Therapeutic potential of targeting mitochondrial dynamics in cancer

Rodrigues, Tiago; Ferraz, Letícia Silva

doi:10.1016/j.bcp.2020.114282

Cited by 114 publications

(95 citation statements)

References 97 publications

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“…The level of ROS in the cells is a critical factor that regulates cell proliferation and cell death. Excessive accumulation of ROS can lead to cell cycle arrest and apoptosis through the regulation of various pathways (Moloney and Cotter 2018 ; Rodrigues and Ferraz 2020 ). After referencing a lot of literature, we found that BA can induce ROS formation in cancer cells (Wang et al 2017 , 2019 ; Xu et al 2017 ; Goswami et al 2018 ; Shen et al 2019 ), but may reduce ROS production in normal cells (Cheng et al 2019 ; Cheng et al 2019 ; Kong et al 2021 ), which means that BA has potent antioxidant activity in normal cells.…”

Section: Discussionmentioning

confidence: 99%

“…BA also enhanced the activity of caspase-9 and -3, but not caspase-8, and induced the degradation of PARP, indicating that BA promoted apoptosis in U937 cells through the activation of the intrinsic pathway. Meanwhile, disturbance of mitochondrial membrane permeability due to mitochondrial dysfunction caused by excessive ROS production trigger apoptosis through the activation of the intrinsic pathway (Moloney and Cotter 2018 ; Rodrigues and Ferraz 2020 ). In this study, BA-induced loss of MMP was significantly suppressed when ROS production was blocked.…”

Section: Discussionmentioning

confidence: 99%

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The anti-cancer effect of betulinic acid in u937 human leukemia cells is mediated through ROS-dependent cell cycle arrest and apoptosis

Park

Jeong

Han

et al. 2021

Animal Cells and Systems

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Although previous studies have shown anti-cancer activity of betulinic acid (BA), a pentacyclic triterpenoid, against various cancer lines, the underlying molecular mechanisms are not well elucidated. In this study, we evaluated the mechanisms involved in the anti-cancer efficacy of BA in U937 human myeloid leukemia cells. BA exerted a significant cytotoxic effect on U937 cells through blocking cell cycle arrest at the G2/M phase and inducing apoptosis, and that the intracellular reactive oxygen species (ROS) levels increased after treatment with BA. The down-regulation of cyclin A and cyclin B1, and up-regulation of cyclin-dependent kinase inhibitor p21WAF1/CIP1 revealed the G2/M phase arrest mechanism of BA. In addition, BA induced the cytosolic release of cytochrome c by reducing the mitochondrial membrane potential with an increasing Bax/Bcl-2 expression ratio. BA also increased the activity of caspase-9 and -3, and subsequent degradation of the poly (ADP-ribose) polymerase. However, quenching of ROS by N -acetyl-cysteine, an ROS scavenger, markedly abolished BA-induced G2/M arrest and apoptosis, indicating that the generation of ROS plays a key role in inhibiting the proliferation of U937 cells by BA treatment. Taken together, our results provide a mechanistic rationale that BA exhibits anti-cancer properties in U937 leukemia cells through ROS-dependent induction of cell cycle arrest at G2/M phase and apoptosis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The anti-cancer effect of betulinic acid in u937 human leukemia cells is mediated through ROS-dependent cell cycle arrest and apoptosis

Park

Jeong

Han

et al. 2021

Animal Cells and Systems

View full text Add to dashboard Cite

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“…DRP1 phosphorylation is regulated by a variety of kinases, including PKCδ [ 73 ], Cdk1/cyclin B [ 49 ], ERK1/2 [ 74 ], Ca 2+ /calmodulin-dependent protein kinase I alpha (CaMKIalpha) [ 75 ], adenosine monophosphate (AMP)–activated protein kinase (AMPK) [ 76 ], and cyclic AMP-dependent protein kinase (PKA) [ 77 ]. Although mitochondrial fission represents the opposite process of mitochondrial fusion, increasing evidence shows an important role of the first process in chemoresistance as well [ 78 ]. Interestingly, latent membrane protein 1 (LMP1), a major Epstein–Barr virus (EBV)-encoded oncoprotein, has been found to regulate DRP1 through two oncogenic signaling axes: AMPK and cyclin B1/Cdk1.…”

Section: Role Of Mitochondrial Remodeling (Fusion Fission Mitophagy and Transfer) In Cancer Chemoresistancementioning

confidence: 99%

Mitochondria: Insights into Crucial Features to Overcome Cancer Chemoresistance

Genovese

Carinci

Modesti

et al. 2021

IJMS

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Mitochondria are key regulators of cell survival and are involved in a plethora of mechanisms, such as metabolism, Ca2+ signaling, reactive oxygen species (ROS) production, mitophagy and mitochondrial transfer, fusion, and fission (known as mitochondrial dynamics). The tuning of these processes in pathophysiological conditions is fundamental to the balance between cell death and survival. Indeed, ROS overproduction and mitochondrial Ca2+ overload are linked to the induction of apoptosis, while the impairment of mitochondrial dynamics and metabolism can have a double-faceted role in the decision between cell survival and death. Tumorigenesis involves an intricate series of cellular impairments not yet completely clarified, and a further level of complexity is added by the onset of apoptosis resistance mechanisms in cancer cells. In the majority of cases, cancer relapse or lack of responsiveness is related to the emergence of chemoresistance, which may be due to the cooperation of several cellular protection mechanisms, often mitochondria-related. With this review, we aim to critically report the current evidence on the relationship between mitochondria and cancer chemoresistance with a particular focus on the involvement of mitochondrial dynamics, mitochondrial Ca2+ signaling, oxidative stress, and metabolism to possibly identify new approaches or targets for overcoming cancer resistance.

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“…Moreover, the data in this work support our previous study in that the LDHA/B-DKO cell line triggered a metabolic response with heightened OXPHOS capacity (15). The baseline respiratory differential may have contributed to a resistance to MPP+ either by necessitating a higher required concentration of MPP+ to elicit damage, or possibly by extruding the drug equipped with high capacity ATPase multi-drug resistance pumps, as there is a clear relationship between higher OXPHOS stem cell metabolism, chemo-resistance, enhanced expression of ATP binding cassette multi-drug resistance pumps and poor clinical outcomes (77)(78)(79).…”

Section: Table II David Functional Annotation Pathway Analysis Of Up-regulated Degs Caused By Mpp+ When Comparing Controls Vs Controls + mentioning

confidence: 99%

Metabolic Response to the Mitochondrial Toxin 1-Methyl-4-phenylpyridinium (MPP+) in LDH-A/B Double-knockout LS174T Colon Cancer Cells

Mack

Mazzio

Badisa

et al. 2021

Cancer Genomics Proteomics

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Background/Aim: Rapid glycolytic substrate-level phosphorylation (SLP) and accumulation of lactic acid are characteristics of diverse cancers. Recent advances in drug discovery have included the use of glycolytic inhibitors with mitochondrial targeting drugs to attempt to invoke an energy crisis in aggressive metabolically active chemo-resistant cancers. In this work, we examine the consequences of inhibiting mitochondrial oxidative phosphorylation (OXPHOS) with 1-methyl-4-phenylpyridinium (MPP+) in LS14T colon cancer cells containing a genetic double knock out (DKO) of lactic acid dehydrogenase (LDHA and LDHB). Materials and Methods: Several metabolic parameters were evaluated concomitant to whole transcriptomic (WT) mRNA, microRNA, and long intergenic non-coding RNAs using Affymetrix 2.1 human ST arrays. Results: MPP+ effectively blocked OXPHOS where a compensatory shift toward anaerobic SLP was only observed in the control vector (CV), and not observed in the LDH-A/B DKOs (lacking the ability to produce lactic acid). Despite this, there was an unexpected resilience to MPP+ in the latter in terms of energy, which displayed significantly higher resting baseline respiratory OXPHOS capacity relative to controls. At the transcriptome level, MPP+ invoked 1738 differential expressed genes (DEGs) out of 48,226; LDH-A/B DKO resulted in 855 DEGs while 349 DEGs were found to be overlapping in both groups versus respective controls, including loss of mitochondrial complex I (subunits 3 and 6), cell cycle transcripts and fluctuations in epigenetic chromatin remodeling systems. In terms of energy, the effects of MPP+ in the CV transcripts reflect the funneling of carbon intermediates toward glycolysis. The LDH-A/B DKO transcripts reflect a flow of carbons away from glycolysis toward the production of acetyl-CoA. Conclusion: The findings from this study suggest a metabolic resilience to MPP+ in cancer cells devoid of LDH-A/B, explainable in-part by higher baseline OXPHOS respiratory ATP production, necessitating more toxin to suppress the electron transport chain.

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Therapeutic potential of targeting mitochondrial dynamics in cancer

Cited by 114 publications

References 97 publications

The anti-cancer effect of betulinic acid in u937 human leukemia cells is mediated through ROS-dependent cell cycle arrest and apoptosis

The anti-cancer effect of betulinic acid in u937 human leukemia cells is mediated through ROS-dependent cell cycle arrest and apoptosis

Mitochondria: Insights into Crucial Features to Overcome Cancer Chemoresistance

Metabolic Response to the Mitochondrial Toxin 1-Methyl-4-phenylpyridinium (MPP+) in LDH-A/B Double-knockout LS174T Colon Cancer Cells

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