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Nathan Goodyear

Antitumor activity of dichloroacetate on C6 glioma cell: in vitro and in vivo evaluation - 0 views

www.ncbi.nlm.nih.gov/...PMC3601023

cancer DCA

shared by Nathan Goodyear on 12 Nov 14 - No Cached
  • the oral bioavailability of DCA is nearly 100%
  • the oral bioavailability of DCA is almost 100%.
  • DCA can penetrate into the traditional chemotherapy sanctuary sites. Interestingly, it was reported that DCA could penetrate across the BBB,30 exhibiting the potential activity for brain therapy.
  • ...23 more annotations...
  • Clinical studies of DCA have shown reduced lactate levels
  • It has been reported that DCA activates the PDH by inhibition of PDK in a dose-dependent manner, and results in increased delivery of pyruvate into the mitochondria
  • The antitumor activity of DCA on nonsmall cell lung cancer, breast cancer, glioblastomas, and endometrial and prostate cancer cells has been demonstrated
  • It is well known that many chemotherapeutic agents have a low therapeutic index in brain tumors.
  • The most common metabolic hallmark of cancer cells is their propensity to metabolize glucose to lactic acid at a high rate even in the presence of oxygen
  • Pyruvate dehydrogenase kinase (PDK) is a gate-keeping enzyme that regulates the flux of carbohydrates (pyruvate) into the mitochondria
  • In the presence of activated PDK, pyruvate dehydrogenase (PDH), a critical enzyme that converts pyruvate to acetyl-CoA instead of lactate in glycolysis, is inhibited, limiting the entry of pyruvate into the mitochondria.
  • the level of Hsp70 was significantly decreased
  • DCA can penetrate the BBB
  • It has been reported that DCA treatment resulted in an increase in the proportion of tumor cells in the S phase, showing a decrease in proliferation as well as the induction of apoptosis
  • Heat shock proteins (HSPs) are involved in protein folding, aggregation, transport, and/or stabilization by acting as a molecular chaperone, leading to the inhibition of apoptosis by both caspase-dependent and/or independent pathways
  • HSPs are overexpressed in a wide range of human cancers and are implicated in tumor cell proliferation, differentiation, invasion, and metastasis
  • Considering the fact that high expression of HSPs is essential for cancer survival, the inhibition of HSPs is an important strategy of anticancer therapy.
  • In addition, after 5 years of continued treatment with oral DCA at a dose of 25 mg/kg, the serum DCA levels are only slightly increased compared with the levels after the first several doses, also showing its safety for oral administration at this dose.
  • DCA can enter the circulation rapidly after oral administration and then generate the stimulation of PDH activity generally within minutes.
  • Our in vivo results in tumor tissues indicated that DCA significantly induced ROS production and decreased MMP in tumor tissues
  • The numbers of microvessels in the DCA treatment groups were significantly decreased, suggesting the potential antiangiogenic effect of DCA
  • Under hypoxic conditions, hypoxia-inducible factor (HIF-1α) is activated and induces angiogenesis
  • In addition, HIF-1α can also induce the expression of PDK,48 which can inhibit the activity of PDH
  • The inhibition effect of DCA on HIF-1α would decrease vascular endothelial growth factor and inhibit angiogenesis
  • the antiangiogenic effect in the 25 mg/kg treatment group was lower than that in 75 mg/kg or 125 mg/kg treatment groups
  • In conclusion, DCA induces the apoptosis of C6 cells through the activation of the mitochondrial pathway, arresting the cell cycle of C6 cells in S phase and down-regulating Hsp70 expression.
  • DCA significantly induced the ROS production and decreased the MMP in tumor tissues. Our in vivo antitumor activity results also indicated that DCA has an antiangiogenic effect
  • Nathan Goodyear on 12 Nov 14
     
    DCA as proposed therapy in cancer.
Nathan Goodyear

Role of Oxidative Stress and the Microenvironment in Breast Cancer Development and Prog... - 0 views

www.ncbi.nlm.nih.gov/...PMC3950899

cancer oxidative stress warburg effect reverse warburg effect ROS

shared by Nathan Goodyear on 11 Nov 14 - No Cached
  • oxidative stress leads to HIF-1α accumulation
  • increased levels of hydrogen peroxide in exhaled breath condensate from patients with localized breast malignancy, associated with increased clinical severity
  • Oxidative stress generated by breast cancer cells activates HIF-1α and NFκB in fibroblasts, leading to autophagy and lysosomal degradation of Cav-1
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  • Comparing mitochondrial metabolic activity revealed a difference between stroma and epithelial cells
  • metalloproteinases (MMP) such as MMP-2, MMP-3, and MMP-9 increase extracellular matrix turnover and are themselves activated by oxidative stress
  • Overexpression of NOX4 in normal breast epithelial cells results in cellular senescence, resistance to apoptosis, and tumorigenic transformation, as well as increased aggressiveness of breast cancer cells
  • Lowered expression of Cav-1 not only leads to myofibroblast conversion and inflammation but also seems to impact aerobic glycolysis, leading to secretion of high energy metabolites such as pyruvate and lactate that drive mitochondrial oxidative phosphorylation in cancer cells
  • Reverse Warburg Effect
  • secreted transforming growth factor β (TGFβ), insulin-like growth factor (IGF), platelet-derived growth factor (PDGF), fibroblast growth factor 2, and stromal-derived factor 1 (SDF1) are able to activate fibroblasts and increase cancer cell proliferation
  • oxidative stress has an important role in the initiation and preservation of breast cancer progression
  • cancer preventive role of healthy mitochondria
  • the cancer cells produce hydrogen peroxide and by driving the “Reverse Warburg Effect” initiate oxidative stress in fibroblasts. As a result of this process, fibroblasts exhibited reduced mitochondrial activity, increased glucose uptake, ROS, and metabolite production.
  • Oxidative stress results from an imbalance between unstable reactive species lacking one or more unpaired electrons (superoxide anion, hydrogen peroxide, hydroxyl radical, reactive nitrogen species) and antioxidants
  • cancer cells are able to induce drivers of oxidative stress, autophagy and mitophagy: HIF-1α and NFκB in surrounding stroma fibro-blasts
  • Studies show that loss of Cav-1 in adjacent breast cancer stroma fibroblasts can be prevented by treatment with N-acetyl cysteine, quercetin, or metformin
  • However, diets rich in antioxidants have fallen short in sufficiently preventing cancer
  • obstructing oxidative stress in the tumor microenvironment can lead to mitophagy and promote breast cancer shutdown is a promising discovery for the development of future therapeutic interventions.
  • It is widely held that HIF-1α function is dependent upon its location within the tumor microenvironment. It acts as a tumor promoter in CAFs and as a tumor suppressor in cancer cells
  • It was reported that overexpression of recombinant (SOD2) (Trimmer et al., 2011) or injection of SOD, catalase, or their pegylated counterparts can block recurrence and metastasis in mice
  • hydrogen peroxide is one of the main factors that can push fibroblasts and cancer cells into senescence
  • Recent studies show that in the breast cancer microenvironment, oxidative stress causes mitochondrial dysfunction
  • Nathan Goodyear on 11 Nov 14
     
    Really fascinating article on tumor signaling. The article points to a complex signaling between cancer cells and stromal fibroblasts that results in myofibroblast transformation that increases the microenvironment favorability of cancer. This article points to oxidative stress as the primary driving force.  
Nathan Goodyear

Curcumin decreases Warburg effect in cancer cells by down-regulating pyruvate... - 0 views

www.ncbi.nlm.nih.gov/...PMC5974195

lactate Curcumin HIF-1 HIF-1alpha Warburg effect PKM2 oncogenic metabolism mTOR

shared by Nathan Goodyear on 07 May 21 - No Cached
  • Nathan Goodyear on 07 May 21
     
    Curcumin is anti-warburg effect through its inhibition of PKM2
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