Betulinic acid-induced mitochondria-dependent cell death is counterbalanced by an autophagic salvage response

Potze, Lisette; Mullauer, Franziska B.; Colak, Selçuk; Kessler, Jacqueline; Medema, Jan Paul

doi:10.1038/cddis.2014.139

Cited by 61 publications

(51 citation statements)

References 47 publications

(70 reference statements)

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“…MPT is a key event in the mitochondrial apoptotic pathway. BA-induced MPT was a consequence of the opening of the mitochondrial PT pore, which was abolished by cyclosporine A (CsA) or bongkrekic acid [59, 60]. In contrast to these data, we found that cyclosporine failed to alleviate B5G9-induced MPT and cell death (Additional file 2: Figure S1G&H).…”

Section: Discussionmentioning

confidence: 77%

A piperazidine derivative of 23-hydroxy betulinic acid induces a mitochondria-derived ROS burst to trigger apoptotic cell death in hepatocellular carcinoma cells

Yao

Lei

et al. 2016

J Exp Clin Cancer Res

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BackgroundElevated production of reactive oxygen species (ROS) and an altered redox state have frequently been observed in hepatocellular carcinoma (HCC); therefore, selective killing of HCC cells by chemotherapeutic agents that stimulate ROS generation or impair antioxidant systems may be a feasible approach in HCC chemotherapy. Recently, betulinic acid and its derivatives have attracted attention because they showed anti-cancer effects via a ROS- and mitochondria-related mechanism. However, the source of ROS overproduction and the role of mitochondria were poorly identified, and the weak in vivo antitumour activity of these compounds limits their development as drugs.MethodsCytotoxicity was detected using MTT assays. In vivo anti-HCC effects were assessed using nude mice bearing HepG2 tumour xenografts. Cell cycle analysis, apoptosis rate and mitochondrial membrane potential were measured by flow cytometry. ROS production was detected using a microplate reader or a fluorescence microscope. Changes in gene and protein levels were measured by RT-PCR and western blotting, respectively. Other assays were performed using related detection kits.ResultsB5G9, a piperazidine derivative of 23-hydroxy betulinic acid (23-HBA), showed excellent in vivo anti-HCC effects, with a tumour growth inhibitory rate of greater than 80%, and no significant side effects. B5G9 stimulated the production of ROS, which were derived from the mitochondria, but it had no effect on various other antioxidant systems. Moreover, B5G9 induced mitochondrial dysfunction, which was characterized by morphological changes, membrane potential collapse, membrane permeabilization, and decreases in the O2 consumption rate and ATP production. Furthermore, mtDNA-depleted ρ0 HepG2 cells were less sensitive to B5G9 treatment than wt HepG2 cells, indicating the importance of mitochondria in B5G9-induced cell death.ConclusionWe discovered a piperazidine derivative of 23-HBA, B5G9, with excellent anti-HCC effects both in vivo and in vitro and no obvious toxic effects. The underlying mechanism was associated with mitochondria-derived ROS overproduction, and mitochondria played essential roles in B5G9-induced cell death. This study identified a potential agent for anti-HCC therapy and elucidated the mitochondria-related mechanism of BA and its derivatives.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-016-0457-1) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 77%

A piperazidine derivative of 23-hydroxy betulinic acid induces a mitochondria-derived ROS burst to trigger apoptotic cell death in hepatocellular carcinoma cells

Yao

Lei

et al. 2016

J Exp Clin Cancer Res

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“…MitoTracker ® Orange CMTMRos is a rosamine‐based fluorescent dye that stains mitochondria in live cells. The accumulation of this version of MitoTracker stain is dependent upon membrane potential, such that stain is sequestered into mitochondria in response to highly negative mitochondrial membrane potential (Kholmukhamedov, Schwartz & Lemasters, ; Potze, Mullauer, Colak, Kessler & Medema, ). Potze et al.…”

Section: Methodsmentioning

confidence: 99%

The capacity of oysters to regulate energy metabolism‐related processes may be key to their resilience against ocean acidification

et al. 2018

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Bivalve molluscs, such as oysters, are threatened by shifts in seawater chemistry resulting from climate change. However, a few species and populations within a species stand out for their capacity to cope with the impacts of climate change‐associated stressors. Understanding the intracellular basis of such differential responses can contribute to the development of strategies to minimise the pervasive effects of a changing ocean on marine organisms. In this study, we explored the intracellular responses to ocean acidification in two genetically distinct populations of Sydney rock oysters (Saccostrea glomerata). Selectively bred and wild type oysters exhibited markedly different mitochondrial integrities (mitochondrial membrane potential) and levels of reactive oxygen species (ROS) in their hemocytes under CO2 stress. Analysis of these cellular parameters after 4 and 15 days of exposure to elevated CO2 indicated that the onset of intracellular responses occurred earlier in the selectively bred oysters when compared to the wild type population. This may be due to an inherent capacity for increased intracellular energy production or adaptive energy reallocation in the selectively bred population. The differences observed in mitochondrial integrity and in ROS formation between oyster breeding lines reveal candidate biological processes that may underlie resilience or susceptibility to ocean acidification. Such processes can be targeted in breeding programs aiming to mitigate the impacts of climate change on threatened species.

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“…Analysis of LC3 puncta was performed using ImageJ software, generating a basal cutoff of LC3 puncta (threshold, 10), then using the Analyze Particle feature for counting to generate a mean of positive pixels per cell (%) AE SEM of three fields of view per sample. 26 Immunofluorescence experiments were performed using this secondary antibody instead of the one previously mentioned, because of the change in confocal microscope.…”

Section: Immunofluorescencementioning

confidence: 99%

The Microbiota Protects against Ischemia/Reperfusion-Induced Intestinal Injury through Nucleotide-Binding Oligomerization Domain-Containing Protein 2 (NOD2) Signaling

Perez‐Chanona¹,

Mühlbauer²,

Jobin³

2014

The American Journal of Pathology

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Nucleotide-binding oligomerization domain-containing protein 2 (NOD2), an intracellular pattern recognition receptor, induces autophagy on detection of muramyl dipeptide (MDP), a component of microbial cell walls. The role of bacteria and NOD2 signaling toward ischemia/reperfusion (I/R)-induced intestinal injury response is unknown. Herein, we report that I/R-induced intestinal injury in germ-free (GF) C57BL/6 wild-type (WT) mice is worse than in conventionally derived mice. More important, microbiota-mediated protection against I/R-induced intestinal injury is abrogated in conventionally derived Nod2(-/-) mice and GF Nod2(-/-) mice. Also, WT mice raised in specific pathogen-free (SPF) conditions fared better against I/R-induced injury than SPF Nod2(-/-) mice. Moreover, SPF WT mice i.p. administered 10 mg/kg MDP were protected against injury compared with mice administered the inactive enantiomer, l-MDP, an effect lost in Nod2(-/-) mice. However, MDP administration failed to protect GF mice from I/R-induced intestinal injury compared with control, a phenomenon correlating with undetectable Nod2 mRNA level in the epithelium of GF mice. More important, the autophagy-inducer rapamycin protected Nod2(-/-) mice against I/R-induced injury and increased the levels of LC3(+) puncta in injured tissue of Nod2(-/-) mice. These findings demonstrate that NOD2 protects against I/R and promotes wound healing, likely through the induction of the autophagy response.

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Betulinic acid-induced mitochondria-dependent cell death is counterbalanced by an autophagic salvage response

Cited by 61 publications

References 47 publications

A piperazidine derivative of 23-hydroxy betulinic acid induces a mitochondria-derived ROS burst to trigger apoptotic cell death in hepatocellular carcinoma cells

A piperazidine derivative of 23-hydroxy betulinic acid induces a mitochondria-derived ROS burst to trigger apoptotic cell death in hepatocellular carcinoma cells

The capacity of oysters to regulate energy metabolism‐related processes may be key to their resilience against ocean acidification

The Microbiota Protects against Ischemia/Reperfusion-Induced Intestinal Injury through Nucleotide-Binding Oligomerization Domain-Containing Protein 2 (NOD2) Signaling

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