Autophagy and mitophagy in the context of doxorubicin-induced cardiotoxicity

Koleini, Navid; Kardami, Elissavet

doi:10.18632/oncotarget.16944

Cited by 261 publications

(242 citation statements)

References 131 publications

(179 reference statements)

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“…mTOR can inhibit autophagy, and acts as a critical negative regulator (28,29). We found that TPI decreased mTOR phosphorylation, and thus has an antithetical role in the inhibition of autophagy initiation (23).…”

Section: Discussionmentioning

confidence: 67%

Triptolide induces autophagy and apoptosis through ERK activation in human breast cancer MCF‑7 cells

et al. 2018

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Abstract.To investigate the effects of triptolide (TPI) on proliferation, autophagy and death in human breast cancer MCF-7 cells, and to elucidate the associated molecular mechanisms, intracellular alterations were analyzed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and flow cytometry assays. The results of the MTT assay revealed that TPI significantly reduced the MCF-7 cell survival rate when the concentration was >10 nmol/l. TPI activated a caspase cascade reaction by regulating Bcl-2-associated X protein (Bax), caspase-3 and B-cell lymphoma 2 expression, and promoted programmed cell death via the mitochondrial pathway. The results demonstrated that TPI significantly reduced the cell proliferation rate and viability in a time-and dose-dependent manner, which was confirmed by western blotting and immunofluorescent staining. TPI induced autophagy and influenced p38 mitogen-activated protein kinases, extracellular signal-regulated kinase (Erk)1/2, and mammalian target of rapamycin (mTOR) phosphorylation, which resulted in apoptosis. When cells were treated with a combination of TPI and the Erk1/2 inhibitor U0126, the downregulation of P62 and upregulation of Bax were inhibited, which demonstrated that the inhibition of Erk1/2 reversed the autophagy changes induced by TPI. The results indicated that Erk1/2 activation may be a novel mechanism by which TPI induces autophagy and apoptosis in MCF-7 breast cancer cells. In conclusion, TPI affects the proliferation and apoptosis of MCF-7 cells, potentially via autophagy and p38/Erk/mTOR phosphorylation. The present study offers a novel view of the mechanisms by which TPI regulates cell death.

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Section: Discussionmentioning

confidence: 67%

Triptolide induces autophagy and apoptosis through ERK activation in human breast cancer MCF‑7 cells

et al. 2018

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“…Although mitophagy is protective in most cases (28), it becomes detrimental under certain conditions (29,30). The effect of Dox on mitophagy has been previously assessed, but neither mitophagy activity nor its functional role in Dox cardiotoxicity has been unequivocally defined (33). Dox was reported to inhibit cardiac mitophagy because of the sequestration of parkin by p53 that led to decreased mitochondrial translocation of parkin and reduced mitochondria incorporation into autophagic vacuoles (34).…”

Section: Discussionmentioning

confidence: 99%

“…It is still debatable whether and how mitophagy is involved in Dox cardiotoxicity (33). Parkin is an E3 ubiquitin ligase that ubiquitinates mitochondria to trigger their degradation by mitophagy.…”

Section: Mitophagy Contributed To Dox-induced H9c2 Cell Deathmentioning

confidence: 99%

“…In the heart, ablation of parkin rescued the cardiac phenotype of DRP1-homozygous knockout mice, suggesting that parkin-mediated mitophagy contributed to cardiac damage in DRP1 2/2 mice (32). However, it remains controversial whether mitophagy contributes to or protects against Dox cardiotoxicity (33)(34)(35). In addition, fission can segregate damaged segments of mitochondria and facilitate their removal by mitophagy (36).…”

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confidence: 99%

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Doxorubicin‐induced cardiomyocyte death is mediated by unchecked mitochondrial fission and mitophagy

Catanzaro

Weiner²,

Kaminaris³

et al. 2019

FASEB j.

136

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Doxorubicin (Dox) is a widely used antineoplastic agent that can cause heart failure. Dox cardiotoxicity is closely associated with mitochondrial damage. Mitochondrial fission and mitophagy are quality control mechanisms that normally help maintain a pool of healthy mitochondria. However, unchecked mitochondrial fission and mitophagy may compromise the viability of cardiomyocytes, predisposing them to cell death. Here, we tested this possibility by using Dox‐treated H9c2 cardiac myoblast cells expressing either the mitochondria‐targeted fluorescent protein MitoDsRed or the novel dual‐fluorescent mitophagy reporter mt‐Rosella. Dox induced mitochondrial fragmentation as shown by reduced form factor, aspect ratio, and mean mitochondrial size. This effect was abolished by short interference RNA–mediated knockdown of dynamin‐related protein 1 (DRP1), a major regulator of fission. Importantly, DRP1 knockdown decreased cell death as indicated by the reduced number of propidium iodide‐positive cells and the cleavage of caspase‐3 and poly (ADP‐ribose) polymerase. Moreover, DRP1‐deficient mice were protected from Dox‐induced cardiac damage, strongly supporting a role for DRP1‐dependent mitochondrial fragmentation in Dox cardiotoxicity. In addition, Dox accelerated mitophagy flux, which was attenuated by DRP1 knockdown, as assessed by the mitophagy reporter mt‐Rosella, suggesting the necessity of mitochondrial fragmentation in Dox‐induced mitophagy. Knockdown of parkin, a positive regulator of mitophagy, dramatically diminished Dox‐induced cell death, whereas overexpression of parkin had the opposite effect. Together, these results suggested that Dox cardiotoxicity was mediated, at least in part, by the increased mitochondrial fragmentation and accelerated mitochondrial degradation by the lysosome. Strategies that limit mitochondrial fission and mitophagy in the physiologic range may help reduce Dox cardiotoxicity.—Catanzaro, M. P., Weiner, A., Kaminaris, A., Li, C., Cai, F., Zhao, F., Kobayashi, S., Kobayashi, T., Huang, Y., Sesaki, H., Liang, Q. Doxorubicin‐induced cardiomyocyte death is mediated by unchecked mitochondrial fission and mitophagy. FASEB J. 33, 11096–11108 (2019). http://www.fasebj.org

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“…Dox cardiotoxicity is attributed to elevated oxidative stress, DNA and mitochondrial damage and deleterious changes in gene expression, culminating in the dysregulation of multiple signal transduction pathways leading to cardiac cell death (Koleini and Kardami 2017). Currently, the only FDA-approved drug to mitigate Dox-induced cardiotoxicity is dexrazoxane, which has been of restricted use due to the concern for cancer outcomes (van Dalen et al 2011).…”

Section: Introductionmentioning

confidence: 99%

Non-mitogenic FGF2 protects cardiomyocytes from acute doxorubicin-induced toxicity independently of the protein kinase CK2/heme oxygenase-1 pathway

et al. 2018

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Doxorubicin (Dox)-induced cardiotoxicity, a limiting factor in the use of Dox to treat cancer, can be mitigated by the mitogenic factor FGF2 in vitro, via a heme oxygenase 1 (HO-1)-dependent pathway. HO-1 upregulation was reported to require protein kinase CK2 activity. We show that a mutant non-mitogenic FGF2 (S117A-FGF2), which does not activate CK2, is cardioprotective against acute cardiac ischemic injury. We now investigate the potential of S117A-FGF2 to protect cardiomyocytes against acute Dox injury and decrease Dox-induced upregulation of oxidized phospholipids. The roles of CK2 and HO-1 in cardiomyocyte protection are also addressed.Rat neonatal cardiomyocyte cultures were used as an established in vitro model of acute Dox toxicity. Pretreatment with S117A-FGF2 protected against Dox-induced: oxidative stress; upregulation of fragmented and non-fragmented oxidized phosphatidylcholine species, measured by LC/MS/MS; and cardiomyocyte injury and cell death measured by LDH release and a live-dead assay. CK2 inhibitors (TBB and Ellagic acid), did not affect protection by S117A-FGF2 but prevented protection by mitogenic FGF2. Furthermore, protection by S117A-FGF2, unlike that of FGF2, was not prevented by HO-1 inhibitors and S117A-FGF2 did not upregulate HO-1. Protection by S117A-FGF2 required the activity of FGF receptor 1 and ERK.We conclude that mitogenic and non-mitogenic FGF2 protect from acute Dox toxicity by common (FGFR1) and distinct, CK2/HO-1- dependent or CK2/HO-1-independent (respectively), pathways. Non-mitogenic FGF2 merits further consideration as a preventative treatment against Dox cardiotoxicity.

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Autophagy and mitophagy in the context of doxorubicin-induced cardiotoxicity

Cited by 261 publications

References 131 publications

Triptolide induces autophagy and apoptosis through ERK activation in human breast cancer MCF‑7 cells

Triptolide induces autophagy and apoptosis through ERK activation in human breast cancer MCF‑7 cells

Doxorubicin‐induced cardiomyocyte death is mediated by unchecked mitochondrial fission and mitophagy

Non-mitogenic FGF2 protects cardiomyocytes from acute doxorubicin-induced toxicity independently of the protein kinase CK2/heme oxygenase-1 pathway

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