condition found tbRes List
ART/DHA, Artemisinin: Click to Expand ⟱
Features:
Artemisinin a compound in a Chinese herb that may inhibit tumor growth and metastasis Artemisinin (antimalarial drugs)
Artesunic acid (Artesunate) , Dihydroartemisinin (DHA), artesunate, arteether, and artemether, SM735, SM905, SM933, SM934, and SM1044

The induction of OS in tumor cells via the production of ROS is the key mechanism of ART against cancer.
combination of ART and Nrf2 inhibitors to promote ferroptosis may have more efficient anticancer effects without damaging normal cells.

Summary:
- Pro-oxidant, mechanism related with iron (hence avoid supplements containing iron? Or perhaps take with iron?)
-ROS seems to affect both cancer and normal cells
- Delivery of artemisinin in conjugate form with transferrin or holotransferrin (serum iron transport proteins) have been shown to greatly improve its effectiveness.
- Potential direct inhibitor of STAT3
- Artemisinin synergized with the glycolysis inhibitor 2DG (2-deoxy- D -glucose)
ART Combined Therapy: Allicin, Resveratrol, Curcumin, VitC (but not orally at same time), Butyrate , 2-DG, Aminolevulinic AcidG
-possible problems with liver toxicity??

-Artesunate (ART), an artemisinin compound, is known for lysosomal degradation of ferritin, inducing oxidative stress and promoting cancer cell death.

Pathways:
- Increasing reactive oxygen species (ROS) production. This oxidative stress can cause the loss of mitochondrial membrane potential, leading to cytochrome c release and subsequent activation of caspase cascades.
- Downregulate HIF-1α
- By impairing glycolysis, artemisinin might force cells to rely on oxidative phosphorylation (OXPHOS) for energy production.
- Inhibit GLUT1 (glucose uptake), HK2, PKM2 (slow the glycolytic flux, thereby reducing the energy supply)

-Artemisinin has a half-life of about 3-4 hours, Artesunate 40 minutes and Artemether 12 hours. Peak plasma levels occur in 1-2 hour.
BioAv 21%, poor-good solubility. Artesunate (ART), a water soluble derivative of artemisinin. concentrations higher in blood, colon, liver, kidney (highly perfused organs)
Pathways:
- induce ROS production, iron dependent (affect both cancer and normal cells)
- ROS↑ related: MMP↓(ΔΨm), ER Stress↑, UPR↑, GRP78↑, Ca+2↑, Cyt‑c↑, Caspases↑, DNA damage↑, cl-PARP↑, HSP↓,
- Both Lowers (and raises) AntiOxidant defense in Cancer Cells: NRF2↓(contary), SOD↓, GSH↓ Catalase↓ GPx↓
- Small evidence of Raising AntiOxidant defense in Normal Cells: ROS↓(contary), NRF2↑, SOD↑(contary), GSH↑, Catalase↑,
- lowers Inflammation : NF-kB↓, COX2↓, p38↓, Pro-Inflammatory Cytokines : NLRP3↓, TNF-α↓, IL-6↓, IL-8↓
- inhibit Growth/Metastases : TumMeta↓, TumCG↓, EMT↓, MMPs↓, MMP2↓, MMP9↓, TIMP2, IGF-1↓, uPA↓, VEGF↓, ROCK1↓, NF-κB↓, TGF-β↓, ERK↓
- cause Cell cycle arrest : TumCCA↑, cyclin D1↓, cyclin E↓, CDK2↓, CDK4↓, CDK6↓,
- inhibits Migration/Invasion : TumCMig↓, TumCI↓, TNF-α↓, ERK↓, EMT↓, TOP1↓,
- inhibits glycolysis /Warburg Effect and ATP depletion : HIF-1α↓, PKM2↓, cMyc↓, GLUT1↓, LDH↓, LDHA↓, HK2↓, ECAR↓, GRP78↑, GlucoseCon↓
- inhibits angiogenesis↓ : VEGF↓, HIF-1α↓, EGFR↓, Integrins↓,
- some small indication of inhibiting Cancer Stem Cells : CSC↓, Hh↓, β-catenin↓, sox2↓, OCT4↓,
- Others: PI3K↓, AKT↓, JAK↓, STAT↓, Wnt↓, β-catenin↓, AMPK, ERK↓, JNK,
- Synergies: chemo-sensitization, RadioSensitizer, Others(review target notes),

- Selectivity: Cancer Cells vs Normal Cells


ChemoSen, chemo-sensitization: Click to Expand ⟱
Source:
Type:
The effectiveness of chemotherapy by increasing cancer cell sensitivity to the drugs used to treat them, which is known as “chemo-sensitization”.

Chemo-Sensitizers:
-Curcumin
-Resveratrol
-EGCG
-Quercetin
-Genistein
-Berberine
-Piperine: alkaloid from black pepper
-Ginsenosides: active components of ginseng
-Silymarin
-Allicin
-Lycopene
-Ellagic acid
-caffeic acid phenethyl ester
-flavopiridol
-oleandrin
-ursolic acid
-butein
-betulinic acid
Scientific Papers found: Click to Expand⟱
2572- ART/DHA,  SRF,    Antileukemic efficacy of a potent artemisinin combined with sorafenib and venetoclax
- in-vitro, AML, NA
CHOP↑, Artemisinins increased CHOP, decreased MCL1,
Mcl-1↓,
ChemoSen↑, synergized with BCL2 inhibitors and SOR against human acute leukemia cells in vitro.
selectivity↑, The SAV combination potently inhibited leukemia cell growth but spared normal HSPCs

2577- ART/DHA,    Artemisinin and its derivatives in cancer therapy: status of progress, mechanism of action, and future perspectives
- Review, Var, NA
eff↑, Artemisinin-transferrin conjugate has been shown to be more potent than artemisinin in killing cancer cells
TumCCA↑, ART has been shown to act on the G 1 phase , and DHA and ARS on the G2/M phase arrest
BioAv↑, Artemetherâ's solubility has been increased by 3- to 15-fold using pegylated lysine-based copolymeric den- dritic micelles (5-25 nm, loading 0.5-1 g/g) with prolonged release of up to 1-2 days in vitro
eff↑, ART crystals have been encapsulated with chitosan, gelatin, and alginate (766 nm) with a 90% encapsulation efficiency and improved hydrophilicity
ChemoSen↑, Combining artemisinins with chemotherapy in nano drug delivery systems can improve efficacy through higher com- bination index

2575- ART/DHA,  docx,    Artemisia santolinifolia-Mediated Chemosensitization via Activation of Distinct Cell Death Modes and Suppression of STAT3/Survivin-Signaling Pathways in NSCLC
- in-vitro, Lung, H23
ChemoSen↑, Surprisingly, AS synergistically enhanced the cytotoxic effect of DTX by inducing apoptosis in H23 cells through the caspase-dependent pathway, whereas selectively increased necrotic cell population in A549 cells,
GPx4↓, ollowing the decline in GPX4 level and reactive oxygen species (ROS) activation with the highest rate in the combination treatment group
ROS↑,
Ferroptosis↑, predominant contribution of ferroptosis.
eff↑, Our study demonstrated that AS can be a promising chemosensitizer with the combination of conventional chemotherapeutic agent DTX for NSCLC

2571- ART/DHA,    Cancer combination therapies with artemisinin-type drugs
- Review, Var, NA
AntiTum↑, We and others found that artemisinin and its derivatives also exert profound activity against tumor cells in vitro and in vivo.
ChemoSen↑, Indeed, additive to synergistic interactions of ARS, DHA, or ART have been observed in combination with standard anticancer drugs towards tumor cell lines of diverse origin
hepatoP↝, In a large meta-analysis with 8000 patients, hepatotoxicity occurred in 0.9% of the patients

3396- ART/DHA,    Progress on the study of the anticancer effects of artesunate
- Review, Var, NA
TumCP↓, reported inhibitory effects on cancer cell proliferation, invasion and migration.
TumCI↓,
TumCMig↓,
Apoptosis↑, ART has been reported to induce apoptosis, differentiation and autophagy in colorectal cancer cells by impairing angiogenesis
Diff↑,
TumAuto↑,
angioG↓,
TumCCA↑, inducing cell cycle arrest (11), upregulating ROS levels, regulating signal transduction [for example, activating the AMPK-mTOR-Unc-51-like autophagy activating kinase (ULK1) pathway in human bladder cancer cells]
ROS↑,
AMPK↑,
mTOR↑,
ChemoSen↑, ART has been shown to restore the sensitivity of a number of cancer types to chemotherapeutic drugs by modulating various signaling pathways
Tf↑, ART could upregulate the mRNA levels of transferrin receptor (a positive regulator of ferroptosis), thus inducing apoptosis and ferroptosis in A549 non-small cell lung cancer (NSCLC) cells.
Ferroptosis↑,
Ferritin↓, ferritin degradation, lipid peroxidation and ferroptosis
lipid-P↑,
CDK1↑, Cyclin-dependent kinase 1, 2, 4 and 6
CDK2↑,
CDK4↑,
CDK6↑,
SIRT1↑, Sirt1 levels
COX2↓,
IL1β↓, IL-1? ?
survivin↓, ART can selectively downregulate the expression of survivin and induce the DNA damage response in glial cells to increase cell apoptosis and cell cycle arrest, resulting in increased sensitivity to radiotherapy
DNAdam↑,
RadioS↑,

3382- ART/DHA,    Repurposing Artemisinin and its Derivatives as Anticancer Drugs: A Chance or Challenge?
- Review, Var, NA
AntiCan↑, antimalarial drug, artemisinin that has shown anticancer activities in vitro and in vivo.
toxicity↑, safety of artemisinins in long-term cancer therapy requires further investigation.
Ferroptosis↑, Artemisinins acts against cancer cells via various pathways such as inducing apoptosis (Zhu et al., 2014; Zuo et al., 2014) and ferroptosis via the generation of reactive oxygen species (ROS) (Zhu et al., 2021) and causing cell cycle arrest
ROS↑,
TumCCA↑,
BioAv↝, absolute bioavailability was estimated to be 21.6%. ART has good solubility and is not lipophilic
eff↝, ART would not distribute well to the tissues and might be more effective in treating cancers such as leukemia, hepatocellular carcinoma (HCC), or renal cell carcinoma because the liver and kidney are highly perfused organs.
Half-Life↓, Pharmacokinetic studies showed a relatively short t1/2 of artemisinins. For ART, t1/2 was 0.41 h
Ferritin↓, Figure 3
GPx4↓,
NADPH↓,
GSH↓,
BAX↑,
Cyt‑c↑,
cl‑Casp3↑,
VEGF↓, angiogenesis
IL8↓,
COX2↓,
MMP9↓,
E-cadherin↑,
MMP2↓,
NF-kB↓,
p16↑, cell cycle arrest
CDK4↓,
cycD1↓,
p62↓, autophagy
LC3II↑,
EMT↓, suppressing EMT and CSCs
CSCs↓,
Wnt↓, Depress Wnt/β-catenin signaling pathway
β-catenin/ZEB1↓,
uPA↓, Inhibit u-PA activity, protein and mRNA expression
TumAuto↑, Emerging evidence suggests that autophagy induction is one of the molecular mechanisms underlying anticancer activity of artemisinins
angioG↓, Inhibition of Angiogenesis
ChemoSen↑, Many studies also reported that the use of artemisinins sensitized cancer cells to conventional chemotherapy and exerted a synergistic effect on apoptosis, inhibition of cell growth, and a reduction of cell viability, leading to a lower IC50 value

571- ART/DHA,  TMZ,    Artesunate enhances the therapeutic response of glioma cells to temozolomide by inhibition of homologous recombination and senescence
- vitro+vivo, GBM, A172 - vitro+vivo, GBM, U87MG
HR↓,
RAD51↓,
Apoptosis↑,
necrosis↑,
ROS↑,
ChemoSen↑, Enhancement of the antitumor effect of TMZ by co-administration of ART was also observed in a mouse tumor model.

564- ART/DHA,  Cisplatin,    Dihydroartemisinin as a Putative STAT3 Inhibitor, Suppresses the Growth of Head and Neck Squamous Cell Carcinoma by Targeting Jak2/STAT3 Signaling
- in-vitro, NA, HN30
JAK2↓,
STAT3↓,
MMP2↓,
MMP9↓,
Mcl-1↓,
Bcl-xL↓,
cycD1↓,
VEGF↓,
TumCCA↑, G1 cell cycle arrest in HNSCC
ChemoSen↑, DHA also synergized with cisplatin in tumor inhibition in HNSCC cells

1076- ART/DHA,    The Potential Mechanisms by which Artemisinin and Its Derivatives Induce Ferroptosis in the Treatment of Cancer
- Review, NA, NA
Ferroptosis↑,
ROS↑, interaction between heme-derived iron and ART will result in the production of ROS
ER Stress↑,
i-Iron↓, DHA can cause intracellular iron depletion in a time- and dose-dependent manner
TumAuto↑,
AMPK↑,
mTOR↑,
P70S6K↑,
Fenton↑,
lipid-P↑,
ROS↑,
ChemoSen↑, combination of ART and Nrf2 inhibitors to promote ferroptosis may have more efficient anticancer effects without damaging normal cells.
NRF2↑, Liu et al. discovered that ART covalently targets Keap1 at Cys151 to activate the Nrf2-dependent pathway [94


* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 9

Results for Effect on Cancer/Diseased Cells:
AMPK↑,2,   angioG↓,2,   AntiCan↑,1,   AntiTum↑,1,   Apoptosis↑,2,   BAX↑,1,   Bcl-xL↓,1,   BioAv↑,1,   BioAv↝,1,   cl‑Casp3↑,1,   CDK1↑,1,   CDK2↑,1,   CDK4↓,1,   CDK4↑,1,   CDK6↑,1,   ChemoSen↑,9,   CHOP↑,1,   COX2↓,2,   CSCs↓,1,   cycD1↓,2,   Cyt‑c↑,1,   Diff↑,1,   DNAdam↑,1,   E-cadherin↑,1,   eff↑,3,   eff↝,1,   EMT↓,1,   ER Stress↑,1,   Fenton↑,1,   Ferritin↓,2,   Ferroptosis↑,4,   GPx4↓,2,   GSH↓,1,   Half-Life↓,1,   hepatoP↝,1,   HR↓,1,   IL1β↓,1,   IL8↓,1,   i-Iron↓,1,   JAK2↓,1,   LC3II↑,1,   lipid-P↑,2,   Mcl-1↓,2,   MMP2↓,2,   MMP9↓,2,   mTOR↑,2,   NADPH↓,1,   necrosis↑,1,   NF-kB↓,1,   NRF2↑,1,   p16↑,1,   p62↓,1,   P70S6K↑,1,   RAD51↓,1,   RadioS↑,1,   ROS↑,6,   selectivity↑,1,   SIRT1↑,1,   STAT3↓,1,   survivin↓,1,   Tf↑,1,   toxicity↑,1,   TumAuto↑,3,   TumCCA↑,4,   TumCI↓,1,   TumCMig↓,1,   TumCP↓,1,   uPA↓,1,   VEGF↓,2,   Wnt↓,1,   β-catenin/ZEB1↓,1,  
Total Targets: 71

Results for Effect on Normal Cells:

Total Targets: 0

Scientific Paper Hit Count for: ChemoSen, chemo-sensitization
9 Artemisinin
1 Sorafenib (brand name Nexavar)
1 Docetaxel
1 temozolomide
1 Cisplatin
Filter Conditions: Pro/AntiFlg:%  IllCat:%  CanType:%  Cells:%  prod#:34  Target#:1106  State#:%  Dir#:%
  wNotes=on  sortOrder:rid,rpid

 

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