Mitochondria-Centric Review of Polyphenol Bioactivity in Cancer Models

Stevens, Jan F.; Revel, Johana S.; Maier, Christoph

doi:10.1089/ars.2017.7404

Cited by 71 publications

(70 citation statements)

References 220 publications

(215 reference statements)

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“…Concerning PCA, we suggest that increased respiratory chain activity is responsible for elevated ATP concentrations; lactate/pyruvate ratio is not altered, but ΔΨm is significantly improved. It has been well documented that polyphenols have an impact on oxidative phosphorylation, as well as glycolysis [97]. Curcumin and carnosol have proven to up-regulate glycolysis [98], as well as resveratrol [99] and caffeic acid [100], from which 3,4-dihydroxyhydrocinnamic acid is derived [101].…”

Section: Discussionmentioning

confidence: 99%

Polyphenols and Metabolites Enhance Survival in Rodents and Nematodes—Impact of Mitochondria

et al. 2019

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(1) Background: Polyphenols (PP) play an important role in the prevention of non-communicable diseases and may contribute to healthy aging. To investigate the molecular and cellular aspects of PP metabolites on longevity with a focus on mitochondrial function, we applied a pre-fermented mixture of polyphenols (Rechtsregulat®, RR) to rodents and nematodes. (2) Methods: The lifespans of Navar Medical Research Institute (NMRI) mice and C. elegans were recorded. The heat-stress resistance (37 °C) of C. elegans N2 was measured using nucleic staining. Respiration and membrane potential (ΔΨm) were measured in isolated mitochondria. The energetic metabolites adenosine triphosphate (ATP), lactate, and pyruvate were determined in lysates. Expression levels of longevity related genes were determined using quantitative real time polymerase chain reaction (qRT-PCR). Phenolic compounds were identified using ultra high performance liquid chromatography-diode array detection-Iontrap-multiple stage mass spectrometry (UHPLC-DAD-Iontrap-MSn). (3) Results: Several phenolic metabolites including protocatechuic acid (PCA) were identified in RR. Feeding of mice with RR resulted in a significantly increased lifespan. Heat-stress resistance (RR *** p = 0.0006; PCA **** p < 0.0001), median lifespan (NMRI: RR ** p = 0.0035; C. elegans RR * p = 0.0279; PCA **** p < 0.0001), and activity of mitochondrial respiratory chain complexes (RR *−** p = 0.0237 − 0.0052; PCA * p = 0.019 − 0.0208) of C. elegans were significantly increased after incubation with RR (10%) or PCA (780 µM). PCA significantly improved nematodes ΔΨm (* p = 0.02058) and ATP levels (* p = 0.029). RR significantly up-regulated lactate levels, indicating enhanced glycolysis. The expression levels of longevity related genes daf-16, sir-2.1, and skn-1 were significantly upregulated after PCA, and partially after RR administration. (4) Conclusion: Phenolic metabolites such as PCA have the potential to enhance health and lifespan and mitochondrial function, and thus may contribute to healthy aging.

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Section: Discussionmentioning

confidence: 99%

Polyphenols and Metabolites Enhance Survival in Rodents and Nematodes—Impact of Mitochondria

et al. 2019

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“…ETC complexes I and III are the main sources of intracellular ROS generation 16 . Disruption of ETC complex results in the leakage of electrons, which can be captured by oxygen to produce ROS 17 . Herein, we used ROS-sensitive fluorescent probe DCFH-DA to evaluate the effects of AVNs on intracellular ROS levels.…”

Section: Resultsmentioning

confidence: 99%

Avenanthramide A triggers potent ROS-mediated anti-tumor effects in colorectal cancer by directly targeting DDX3

Yang

et al. 2019

Cell Death Dis

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Colorectal cancer (CRC) is a common malignant gastrointestinal tumor with high mortality worldwide. Drug resistance and cytotoxicity to normal cells are the main causes of chemotherapeutic treatment failure in CRC. Therefore, extracting the bioactive compounds from natural products with anti-carcinogenic activity and minimal side-effects is a promising strategy against CRC. The present study aims to evaluate the anti-carcinogenic properties of avenanthramides (AVNs) extracted from oats bran and clarify the underlying molecular mechanisms. We demonstrated that AVNs treatment suppressed mitochondrial bioenergetic generation, resulting in mitochondrial swelling and increased reactive oxygen species (ROS) production. Further study indicated that AVNs treatment significantly reduced DDX3 expression, an oncogenic RNA helicase highly expressed in human CRC tissues. DDX3 overexpression reversed the ROS-mediated CRC apoptosis induced by AVNs. Of note, we identified Avenanthramide A (AVN A) as the effective ingredient in AVNs extracts. AVN A blocked the ATPase activity of DDX3 and induced its degradation by directly binding to the Arg287 and Arg294 residues in DDX3. In conclusion, these innovative findings highlight that AVNs extracts, in particular its bioactive compound AVN A may crack the current hurdles in the way of CRC treatment.

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“…This is further characterized by an increased glycolysis rate and an increase in lactic fermentation at the expense of OXPHOS. Various studies have suggested that to facilitate the transportation of ADP and ATP across the mitochondrial membrane, two types of ANT channels, ANT1 and ANT2, are present in mitochondria’s inner membrane [ 29 ]. ANT1 helps to transport ADP into the matrix and ATP (produced by ATP synthase) in the intermembrane space.…”

Section: Mitocans: the Alternative Cancer Therapymentioning

confidence: 99%

“…This drop in ATP levels can also facilitate cytosolic glycolysis and further lactate production. The hyperpolarized state is predicted to protect the cancer cells from apoptosis, too [ 29 ].…”

Section: Mitocans: the Alternative Cancer Therapymentioning

confidence: 99%

“…This hyperpolarization may be due to the increased intracellular Ca 2+ levels and upregulation of anti-apoptotic Bcl-2 protein in the cancer cells [ 27 , 28 ]. The change in expression levels of different adenine nucleotide translocase (ANT) in cancer cells may also contribute to the hyperpolarization of mitochondria [ 29 ]. Therefore, including change in acidification of cytosol, the higher mitochondrial membrane potential is also observed as other mitochondria-associated hallmarks of cancer cells.…”

Section: Introductionmentioning

confidence: 99%

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Natural Agents Targeting Mitochondria in Cancer

Mani,

Swargiary,

Singh

2020

IJMS

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Mitochondria are the key energy provider to highly proliferating cancer cells, and are subsequently considered one of the critical targets in cancer therapeutics. Several compounds have been studied for their mitochondria-targeting ability in cancer cells. These studies’ outcomes have led to the invention of “mitocans”, a category of drug known to precisely target the cancer cells’ mitochondria. Based upon their mode of action, mitocans have been divided into eight classes. To date, different synthetic compounds have been suggested to be potential mitocans, but unfortunately, they are observed to exert adverse effects. Many studies have been published justifying the medicinal significance of large numbers of natural agents for their mitochondria-targeting ability and anticancer activities with minimal or no side effects. However, these natural agents have never been critically analyzed for their mitochondria-targeting activity. This review aims to evaluate the various natural agents affecting mitochondria and categorize them in different classes. Henceforth, our study may further support the potential mitocan behavior of various natural agents and highlight their significance in formulating novel potential anticancer therapeutics.

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Mitochondria-Centric Review of Polyphenol Bioactivity in Cancer Models

Abstract: Polyphenol-induced dissipation of Δψ is a physicochemical process that cancer cells cannot develop resistance against by gene mutation. Therefore, polyphenols should receive more attention as agents for cotherapy with cancer drugs to gain synergistic activity. Antioxid. Redox Signal.

Cited by 71 publications

References 220 publications

Polyphenols and Metabolites Enhance Survival in Rodents and Nematodes—Impact of Mitochondria

Polyphenols and Metabolites Enhance Survival in Rodents and Nematodes—Impact of Mitochondria

Avenanthramide A triggers potent ROS-mediated anti-tumor effects in colorectal cancer by directly targeting DDX3

Natural Agents Targeting Mitochondria in Cancer

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