of the field, there are still some pitfalls in the autophagy monitoring assays and interpretation of the experimental data. This critical review provides an overview of the marine natural compounds, which have been reported to affect autophagy. The time period from the beginning of 2016 to the middle of 2020 is covered. Additionally, the published data and conclusions based on the experimental results are re-analyzed with regard to the guidelines developed by Klionsky and colleagues (Autophagy. 2016; 12(1): 1–222), which are widely accepted by the autophagy research community. Remarkably and surprisingly, more than half of the compounds reported to be autophagy activators or inhibitors could not ultimately be assigned to either category. The experimental data reported for those substances could indicate both autophagy activation and inhibition, requiring further investigation. Thus, the reviewed molecules were divided into two groups: having validated and non-validated autophagy modulatory effects. This review gives an analysis of the recent updates in the field and raises an important problem of standardization in the experimental design and data interpretation.

“…Autophagic cell death is not a common occurrence. While many marine natural compounds can affect autophagy either inducing it (chromomycin A2, psammaplin A, ilimaquinone [ 86 ], coibamide A, and apratoxin A [ 87 ]), or inhibiting it (manzamine A [ 88 ] and scalarin [ 89 ]), to our knowledge, only yessotoxin has been reported to induce autophagic cell death in glioma cell lines [ 90 ].…”

Section: Autophagy-dependent Cell Deathmentioning

confidence: 99%

Regulated Cell Death Signaling Pathways and Marine Natural Products That Target Them

Guzmán

2019

Our understanding of cell death used to consist in necrosis, an unregulated form, and apoptosis, regulated cell death. That understanding expanded to acknowledge that apoptosis happens through the intrinsic or extrinsic pathways. Actually, many other regulated cell death processes exist, including necroptosis, a regulated form of necrosis, and autophagy-dependent cell death. We also understand that apoptosis occurs beyond the intrinsic and extrinsic pathways with caspase independent forms of apoptosis existing. Our knowledge of the signaling continues to grow, and with that, so does our ability to target different parts of the pathways with small molecules. Marine natural products co-evolve with their targets, and these unique molecules have complex structures with exquisite biological activities and specificities. This article offers a review of our current understanding of the signaling pathways regulating cell death, and highlights marine natural products that can affect these signaling pathways.