condition found tbRes List
CUR, Curcumin: Click to Expand ⟱
Features:
Curcumin is the main active ingredient in Tumeric. Member of the ginger family.Curcumin is a polyphenol extracted from turmeric with anti-inflammatory and antioxidant properties.
- Has iron-chelating, iron-chelating properties. Ferritin. But still known to increase Iron in Cancer cells.
- GSH depletion in cancer cells, exhaustion of the antioxidant defense system. But still raises GSH↑ in normal cells.
- Higher concentrations (5-10 μM) of curcumin induce autophagy and ROS production
- Inhibition of TrxR, shifting the enzyme from an antioxidant to a prooxidant
- Strong inhibitor of Glo-I, , causes depletion of cellular ATP and GSH
- Curcumin has been found to act as an activator of Nrf2, (maybe bad in cancer cells?), hence could be combined with Nrf2 knockdown

Clinical studies testing curcumin in cancer patients have used a range of dosages, often between 500 mg and 8 g per day; however, many studies note that doses on the lower end may not achieve sufficient plasma concentrations for a therapeutic anticancer effect in humans.
• Formulations designed to improve curcumin absorption (like curcumin combined with piperine, nanoparticle formulations, or liposomal curcumin) are often employed in clinical trials to enhance its bioavailability.

-Note half-life 6 hrs.
BioAv is poor, use piperine or other enhancers
Pathways:
- induce ROS production at high concentration. Lowers ROS at lower concentrations
- ROS↑ related: MMP↓(ΔΨm), ER Stress↑, UPR↑, GRP78↑, Cyt‑c↑, Caspases↑, DNA damage↑, cl-PARP↑, HSP↓
- Lowers AntiOxidant defense in Cancer Cells: GSH↓ Catalase↓ HO1↓ GPx↓
but conversely is known as a NRF2↑ activator in cancer
- Raises AntiOxidant defense in Normal Cells: ROS↓, NRF2↑, SOD↑, GSH↑, Catalase↑,
- lowers Inflammation : NF-kB↓, COX2↓, p38↓, Pro-Inflammatory Cytokines : TNF-α↓, IL-6↓, IL-8↓
- inhibit Growth/Metastases : TumMeta↓, TumCG↓, EMT↓, MMPs↓, MMP2↓, MMP9↓, uPA↓, VEGF↓, NF-κB↓, CXCR4↓, SDF1↓, TGF-β↓, α-SMA↓, ERK↓
- reactivate genes thereby inhibiting cancer cell growth : HDAC↓, DNMT1↓, DNMT3A↓, EZH2↓, P53↑, HSP↓, Sp proteins↓,
- cause Cell cycle arrest : TumCCA↑, cyclin D1↓, CDK2↓, CDK4↓, CDK6↓,
- inhibits Migration/Invasion : TumCMig↓, TumCI↓, ERK↓, EMT↓, TOP1↓, TET1↓,
- inhibits glycolysis /Warburg Effect and ATP depletion : HIF-1α↓, PKM2↓, cMyc↓, GLUT1↓, LDHA↓, HK2↓, PFKs↓, PDKs↓, HK2↓, ECAR↓, OXPHOS↓, GRP78↑, GlucoseCon↓
- inhibits angiogenesis↓ : VEGF↓, HIF-1α↓, Notch↓, FGF↓, PDGF↓, EGFR↓, Integrins↓,
- inhibits Cancer Stem Cells : CSC↓, CK2↓, Hh↓, GLi1↓, CD133↓, CD24↓, β-catenin↓, n-myc↓, sox2↓, OCT4↓,
- Others: PI3K↓, AKT↓, JAK↓, STAT↓, Wnt↓, β-catenin↓, AMPK↓, ERK↓, JNK, TrxR**,
- Synergies: chemo-sensitization, chemoProtective, RadioSensitizer, RadioProtective, Others(review target notes), Neuroprotective, Cognitive, Renoprotection, Hepatoprotective, CardioProtective,

- Selectivity: Cancer Cells vs Normal Cells


PKM2, Pyruvate Kinase, Muscle 2: Click to Expand ⟱
Source:
Type: enzyme
PKM2 (Pyruvate Kinase, Muscle 2) is an enzyme that plays a crucial role in glycolysis, the process by which cells convert glucose into energy. PKM2 is a key regulatory enzyme in the glycolytic pathway, and it is primarily expressed in various tissues, including muscle, brain, and cancer cells.
-C-myc is a common oncogene that enhances aerobic glycolysis in the cancer cells by transcriptionally activating GLUT1, HK2, PKM2 and LDH-A
-PKM2 has been shown to be overexpressed in many types of tumors, including breast, lung, and colon cancer. This overexpression may contribute to the development and progression of cancer by promoting glycolysis and energy production in cancer cells.
-inhibition of PKM2 may cause ATP depletion and inhibiting glycolysis.
-PK exists in four isoforms: PKM1, PKM2, PKR, and PKL
-PKM2 plays a role in the regulation of glucose metabolism in diabetes.
-PKM2 is involved in the regulation of cell proliferation, apoptosis, and autophagy.
– Pyruvate kinase catalyzes the final, rate-limiting step of glycolysis, converting phosphoenolpyruvate (PEP) to pyruvate with the production of ATP.
– The PKM2 isoform is uniquely regulated and can exist in both highly active tetrameric and less active dimeric forms.
– Cancer cells often favor the dimeric form of PKM2 to slow pyruvate production, thereby accumulating upstream glycolytic intermediates that can be diverted into anabolic pathways to support cell growth and proliferation.
– Under low oxygen conditions, cancer cells rely on altered metabolic pathways in which PKM2 is a key player. – The shift to aerobic glycolysis (Warburg effect) orchestrated in part by PKM2 helps tumor cells survive and grow in hypoxic conditions.

– Elevated expression of PKM2 is frequently observed in many cancer types, including lung, breast, colorectal, and pancreatic cancers.
– High levels of PKM2 are often correlated with enhanced tumor aggressiveness, poor differentiation, and advanced clinical stage.

PKM2 in carcinogenesis and oncotherapy

Inhibitors of PKM2:
-Shikonin, Resveratrol, Baicalein, EGCG, Apigenin, Curcumin, Ursolic Acid, Citrate (best known as an allosteric inhibitor of phosphofructokinase-1 (PFK-1), a key rate-limiting enzyme in glycolysis) potential to directly inhibit or modulate PKM2 is less well established

Full List of PKM2 inhibitors from Database
-key connected observations: Glycolysis↓, lactateProd↓, ROS↑ in cancer cell, while some result for opposite effect on normal cells.
Tumor pyruvate kinase M2 modulators

Flavonoids effect on PKM2
Compounds name IC50/AC50uM Effect
Flavonols
1. Fisetin 0.90uM Inhibition
2. Rutin 7.80uM Inhibition
3. Galangin 8.27uM Inhibition
4. Quercetin 9.24uM Inhibition
5. Kaempferol 9.88uM Inhibition
6. Morin hydrate 37.20uM Inhibition
7. Myricetin 0.51uM Activation
8. Quercetin 3-b- D-glucoside 1.34uM Activation
9. Quercetin 3-D -galactoside 27-107uM Ineffective
Flavanons
10. Neoeriocitrin 0.65uM Inhibition
11. Neohesperidin 14.20uM Inhibition
12. Naringin 16.60uM Inhibition
13. Hesperidin 17.30uM Inhibition
14. Hesperitin 29.10uM Inhibition
15. Naringenin 70.80uM Activation
Flavanonols
16. (-)-Catechin gallateuM 0.85 Inhibition
17. (±)-Taxifolin 1.16uM Inhibition
18. (-)-Epicatechin 1.33uM Inhibition
19. (+)-Gallocatechin 4-16uM Ineffective
Phenolic acids
20. Ferulic 11.4uM Inhibition
21. Syringic and 13.8uM Inhibition
22. Caffeic acid 36.3uM Inhibition
23. 3,4-Dihydroxybenzoic acid 78.7uM Inhibition
24. Gallic acid 332.6uM Inhibition
25. Shikimic acid 990uM Inhibition
26. p-Coumaric acid 22.2uM Activation
27. Sinapinic acids 26.2uM Activation
28. Vanillic 607.9uM Activation


Scientific Papers found: Click to Expand⟱
2304- CUR,    Curcumin decreases Warburg effect in cancer cells by down-regulating pyruvate kinase M2 via mTOR-HIF1α inhibition
- in-vitro, Lung, H1299 - in-vitro, BC, MCF-7 - in-vitro, Cerv, HeLa - in-vitro, Pca, PC3 - in-vitro, Nor, HEK293
Glycolysis↓, curcumin inhibits glucose uptake and lactate production (Warburg effect) in a variety of cancer cell lines
GlucoseCon↓,
lactateProd↓,
PKM2↓, by down-regulating PKM2 expression, via inhibition of mTOR-HIF1α axis.
mTOR↓,
Hif1a↓,
selectivity↑, however, no appreciable decrease in Warburg effect was observed in HEK 293 cells
Dose↝, Dose-dependent decrease in Warburg effect started at 2.5 μM with maximal decrease at 20 μM curcumin.
tumCV↓, Curcumin decreases viability of cancer cells

2305- CUR,    Mitochondrial targeting nano-curcumin for attenuation on PKM2 and FASN
- in-vitro, BC, MCF-7
BioAv↑, This nano-curcumin can readily enter mitochondrion in MCF-7 cancer cells.
PKM2↓, expression of both pyruvate kinase M2 and fatty acid synthase in the MCF-7 cancer cells were noticeably inhibited by CUR@DNA-FeS2-DA
FASN↓,
Glycolysis↓,

2307- CUR,    Cell-Type Specific Metabolic Response of Cancer Cells to Curcumin
- in-vitro, Colon, HT29 - in-vitro, Laryn, FaDu
PKM2↓, Siddiqui et al. have recently reported that curcumin downregulates PKM2 expression in cancer cells, consequently decreasing the Warburg effect.
Warburg↓,
mTOR↓, pKM2 downregulation coincided with the inhibition of the mammalian target of rapamycin (mTOR) pathway and consequential downregulation of hypoxia-inducible factor 1-alpha HIF1α
Hif1a↓,
Glycolysis↓, showed that a decrease of PKM2 (mediated by curcumin or by targeted PKM2 silencing) significantly reduces aerobic glycolysis and is also consequential for cell survival.

2308- CUR,    Counteracting Action of Curcumin on High Glucose-Induced Chemoresistance in Hepatic Carcinoma Cells
- in-vitro, Liver, HepG2
GlucoseCon↓, Curcumin obviated the hyperglycemia-induced modulations like elevated glucose consumption, lactate production, and extracellular acidification, and diminished nitric oxide and reactive oxygen species (ROS) production
lactateProd↓,
ECAR↓,
NO↓,
ROS↑, Curcumin favors the ROS production in HepG2 cells in normal as well as hyperglycemic conditions. ROS production was detected in cancer cells treated with curcumin, or doxorubicin, or their combinations in NG or HG medium for 24 h
HK2↓, HKII, PFK1, GAPDH, PKM2, LDH-A, IDH3A, and FASN. Metabolite transporters and receptors (GLUT-1, MCT-1, MCT-4, and HCAR-1) were also found upregulated in high glucose exposed HepG2 cells. Curcumin inhibited the elevated expression of these enzymes, tr
PFK1↓,
GAPDH↓,
PKM2↓,
LDHA↓,
FASN↓,
GLUT1↓, Curcumin treatment was able to significantly decrease the expression of GLUT1, HKII, and HIF-1α in HepG2 cells either incubated in NG or HG medium.
MCT1↓,
MCT4↓,
HCAR1↓,
SDH↑, Curcumin also uplifted the SDH expression, which was inhibited in high glucose condition
ChemoSen↑, Curcumin Prevents High Glucose-Induced Chemoresistance
ROS↑, Treatment of cells with doxorubicin in presence of curcumin was found to cooperatively augment the ROS level in cells of both NG and HG groups.
BioAv↑, Curcumin Favors Drug Accumulation in Cancer Cells
P53↑, An increased expression of p53 in curcumin-treated cells can be suggestive of susceptibility towards cytotoxic action of anticancer drugs
NF-kB↓, curcumin has therapeutic benefits in hyperglycemia-associated pathological manifestations and through NF-κB inhibition
pH↑, Curcumin treatment was found to resist the lowering of pH of culture supernatant both in NG as well in HG medium.

2312- CUR,    Dual Role of Reactive Oxygen Species and their Application in Cancer Therapy
- Review, Var, NA
ROS↑,
PKM2↓, ROS accumulation inhibits PKM2

2306- SIL,  CUR,  RES,  EA,    Identification of Natural Compounds as Inhibitors of Pyruvate Kinase M2 for Cancer Treatment
- in-vitro, BC, MDA-MB-231
PKM2↓, silibinin, curcumin, resveratrol, and ellagic acid as potential inhibitors of PKM2
Dose↝, IC50 values of 0.91 µM, 1.12 µM, 3.07 µM, and 4.20 µM respectively(enzymatic-assay-based screening)
Dose↝, IC50 against MDA-MB231 cells 208uM, 26uM, 306uM, 20um respectively


* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 6

Results for Effect on Cancer/Diseased Cells:
BioAv↑,2,   ChemoSen↑,1,   Dose↝,3,   ECAR↓,1,   FASN↓,2,   GAPDH↓,1,   GlucoseCon↓,2,   GLUT1↓,1,   Glycolysis↓,3,   HCAR1↓,1,   Hif1a↓,2,   HK2↓,1,   lactateProd↓,2,   LDHA↓,1,   MCT1↓,1,   MCT4↓,1,   mTOR↓,2,   NF-kB↓,1,   NO↓,1,   P53↑,1,   PFK1↓,1,   pH↑,1,   PKM2↓,6,   ROS↑,3,   SDH↑,1,   selectivity↑,1,   tumCV↓,1,   Warburg↓,1,  
Total Targets: 28

Results for Effect on Normal Cells:

Total Targets: 0

Scientific Paper Hit Count for: PKM2, Pyruvate Kinase, Muscle 2
6 Curcumin
1 Silymarin (Milk Thistle) silibinin
1 Resveratrol
1 Ellagic acid
Filter Conditions: Pro/AntiFlg:%  IllCat:%  CanType:%  Cells:%  prod#:65  Target#:772  State#:%  Dir#:%
  wNotes=on  sortOrder:rid,rpid

 

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