ETC Cancer Research Results
ETC, Electron Transport Chain: Click to Expand ⟱
Scientific Papers found: Click to Expand⟱
*UCPs↝, The core role of UCP2‑5 is to reduce oxidative stress under certain conditions
*ETC↝, Under physiological conditions, 0.2‑2% of the electrons in the ETC do not follow the normal transfer order but instead directly leak out of the ETC and interact with oxygen to produce superoxide or hydrogenperoxide (48,49).
*ROS↝,
| - |
in-vitro, |
CRC, |
HCT116 |
|
|
|
- |
in-vitro, |
Nor, |
HEK293 |
|
|
|
NRF2↑, Nanosilver increased Nrf2 protein expression and disrupted the cell cycle at the G1 and G2/M phases.
TumCCA↑, AgNPs interact with DNA to stop
the cell cycle and lead to apoptosis
ROS↑, Nanosilver induced significant mitochondrial oxidative stress in HCT116, whereas it did not in the non-cancer HIEC-6 and nanosilver/sodium ascorbate co-treatment was preferentially lethal to HCT116 cells,
selectivity↑,
*AntiViral↑, AgNPs are effective antiviral agents against various viruses such as human
immunodeficiency virus, hepatitis B virus, and monkey pox virus through interaction with
surface glycoproteins on the virus
*toxicity↝, Citrate and PVP-coated AgNPs have been found to be less toxic than non-coated AgNPs
ETC↓, AgNPs affects mitochondrial function through the disruption of the electron transport
chain2,24,26,33,39–41
MMP↓, Studies have shown that exposure to AgNPs resulted in a decrease of mitochondrial membrane potential (MMP) in various in vitro and in vivo experiments
DNAdam↑, AgNPs has also been shown to interact with and induce damage to DNA, DNA strand breaks, DNA damage
Apoptosis↑, apoptosis induced by AgNPs were through membrane lipid peroxidation, ROS, and oxidative stress
lipid-P↑,
other↝, Several studies have showed AgNPs interact with various proteins such as haemoglobin, serum albumin, metallothioneins, copper transporters, glyceraldehyde 3-phosphate dehydrogenase (GAPDH), malate dehydrogenase (MDH), and bacterial proteins.
UPR↑, Studies have shown exposure to AgNPs induces activation of the UPR
*GRP78/BiP↑, AgNPs induced increased levels of GRP78, phosphorylated PERK, phosphorylated eIF2-α, and
phosphorylated IRE1α, spliced XBP1, cleaved ATF-6, CHOP, JNK and caspase 12
*p‑PERK↑,
*cl‑eIF2α↑,
*CHOP↑,
*JNK↑,
Hif1a↓, One study showed AgNPs inhibits HIF-1 accumulation and suppresses expression of HIF-1 target genes in breast cancer cells (MCF-7) and also found the protein
levels of HIF-1α and HIF-1β decreased
AntiCan↑, Many studies have shown that ascorbic acid, on its own, has anti-cancer effects
*toxicity↓, However, when the rats were treated with both ascorbic acid
and AgNPs, a decrease in toxic effects was observed in non-cancer parotid glands in rats
eff↑, Studies have shown both AgNPs and ascorbic acid have greater effects and toxicity in
cancer cells relative to non-cancer cells
| - |
Review, |
neuroblastoma, |
SK-N-BE |
|
|
|
Apoptosis↑, bufalin-induced mitochondrial-dependent apoptosis may be caused by disruption of the ETC.
TumCP↓, Bufalin inhibits the proliferation and migration of neuroblastoma cells
TumCMig↓,
MMP↓, As shown in Fig. 3I and J, the ΔΨm of SK-N-BE(2) cells was significantly reduced following treatment with CS-P1.
ROS↑, intracellular ROS levels were significantly increased after treatment with bufalin
ETC↓, These results suggested that bufalin induces its antitumor effects by targeting the ETC.
Bcl-2↓, downregulation of Bcl-2, as well as upregulation of Bax, cleaved caspase-3 and cleaved PARP, was observed following bufalin treatment
BAX↑,
cl‑Casp3↑,
cl‑PARP↑,
eff↓, the increase in intracellular ROS levels following treatment with bufalin was significantly reversed by NAC in SK-N-BE(2) and SH-SY5Y cells.
TumCG↓, Bufalin inhibits tumor growth in vivo
Ki-67↓, expression levels of the proliferation indicators Ki67 and PCNA were significantly decreased
PCNA↓,
tumCV↓, Treatment of U251 glioma cells with Cap and DHC resulted in a dose- and time-dependent inhibition of cell viability and induction of apoptosis,
Apoptosis↑,
selectivity↑, whereas few effects were observed on the viability of L929 normal murine fibroblast cells.
ROS↑, The apoptosis-inducing effects of Cap and DHC in U251 cells were associated with the generation of reactive oxygen species, increased Ca2+ concentrations, mitochondrial depolarization, release of cytochrome c into the cytosol and activation of caspas
Ca+2↑, Cap and DHC treatment increases ROS generation and [Ca2+]i in U251 cells
MMP↓,
Cyt‑c↑,
Casp↑,
eff↑, DHC, an analog of Cap, inhibits the proliferation of HCT116, MCF-7 and WI38 cells more potently than Cap,
MPT↑, High levels of Ca2+ can open mitochondrial permeability transition pores, depolarize mitochondrial membrane potential, activate caspase-9 and caspase-3, initiate the mitochondrial apoptosis pathway, to induce cell apoptosis
ETC↓, Cap boosts the generation of ROS in human pancreatic cancer cells by inhibiting mitochondrial complex I and III and destroying mitochondrial functions
Casp3↑, elease of cyto c to the cytosol to activate caspase-9 and −3
Casp9↑,
| - |
Review, |
Arthritis, |
NA |
|
|
|
- |
Review, |
IBD, |
NA |
|
|
|
- |
Review, |
AD, |
NA |
|
|
|
- |
Review, |
Park, |
NA |
|
|
|
*other↝, The most abundant and promising bioactive compound derived from the root of this plant is celastrol, also called tripterine, which possess a broad range of biological activities
*other↝, TW is generally used in the treatment of Crohn’s disease (CD) in China.
*CRP↓, Inflammatory parameters, including c-reactive protein (CRP), also decreased
*eff↝, Etanercept plus TW had an equivalent therapeutic effect to that of Etanercept plus MTX and were both well tolerated
*other↑, TW in human kidney transplantation (26). Rejection occurred in 4.1% of patients treated with TW versus 24.5% of control patients, showing efficacy in the prevention of renal allograph rejection
*CXCR4↓, celastrol decreases hypoxia-induced FLS invasion by inhibiting HIF-1α-mediated CXCR4 transcription
*IL1β↓, Authors have shown that it decreases the production of IL-1β, IL-6, IL-17, IL-18, and TNF by SIC cells harvested from arthritic rats
*IL6↓,
*IL17↓,
*IL18↓,
*TNF-α↓,
*MMP9↓, celastrol reduces MMP-9 production, which limits bone damage
*PGE2↓, celastrol suppresses LPS-induced expression of PEG2 via the downregulation of COX-1 and COX-2 activation
*COX1↓,
*COX2↓,
*PI3K↓, associated with a decrease in PI3K/Akt pathway
*Akt↓,
*other↑, Remarkably, this bone-protective property of celastrol in arthritic models is further supported by studies performed in cancer models
TumCCA↑, celastrol induces cell cycle arrest, apoptosis, and autophagy by the activation of reactive oxygen species (ROS)/c-Jun N-terminal kinases (JNK) signaling pathway
Apoptosis↑,
ROS↑,
JNK↑,
TumAuto↑, celastrol is still able to induce autophagy through HIF/BNIP3 activation
Hif1a↓, The inhibitory effect of celastrol on angiogenesis is mediated by the suppression of HIF-1α,
BNIP3↝,
HSP90↓, The inhibition of HSP90 by celastrol
Fas↑, activation of Fas/Fas ligand pathway in non-small-cell lung cancer
FasL↑,
ETC↓, inhibition of mitochondrial respiratory chain (MRC) complex I
VEGF↓, This inhibition of HIF-1α leads to the decrease of its target genes, such as the VEGF
angioG↓, Angiogenesis Inhibition
RadioS↑, celastrol can overcome tumor resistance to radiotherapy in prostate (129) and lung cancer cells
*neuroP↑, celastrol is a promising neuroprotective agent in animal models of neurodegenerative diseases, such as Parkinson disease (149), Huntington disease (149–151), Alzheimer disease
*HSP70/HSPA5↑, his induction of HSP70 by celastrol explains its beneficial effects not only in neurodegenerative disorders but also in inflammatory diseases.
*ROS↓, celastrol protects human dopaminergic cells from injury and apoptosis and prevents ROS generation and mitochondrial membrane potential loss
*MMP↑,
*Cyt‑c↓, It inhibits cytochrome c release, Bax/Bcl-2 alterations, caspase-9/3 activation, and p38 MAPK activation
*Casp3↓,
*Casp9↓,
*MAPK↓,
*Dose⇅, Authors discuss that it seems to have a narrow therapeutic window, and suggest that it may have a biphasic effect with protective properties at low concentrations and toxic effects at higher concentrations.
*HSPs↑, induces a set of HSPs (HSP27, 32, and 70) in rat cerebral cortical cultures, which are selectively impacted during the progression of this disease
BioAv↓, Due to this poor water solubility, celastrol has low bioavailability. oral administration of celastrol in rats results in ineffective absorption into the systemic circulation, with an absolute bioavailability of 17.06%
Dose↝, narrow therapeutic window of dose together with the occurrence of adverse effects. Our own data showed in vivo that the doses of 2.5 and 5 μg/g/day are effective and non-toxic in the treatment of arthritis in rats;
*CoQ10↑, BPGbio researchers show that BPM31510 significantly increased CoQ10 levels across multiple tissues—including the brain, kidney, muscle, and heart
*BBB↑, Notably, BPM31510 achieved targeted delivery to the cerebellum, a region of the brain whose dysfunction is associated with ataxia, a hallmark symptom of mitochondrial disorders.
*ETC↑, BPM31510, a novel formulation of CoQ10, was developed to overcome these delivery challenges, helping improve mitochondrial functioning.
eff↑, BPM31510IV is BPGbio’s lead candidate in late-stage development for aggressive solid tumors such as glioblastoma multiforme (GBM) and pancreatic cancer.
| - |
vitro+vivo, |
PC, |
MIA PaCa-2 |
|
|
|
ETC?, Here, we used BPM 31510 to assess how modulation of mitochondrial Q-pool homeostasis impacts mitochondrial electron transport chain function to activate regulated cell death.
ROS↑, BPM 31510 exposure increased oxidation of the reactive oxygen species (ROS) probes, CellROX Green and DCF-DA, increased oxidized glutathione, and decreased levels of the cellular reducing equivalent NADPH.
NADPH↓,
AntiCan↑, these data indicate that BPM31510 directly impairs the mitochondrial Q-pool and respiratory function resulting in oxidative stress and consequential cell death and thus provide mechanistic understanding of the anti-cancer activity of BPM31510.
| - |
in-vitro, |
PC, |
NA |
|
|
|
- |
in-vivo, |
PC, |
NA |
|
|
|
*ETC↝, Coenzyme Q10 is a critical cofactor in the electron transport chain with complex biological functions that extend beyond mitochondrial respiration.
ROS↑, This study demonstrates that delivery of oxidized Coenzyme Q10 (ubidecarenone) to increase mitochondrial Q-pool is associated with an increase in ROS generation, effectuating anti-cancer effects in a pancreatic cancer model.
*antiOx↑, In addition to its role in ETC function, CoQ10 has phenolic antioxidant activity via its ability to undergo hydrogen abstraction by free radicals6
ROS↑, Paradoxically, CoQ10 also exhibits pro-oxidant activity that occurs either due to a CoQ10 semiquinone reaction5 or due to a reaction with oxygen when CoQ10 is in its oxidized state
OCR↓, Delivery of supraphysiologic levels of ubidecarenone via BPM31510 decreases oxygen consumption rates (OCR) in pancreatic cancer
MMP↓, Ubidecarenone enhances succinate-dependent and glycerol-3-phosphate-dependent ROS generation, mitochondrial membrane depolarization, and regulated cell death
TumCD↑,
TumCG↓, BPM31510 (25 mg/kg, b.i.d) resulted in a significant decrease in tumour growth by day 45 after inoculation compared to saline-treated mice
other↝, NOTE: this is oxidized CoQ10, not the same as CoQ10!!!!!!
Cupro↑, As copper dysregulation is common in cancer cells, targeting copper levels or metabolic pathways can trigger cuproptosis, thereby inhibiting tumor growth and progression.
TumCG↓,
Apoptosis↑, Copper can trigger multiple forms of cell death, including apoptosis, oxidative stress-induced necrosis, autophagy and ferroptosis
ROS↑,
Ferroptosis↑,
ETC↓, . Their disruption impairs the electron transport chain and decreases ATP synthesis and mitochondrial membrane potential (76).
MMP↓,
Ca+2↑, Consequently, mitochondrial energy production decreases, accompanied by increased inner membrane permeability, elevated Ca2+ concentration and the accumulation of ROS (77).
Fenton↑, Cu2+ catalyzes the Fenton-like reaction, generating hydroxyl radicals that initiate oxidative stress, leading to extensive cell damage and death (96)
lipid-P↑, These radicals also induce lipid peroxidation, compromising the integrity and fluidity of cell membranes and increasing membrane permeability (99).
MPT↑,
ATP↓, Excess ROS decrease the mitochondrial membrane potential and ATP synthesis and promote cytochrome c release, ultimately activating caspase cascades and triggering apoptosis
Cyt‑c↑,
Casp↑,
angioG↑, Mechanistically, copper promotes tumor progression through multiple pathways. First, copper stimulates angiogenesis by activating angiogenic factors and enhancing the proliferation and migration of vascular endothelial cells
TumCP↑,
TumCMig↑,
TumCI↑, Second, copper serves as a cofactor for several metalloenzymes, including MMP-9, SOD1, vascular adhesion protein-1 and lysyl oxidase (LOX), all of which are key for cancer invasion and metastasis
TumMeta↑,
DDS↑, tussah silk fibroin (TSF)-based nanoparticles (NPs) use TME-responsive release mechanisms to deliver copper and the cuproptosis-inducing drug ES directly to pancreatic cancer cells.
eff↑, suppressed by the copper chelator TTM, further confirming the mechanism of copper-induced cell death. Furthermore, 2-deoxy-D-glucose, a glycolysis inhibitor, can significantly enhance cuproptosis
Ferroptosis↑, including the induction of ferroptosis by regulating the SLC7A11/GPX4 axis
GutMicro↑, and modulating gut microbiota metabolism. I
Akt↓, it inhibits pro-tumorigenic signals such as Akt/mTOR, NF-κB, Wnt/β-catenin, and STAT3, thereby blocking tumor proliferation, invasion, and metastasis
mTOR↓,
NF-kB↓,
Wnt↓,
β-catenin/ZEB1↓,
STAT3↓,
TumCP↓,
TumCI↓,
TumMeta↓,
AMPK↑, activates tumor-suppressive and cytoprotective pathways, including AMPK, p53, and nuclear factor erythroid 2-related factor 2 (Nrf2), which induce cell cycle arrest and apoptosis
P53↑,
NRF2↑,
TumCCA↑,
Apoptosis↑,
Casp↑, activation of the Caspase cascade
GPx4↓, as well as ferroptosis by inhibiting the solute carrier family 7 member 11 (SLC7A11)/glutathione peroxidase 4 (GPX4) axis [5]
DNMTs↓, inhibiting epigenetic regulatory mechanisms such as DNMTs and HDACs.
HDAC↓,
VEGF↓, inhibiting VEGF signaling and enhances the immune microenvironment by improving T cell and NK cell function
Imm↑,
NK cell↑,
Warburg↓, Curcumin effectively reverses the Warburg effect and interferes with glucose metabolism by targeting HIF-1α and inhibiting key enzymes, including hexokinase 2 (HK2), pyruvate kinase M2 (PKM2), and lactate dehydrogenase A (LDHA)
Hif1a↓,
HK2↓,
PKM2↓,
LDHA↓,
GLUT1↓, as well as the functions of glucose transporter 1 (GLUT1) and monocarboxylate transporters (MCTs) [12].
MCT1↓,
AMPK↑, curcumin activates signaling pathways such as AMPK, downregulates fatty acid synthase (FASN) and stearoyl-CoA desaturase (SCD1),
FASN↓,
SCD1↓,
GLS↓, Curcumin extensively intervenes in amino acid metabolism by inhibiting the activity of glutaminase (GLS), ornithine decarboxylase (ODC), and other enzymes,
Apoptosis↑, inducing apoptosis through mechanisms such as disrupting the electron transport chain, reducing membrane potential, and promoting the generation of reactive oxygen species (ROS)
ETC↓,
MMP↓,
ROS↑,
lipid-P↑, curcumin induces lipid peroxidation and collapses redox homeostasis, thereby activating the ferroptosis program [
ChemoSen↑, blocking invasion and metastasis, and enhancing chemosensitivity.
PDK1↓, In hypoxic pancreatic cancer cells, curcumin downregulates the expression of GLUT1, HK2, LDHA, and PDK1 by inhibiting the Beclin1/HIF-1α axis, which results in reduced ATP production and inhibited cell proliferation [
Beclin-1↓,
ATP↓,
Glycolysis↓, inhibiting glycolysis
GlucoseCon↓, decreased glucose uptake and increased lactate production
lactateProd↑,
MMPs↓, reduces MMP, GSH, and G6PD activities
GSH↓, inhibition of SLC7A11 to limit GSH synthesis, thereby triggering the collapse of the antioxidant defense system
G6PD↓,
OXPHOS↓, downregulate OXPHOS and glycolysis activities
SREBP2↓, curcumin treatment leads to a marked downregulation of the mRNA expression of SREBP and its target genes. inhibiting the expression of NPC1L1, SREBP-2, and HNF1α
COX2↓, curcumin exerts anti-tumor effects by downregulating the expression of NF-κB, COX-2, and AP-1
AP-1↓,
NADH↓, decreased GPx4 and FSP1 expression, induced ferroptosis by inhibiting GSH-GPx4 and FSP1-CoQ 10-NADH pathways
NRF2↑, it inhibits GPX4 and activates Nrf2 and heme oxygenase-1 (HO-1). This results in an abnormal accumulation of intracellular Fe2+, ROS, lipid peroxides, and malondialdehyde (MDA), along with a depletion of GSH
HO-1↑,
Iron↑,
MDA↑,
*ROS↓, studies have demonstrated that the topical application of curcumin on the skin exerts antitumor effects by synergistically downregulating COX-2 and ODC activities, alleviating oxidative damage, and concurrently inhibiting inflammatory proliferation i
*Inflam↓,
CellMemb↑, In this work, nsPEF treatment is used to demonstrate changes that affect viability, plasma membrane permeability ROS (Reactive Oxygen Species) in the cytosol and mitochondria, and Electron Transport Chain (ETC) in cell cultures.
ROS↑, nsPEF and rotenone synergistically enhanced ROS production in intact cells suggesting that nsPEF and rotenone act at different Complex I sites.
ETC↝, A reduced cellular oxygen consumption after nsPEFs treatment indicates an alteration of the ETC at Complex I in intact and permeabilized cells as well as in isolated hepatocyte mitochondria
OCR↓,
MMP↓, collapse the mitochondrial membrane potential and cause cell death.
ETC↓, NsPEFs attenuated electron transport (ET) (O2 consumption) in the electron transport chain (ETC) of intact and permeabilized cells
OCR↓,
CellMemb↑,
mt-ROS↑, Effects of nsPEFs on increases in mROS were synergistic with the complex I inhibitor rotenone
MMP↓, dissipating the ΔΨm
MMP↓, nsPEF bypasses plasma-membrane shielding to porate organelles, collapse mitochondrial potential, perturb ER calcium, and transiently open the nuclear envelope.
Ca+2↑,
eff↑, synergy with checkpoint blockade.
ER Stress↑, capacity to directly target organelles such as mitochondria, endoplasmic reticulum (ER),
selectivity↑, selectively ablate solid tumors, suppress metastatic spread, and prime systemic anti-tumor immunity while sparing adjacent normal tissue [7,9,10,11,12,13,14,15].
CSCs↓, Preclinical investigations have demonstrated that nsPEFs significantly reduce CSC-associated subpopulations, including CD44+/CD24− cells in breast cancer xenografts and CD133+ glioma stem-like cells
CD44↓,
CD133↓,
ROS↑, nsPEFs release Ca2+ from the ER, disrupt mitochondrial membrane potential, induce reactive oxygen species (ROS) generation, and perturb nuclear chromatin structure within nanoseconds
Imm↑, nsPEFs not only eliminate local tumor cells but also convert the tumor into an in situ vaccine, amplifying their therapeutic relevance in the era of immunotherapy
DNAdam↑, figure 2
MOMP↑, induce mitochondrial outer membrane permeabilization (MOMP)
Cyt‑c↑,
Casp9↑, Subsequent release of cytochrome c enables apoptosome assembly, caspase-9 activation, and downstream activation of caspases-3/7, culminating in cell death
Casp3↑,
Casp9↑,
TumCD↑,
Fas↑, In certain cell types, nsEP can also activate the extrinsic pathway, where Fas receptor clustering stimulates caspase-8.
UPR↑, This rapid surge triggers ER stress pathways, activates unfolded protein response (UPR) signaling, and promotes cross-talk with mitochondria through mitochondria-associated membranes (MAMs)
Dose↝, longer ns pulses (100–300 ns) generate sustained plasma membrane charging, resulting in robust Ca2+ influx, osmotic imbalance, and apoptotic priming.
Dose↝, A critical threshold of 10–20 kV/cm is generally required to initiate pore formation in malignant cells, with higher amplitudes (>30–40 kV/cm) producing more extensive permeabilization [100].
Dose↓, Low pulse counts (<100) frequently produce reversible stress responses, such as transient mitochondrial depolarization or ER Ca2+ release, without committing cells to apoptosis. I
Dose↑, In contrast, higher pulse counts (500–1000) lead to irreversible apoptosis, caspase activation, and release of DAMPs that initiate ICD [80,106].
HMGB1↓, ICD after nsPEF is characterized by surface exposure of calreticulin, extracellular ATP release, and HMGB1 emission
eff↑, The integration of nsPEFs with NP-based systems thus represents a synergistic platform where physical membrane poration and molecular targeting cooperate to maximize therapeutic efficacy.
EPR↑, demonstrates that PEF + AuNPs enhanced membrane permeabilization compared with PEF alone,
ChemoSen↑, The superior efficacy of delayed drug administration following nsPEF exposure can be attributed to transient biophysical and biochemical changes that persist after pulsing.
ETC↝, study demonstrated that nsPEFs dynamically alter trans-plasma membrane electron transport (tPMET) and mitochondrial electron transport chain activity, resulting in differential ROS generation in cancer versus non-cancer cells (Figure 9).
*AntiAge↑, Mechanistically, nsPEFs upregulated HIF-1α and SIRT1, mediators of mitochondrial retrograde signaling, thereby reversing hallmarks of aging
*Hif1a↑,
*SIRT1↑,
| - |
in-vitro, |
BC, |
4T1 |
|
|
|
- |
in-vitro, |
Nor, |
H9c2 |
|
|
|
ETC↓, NsPEFs attenuates ET in the mitochondrial electron transport system (ETS) at Complex I.
ROS↑, NsPEFs increase ROS more in cytosol of cancer cells.
*mt-ROS↑, NsPEFs increase ROS more in mitochondria in non-cancer cells.
ETC↝, nonlethal nsPEFs modulation of electron transport in the plasma membrane and the mitochondria show potential for controlling redox homeostasis and metabolism.
*ETC↓, We report that ELF-WMF efficiently suppresses the mitochondrial mass to 70% by inhibiting the mitochondrial ETC complex II, which subsequently induces mitophagy and rejuvenates mitochondria.
*OCR↑, We found that Opti-ELF-WMF increased both the OCR and mitochondrial membrane potential by approximately 40%
*MMP↑,
*ROS⇅, Opti-ELF-WMF most strongly decreased the level of mitochondrial superoxide at 1 h, mitochondrial mass at 3 h, and mitochondrial membrane potential at 6 h, and most strongly increased them at 12 h
*MMP⇅,
*ROS⇅, Although in most cases, MFs increased ROS levels in human, mouse, rat cells, and tissues, there are also studies showing that ROS levels were decreased or not affected by MFs.
*ETC↓, The electron transport chain (ETC) in the cell respiration process at mitochondrial membrane is the main source of ROS production. During ATP synthesis, electrons may escape from the ETC
Dose↝, Electromagnetic fields (EMFs)-induced ROS level changes were time-dependent.
Dose↝, 50 Hz 2 mT ELF-EMF increased ROS after 2/6 h exposure, but returned to normal level after 12/24 h
ROS↑, formation of reactive oxygen species requires electron leakage from the normal route in the respiratory
chain.
ETC↓, leakage
selectivity↑, For all those reasons, it can be expected that coapplication of a low external magnetic field and mitochondrial inducers of reactive oxygen species should damage cancer cells without any detriment to the normal cells.
ROS↑, In this review, we focus on the ETC as a source of ROS and its modulation by oncogenic pathways, which generates a vicious cycle that resets ROS levels to a higher homoeostatic set point, sustaining the cancer cell phenotype.
ETC↓, Electrons leaking from the ETC can prematurely react with oxygen, resulting in the generation of reactive oxygen species (ROS).
other↝, ETC-derived ROS are pivotal regulators of cell fate, given the central role of mitochondria in life and death.
Fenton↑, The hydroxyl radical (•OH) is a highly damaging ROS with an extremely short half-life that is generated from H2O2 in the presence of iron or copper through the Fenton reaction.
RNS↑, O2•– can also interact with nitric oxide (NO), generating the reactive nitrogen species (RNS) peroxynitrite (ONOO−), which controls signalling molecules through the nitration of tyrosine residues
Dose↝, treatment was for 2 hours on the first day with a 5-min break between the first and the second hour.
Dose↑, On the second day, two 2-hour sessions were conducted with a 1-hour break between the sessions.
Dose↑, 2-hour sessions was increased to three on the third day
OS↑, The longest documented survival for an adult with H3K27A brainstem DMG is 23 months (6). The patient in the present study survived for 30 months
toxicity↓, OMT was well tolerated by the patient
ETC↓, underlying mechanism of action of sOMF in DMG is analogous to that in GBM, involving disruption of electron transport in the mitochondrial respiratory chain, with release of ROS producing cancer cell oncolysis ()
ROS↑,
| - |
in-vitro, |
GBM, |
GBM |
|
|
|
- |
in-vitro, |
Lung, |
NA |
|
|
|
mt-ROS↑, Cytotoxic effects of OMF may be caused by an increase in ROS
Casp3↑, Cell death is associated with activation of caspase 3
selectivity↑, OMF induces highly selective cell death of patient derived GBM cells associated with activation of caspase 3, while leaving normal tissue cells undamaged
TumCD↑, Exposure to OMF causes cancer cell death
ETC↓, The underlying mechanism is a marked increase in ROS in the mitochondria, possibly in part through perturbation of the electron flow in the respiratory chain.
H2O2↑, Figure 6A shows rapid increases in the levels of superoxide and H 2 O 2 in GBM
cells,
eff↓, we used the potent antioxidant Trolox to counteract it,
GSH↑, We tested whether GSH synthesis was upregulated as a feedback protective effect in response to
OMF-induced increase in ROS. An examination of GSH levels showed that there was a 20% elevation in treated cells
MMP↓, underlying mechanism involves a marked increase in ROS, mitochondrial membrane depolarization, fragmentation of mitochondrial network and activation of caspase 3.
| - |
in-vitro, |
GBM, |
GBM115 |
|
|
|
- |
in-vitro, |
GBM, |
DIPG |
|
|
|
ROS↑, both GBM and DIPG cells ROS generated by sOMF
SDH↓, Complex II succinate dehydrogenase
eff↓, antioxidant Trolox reverses the cytotoxic effect of sOMF on glioma cells indicating that ROS play
a causal role in producing the effect
RPM↑, we hypothesized that the interaction of weak and intermediate strength magnetic fields with
the RPM mechanism in the mitochondrial ETC can perturb the electron transfer process (MEP hypothesis) to
generate superoxide.
eff↓, We observed that Helmholtz coil did not produce any significant increase in ROS at 2 and 4 h during stimulation or 2 h poststimulation in GBM and DIPG cells
eff↑, oscillating field alone is not sufficient to induce ROS and that the changing angle of the magnetic field axis is also required to achieve this effect.
eff↝, repeated pulse trains rising to and declining from the peak frequency with intervening pauses are sufficient
to achieve near maximum level of increase in ROS
eff↝, One spinning magnet or three spinning magnets generate similar cellular ROS levels and the effect
of variation of the stimulus off period.
Casp3↑, caspase 3 activation
eff↝, This indicates that the total amount of energy delivered to cancer cells is clearly not the determinant of the potency of stimulation. Instead, it appears that the longer Toff between stimuli of 750 ms in the 4-h stimulation, as opposed to 250 ms in
SOD↓, critical rise in superoxide in two types of human glioma cells (implies SOD capacity exceeded)
ETC↓, found support for the hypothesis that the sOMF-induced increase in ROS is likely due to perturbation of the electron transfer process in the mitochondrial electron transport chain (ETC)
selectivity↑, Our in vitro experiments demonstrated selective cancer cell death while sparing normal cells by sOMF-induced increase in intracellular reactive oxygen species (ROS) levels due to magnetic perturbation of mitochondrial electron transport.
ROS↑,
*ROS∅,
*toxicity∅, no significant adverse effects of chronic or acute sOMF stimulation on the health, behavior, electrocardiographic and electroencephalographic activities, hematologic profile, and brain and other tissue and organ morphology of treated mice
ETC↓, We have evidence that its mechanism of action involves alteration of electron transport in the mitochondrial respiratory chain leading to the production of reactive oxygen species
(ROS)(
TumVol↓, In a case report published recently we reported that 36-day treatment with this device caused a > 30% shrinkage of the contrast-enhanced tumor volume of a left frontal GBM
in a 53-year-old male patient
Dose↝, rrangement of oncoscillators generates a magnetic field strength of >1 mT (range 1 – ~100 mT) in each cage
ROS↑, sOMF
mitResp↓, Inhibit Mitochondrial Respiration
mtDam↑, Produce Loss of Mitochondrial Integrity
Dose↝, Repeated intermittent sOMF was applied for 2 hours at a specific frequency, in the 200-300 Hz frequency range, with on-off epochs of 250 or 500 ms duration.
MMP?, ROS generation has been shown to be driven, in part, by elevated mitochondrial membrane chemiosmotic potential (ΔΨ) and ubiquinol (QH2)
OCR↓, Immediately after cessation of field rotation we observe a loss of mitochondrial integrity (labeled LMI), with a very rapid increase in O2 consumption
mt-H2O2↑, We have previously demonstrated that sOMF treatment of cells generates superoxide/hydrogen peroxide in the mitochondrial matrix
eff↓, we repeated the same experiment in the presence of Trolox, which protects thiols from ROS oxidation (47). sOMF treatment of RLM in State 3u pre-treated with Trolox (15 μM), show minimal inhibition,
SDH↓, SDH Inhibition by sOMF in State 3u RLM Is Caused by ROS Generation
Thiols↓, suggest that thiol oxidation in SDH may result from sOMF.
GSH↓, Glutathione in the mitochondrial matrix can provide some protection from ROS, but after solubilizing the mitochondria, this protection is lost and the SDH becomes more sensitive to sOMF.
TumCD↑, sOMF is highly effective at killing non-dividing GBM cell cultures,
Casp3↑, caspase-3 activation 1 h after sOMF
Casp7↑, rapid activation of caspase-3/7
MPT↑, OMF-treated cell that causes near simultaneous MPT, release of cytochrome c and other apoptosis-inducing factors, resulting in caspase-3/7 activation in these GBM cells.
Cyt‑c↑,
selectivity↑, differential sensitivity to sOMF of cancer cells over ‘normal’ cells becomes apparent. rapid increase in the reactive oxygen species (ROS) in the mitochondria to cytotoxic levels only in cancer cells, and not in normal human cortical neurons
GSH/GSSG↓, increasing GSSG/GSH ratio
ETC↓, completely arrest electron transport in isolated, respiring, rat liver mitochondria and patient derived glioblastoma (GBM)
AntiCan↑, RMF can inhibit the growth of various types of cancer cells in vitro and in vivo and improve clinical symptoms of patients with advanced cancer.
breath↑, 0.4T, 7Hz RMF was applied to treat 13 advanced non-small cell lung cancer patients (2 h/day, 5 days per week, for 6–10 weeks)
Pain↓, Decreased pleural effusion (2 patients, 15.4%), remission of shortness of breath (5 patients, 38.5%), relief of cancer pain (5 patients, 38.5%), increased appetite (6 patients, 46.2%), improved physical strength (9 patients, 69.2%), regular bowel mov
Appetite↑,
Strength↑,
BowelM↑,
TumMeta↓, The same RMF (2 h/day, for 43 days) can also suppress the growth and metastasis of B16-F10 cells in vivo
TumCCA↑, The up-regulated transcription of miR-34a induced cell proliferation inhibition, cell cycle arrest, and cell senescence by targeting E2F1/E2F3, two members of E2F family which are major regulators of the cell cycle,
ETC↓, 2h exposure) effectively inhibited the growth of two types of cultured brain cancer cells, glioblastoma cells and diffuse intrinsic pontine glioma cells. They found that the mitochondrial electron transport chain was significantly disturbed by RMF,
MMP↓, which caused loss of mitochondrial integrity, decreased mitochondrial carbon flux in cancer cells, and eventual cancer cell death (Sharpe et al., 2021).
TumCD↑,
selectivity↑, same group further reported that the
same RMF can also selectively kill cultured human glioblastoma and
non-small cell lung cancer cells, and leave normal cells unharmed
ROS↑, Mechanistic studies revealed that RMF can increase the mitochondrial ROS level, which further activated the caspase-3 and disturbed the electron fflow in the respiratory chain pathway in cancer cells. (Helekar et al., 2021).
Casp3↑,
TumCG↓, 0.4T, 7.5Hz RMF (2 h/day, for 5 days) inhibited the growth of mouse melanoma cell line B16–F10 in vitro,
TumCCA↑, and its mechanism involved cell cycle arrest and decomposition of chromatins.
ChrMod↑,
TumMeta↓, (2 h/day, for 43 days) can also suppress the
growth and metastasis of B16–F10 cells in vivo,
Imm↑, benefiting from improved immune function, including decreased regulatory T cells, increased T cells, and dendritic cells
DCells↑,
Akt↓, inhibiting the activation of the AKT pathway (Tang et al., 2016). T
OS⇅, 51 women with advanced breast cancer underwent RMF treatment. The results showed that 27 patients among them achieved signicant therapeutic effects, and there were no side-effects
toxicity↓,
QoL↑, 13 advanced non-small cell lung cancer patients the quality of life was improved in different degrees. Median survival and 1-year survival rate was 50% and 100% longer
hepatoP↑, In addition, it seems that the RMF can also attenuate liver damage in mice bearing MCF7 and GIST-T1 cells (Zha et al., 2018)
Pain↓, The results showed that the RMF treatment reduced abdominal pain by 42.9% (9/21), nausea/vomiting by 19.0% (4/21), weight loss by 52.4% (11/21), ongoing blood loss by 9.5% (2/21), improved physical strength by 23.8% (5/21) and sleep quality by 19.0%
Weight↑,
Strength↑,
Sleep↑,
IL6↓, Furthermore, decreased levels of interleukin-6 (IL-6), granulocyte colony-stimulating factor (G-CSF) and keratinocyte-derived chemokine (KC) were observed
CD4+↑, it was discovered that macrophages and dendritic cells were
activated, CD4+ T and CD8+ T lymphocytes increased, and the ratio of
Th17/Treg was balanced.
CD8+↑,
Ca+2↑, effects of RMF were strongly
associated with increased calcium tunnel activity and intracellular Ca2+
level in CNS
radioP↑, These results suggest that RMF may be helpful to alleviate the
damage of hematopoietic function caused by radiotherapy and chemotherapy
chemoP↑,
*BMD↑, 0.4T, 8Hz RMF treatment (30min/day, for 30 days) along with calcium supplement, synergistically improved bone density
*AntiAge↑, In 2019, Xu et al. reported that a 4h exposure to a 0.2T, 4Hz RMF
delayed the aging of human umbilical vein endothelial cells (HUVEC)
*AMPK↑, Mechanistic research revealed that RMF treatment increased the expression of AMPK while reducing the expression of p21, p53 and mTOR.
*P21↓,
*P53↓,
*mTOR↓,
*OS↑, They also discovered that the RMF (2 h/day, for 6, 10 or 14days) can prolong the
health status lifespan of Caenorhabditis elegans.
*β-Endo↑, 0.1–0.8T, 0.33Hz RMF treatment signicantly increased the β-endorphin level in the blood of rabbits and humans (23 times higher than before). Moreover, it decreased serotonin (5-HT) in brains, small intestine tissue and serum of mice.
*5HT↓,
Wnt↓, In particular, niclosamide inhibits multiple oncogenic pathways such as Wnt/β-catenin, Ras, Stat3, Notch, E2F-Myc, NF-κB, and mTOR and activates tumor suppressor signaling pathways such as p53, PP2A, and AMPK.
β-catenin/ZEB1↓,
RAS↓,
STAT3↓,
NOTCH↓,
E2Fs↓,
mTOR↓,
eff↑, Moreover, niclosamide potentially improves immunotherapy by modulating pathways such as PD-1/PDL-1.
PD-1↓,
PD-L1↓, primarily through PD-L1 ligand downregulation in cancer cells.
BioAv↝, The original pharmacokinetics study showed that the maximal serum concentration can reach 0.25-6.0ug/ml (0.76-18.34 µM) following administration of a single 2g dose (11).
toxicity↓, a strong safety profile and tolerability in humans.
BioAv↑, A potential solution to the aforementioned challenge is niclosamide ethanolamine (NEN), a salt form of niclosamide that also functions as a mitochondrial uncoupler with a superior safety profile and enhanced bioavailability
ETC↑, NEN activates the ETC to boost NADH oxidation, thereby leading to an increased intracellular NAD+/NADH ratio and driving the TCA cycle forward.
NADH:NAD↓,
TCA↑,
Warburg↓, leading to a reversal of the Warburg effect and the induction of cellular differentiation
Diff↑,
AMPK↑, figure 3
P53↑,
PP2A↑,
HIF-1↓,
KRAS↓,
Myc↓,
RadioS↑, leading to a reversal of the Warburg effect and the induction of cellular differentiation
ChemoSen↑, Niclosamide has shown synergistic anti-tumor effects with a broad spectrum of chemotherapy drugs.
Dose↝, In this trial, either 500mg or 1000mg niclosamide was given three times daily to patients. However, the maximal plasma concentration ranged from 35.7–82 ng/mL (0.1µM-0.25 µM), a range that failed to be consistently above the minimum effective concent
Dose↑, In contrast, the ongoing clinical trial NCT02807805 is administering 1200 mg of reformulated orally bioavailable niclosamide orally (PO) three times daily to patients, resulting in 0.21µM-0.723 plasma niclosamide concentrations exceeding the therape
| - |
in-vitro, |
Pca, |
LNCaP |
|
|
|
- |
in-vitro, |
Pca, |
PC3 |
|
|
|
Apoptosis↑, inhibits growth of human cancer cells by causing apoptotic and autophagic cell death.
TumAuto↑,
ROS↑, we demonstrate that the PEITC-induced cell death is initiated by production of reactive oxygen species (ROS) resulting from inhibition of oxidative phosphorylation (OXPHOS)
OXPHOS↓,
ATP↓, , suppression of OXPHOS, and ATP depletion.
selectivity↑, These effects were not observed in a representative normal human prostate epithelial cell line (PrEC)
ETC↓, PEITC-induced cell death involving ROS production due to inhibition of complex III and OXPHOS.
eff↓, PEITC-mediated increase in CM· signal intensity in PC-3 cells was markedly suppressed in the presence of NAC
eff↓, Rho-0 Variants of LNCaP and PC-3 Cells Were Resistant to PEITC-induced Apoptosis
BAX↑, PEITC Treatment Caused Mitochondrial Translocation of Bax
*ETC↓, Numerous studies revealed the detrimental effects of EMFs from mobile phones, laptops, and other electric devices on sperm quality and provide evidence for extensive electron leakage from the mitochondrial electron transport chain
*ROS↑, a growing body of evidence suggests that EMF exposure during spermatogenesis induces increased ROS production associated with decreased ROS scavenging activity.
*ROS∅, Similarly, numerous authors did not find the increase in ROS levels described above
Showing Research Papers: 1 to 28 of 28
* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 28
Pathway results for Effect on Cancer / Diseased Cells:
Redox & Oxidative Stress ⓘ
Fenton↑, 2, Ferroptosis↑, 2, GPx4↓, 1, GSH↓, 2, GSH↑, 1, GSH/GSSG↓, 1, H2O2↑, 1, mt-H2O2↑, 1, HO-1↑, 1, Iron↑, 1, lipid-P↑, 3, MDA↑, 1, NADH↓, 1, NRF2↑, 3, OXPHOS↓, 2, RNS↑, 1, ROS↑, 20, mt-ROS↑, 2, RPM↑, 1, SOD↓, 1, Thiols↓, 1,
Mitochondria & Bioenergetics ⓘ
ATP↓, 3, ETC?, 1, ETC↓, 17, ETC↑, 1, ETC↝, 3, mitResp↓, 1, MMP?, 1, MMP↓, 11, MPT↑, 3, mtDam↑, 1, OCR↓, 4, SDH↓, 2,
Core Metabolism/Glycolysis ⓘ
AMPK↑, 3, FASN↓, 1, G6PD↓, 1, GLS↓, 1, GlucoseCon↓, 1, Glycolysis↓, 1, HK2↓, 1, lactateProd↑, 1, LDHA↓, 1, NADH:NAD↓, 1, NADPH↓, 1, PDK1↓, 1, PKM2↓, 1, SCD1↓, 1, SREBP2↓, 1, TCA↑, 1, Warburg↓, 2,
Cell Death ⓘ
Akt↓, 2, Apoptosis↑, 8, BAX↑, 2, Bcl-2↓, 1, Casp↑, 3, Casp3↑, 6, cl‑Casp3↑, 1, Casp7↑, 1, Casp9↑, 3, Cupro↑, 1, Cyt‑c↑, 4, Fas↑, 2, FasL↑, 1, Ferroptosis↑, 2, JNK↑, 1, MCT1↓, 1, MOMP↑, 1, Myc↓, 1, TumCD↑, 5,
Transcription & Epigenetics ⓘ
BowelM↑, 1, ChrMod↑, 1, other↝, 3, tumCV↓, 1,
Protein Folding & ER Stress ⓘ
ER Stress↑, 1, HSP90↓, 1, UPR↑, 2,
Autophagy & Lysosomes ⓘ
Beclin-1↓, 1, BNIP3↝, 1, TumAuto↑, 2,
DNA Damage & Repair ⓘ
DNAdam↑, 2, DNMTs↓, 1, P53↑, 2, cl‑PARP↑, 1, PCNA↓, 1,
Cell Cycle & Senescence ⓘ
E2Fs↓, 1, TumCCA↑, 5,
Proliferation, Differentiation & Cell State ⓘ
CD133↓, 1, CD44↓, 1, CSCs↓, 1, Diff↑, 1, HDAC↓, 1, mTOR↓, 2, NOTCH↓, 1, RAS↓, 1, STAT3↓, 2, TumCG↓, 4, Wnt↓, 2,
Migration ⓘ
AP-1↓, 1, Ca+2↑, 4, Ki-67↓, 1, KRAS↓, 1, MMPs↓, 1, TumCI↓, 1, TumCI↑, 1, TumCMig↓, 1, TumCMig↑, 1, TumCP↓, 2, TumCP↑, 1, TumMeta↓, 3, TumMeta↑, 1, β-catenin/ZEB1↓, 2,
Angiogenesis & Vasculature ⓘ
angioG↓, 1, angioG↑, 1, EPR↑, 1, HIF-1↓, 1, Hif1a↓, 3, VEGF↓, 2,
Barriers & Transport ⓘ
CellMemb↑, 2, GLUT1↓, 1,
Immune & Inflammatory Signaling ⓘ
CD4+↑, 1, COX2↓, 1, DCells↑, 1, HMGB1↓, 1, IL6↓, 1, Imm↑, 3, NF-kB↓, 1, NK cell↑, 1, PD-1↓, 1, PD-L1↓, 1,
Protein Aggregation ⓘ
PP2A↑, 1,
Drug Metabolism & Resistance ⓘ
BioAv↓, 1, BioAv↑, 1, BioAv↝, 1, ChemoSen↑, 3, DDS↑, 1, Dose↓, 1, Dose↑, 4, Dose↝, 9, eff↓, 7, eff↑, 8, eff↝, 3, RadioS↑, 2, selectivity↑, 9,
Clinical Biomarkers ⓘ
GutMicro↑, 1, IL6↓, 1, Ki-67↓, 1, KRAS↓, 1, Myc↓, 1, PD-L1↓, 1,
Functional Outcomes ⓘ
AntiCan↑, 3, Appetite↑, 1, breath↑, 1, chemoP↑, 1, hepatoP↑, 1, OS↑, 1, OS⇅, 1, Pain↓, 2, QoL↑, 1, radioP↑, 1, Sleep↑, 1, Strength↑, 2, toxicity↓, 3, TumVol↓, 1, Weight↑, 1,
Infection & Microbiome ⓘ
CD8+↑, 1,
Total Targets: 165
Pathway results for Effect on Normal Cells:
Redox & Oxidative Stress ⓘ
antiOx↑, 1, CoQ10↑, 1, ROS↓, 2, ROS↑, 1, ROS⇅, 2, ROS↝, 1, ROS∅, 2, mt-ROS↑, 1, UCPs↝, 1,
Mitochondria & Bioenergetics ⓘ
ETC↓, 3, ETC↑, 1, ETC↝, 2, MMP↑, 2, MMP⇅, 1, OCR↑, 1,
Core Metabolism/Glycolysis ⓘ
AMPK↑, 1, SIRT1↑, 1,
Cell Death ⓘ
Akt↓, 1, Casp3↓, 1, Casp9↓, 1, Cyt‑c↓, 1, JNK↑, 1, MAPK↓, 1,
Transcription & Epigenetics ⓘ
other↑, 2, other↝, 2,
Protein Folding & ER Stress ⓘ
CHOP↑, 1, cl‑eIF2α↑, 1, GRP78/BiP↑, 1, HSP70/HSPA5↑, 1, HSPs↑, 1, p‑PERK↑, 1,
DNA Damage & Repair ⓘ
P53↓, 1,
Cell Cycle & Senescence ⓘ
P21↓, 1,
Proliferation, Differentiation & Cell State ⓘ
mTOR↓, 1, PI3K↓, 1,
Migration ⓘ
MMP9↓, 1, β-Endo↑, 1,
Angiogenesis & Vasculature ⓘ
Hif1a↑, 1,
Barriers & Transport ⓘ
BBB↑, 1,
Immune & Inflammatory Signaling ⓘ
COX1↓, 1, COX2↓, 1, CRP↓, 1, CXCR4↓, 1, IL17↓, 1, IL18↓, 1, IL1β↓, 1, IL6↓, 1, Inflam↓, 1, PGE2↓, 1, TNF-α↓, 1,
Synaptic & Neurotransmission ⓘ
5HT↓, 1,
Drug Metabolism & Resistance ⓘ
Dose⇅, 1, eff↝, 1,
Clinical Biomarkers ⓘ
BMD↑, 1, CRP↓, 1, IL6↓, 1,
Functional Outcomes ⓘ
AntiAge↑, 2, neuroP↑, 1, OS↑, 1, toxicity↓, 1, toxicity↝, 1, toxicity∅, 1,
Infection & Microbiome ⓘ
AntiViral↑, 1,
Total Targets: 63
Scientific Paper Hit Count for: ETC, Electron Transport Chain
Query results interpretion may depend on "conditions" listed in the research papers.
Such Conditions may include :
-low or high Dose
-format for product, such as nano of lipid formations
-different cell line effects
-synergies with other products
-if effect was for normal or cancerous cells
Filter Conditions: Pro/AntiFlg:% IllCat:% CanType:% Cells:% prod#:% Target#:1386 State#:% Dir#:%
wNotes=on sortOrder:rid,rpid
Home Page