condition found tbRes List
SK, Shikonin: Click to Expand ⟱
Features:
The (R)-enantiomer of alkannin is known as shikonin, and the racemic mixture of the two is known as shikalkin.
Shikonin is a naphthoquinone derivative primarily isolated from the roots of plants in the Boraginaceae family (e.g., Lithospermum erythrorhizon).
Shikonin is the main active component of a Chinese medicinal plant 'Zi Cao'
-Shikonin is a major component of zicao (purple gromwell, the dried root of Lithospermum erythrorhizon), a Chinese herbal medicine with anti-inflammatory properties
-Quinone methides (QMs) are highly reactive intermediates formed from natural compounds like shikonin
-ic50 cancer cells 1-10uM, normal cells >10uM

-known as Glycolysis inhibitor: ( inhibit pyruvate kinase M2 (PKM2*******), a key enzyme in the glycolytic pathway)

Available from mcsformulas.com Shikonin Pro Liposomal, 30 mg
Also In Glycolysis Inhibithree(100 mg PHLORIZIN,10 mg TANSHINONE IIA, 8 mg Shikonin)

-Note half-life15-30mins or 8hr?.
BioAv low, poor water solubility
Pathways:
- usually induce ROS production in cancer cells, and reduce ROS in normal cells.
- ROS↑ related: MMP↓(ΔΨm), ER Stress↑, GRP78↑, Ca+2↑, Cyt‑c↑, Caspases↑, DNA damage↑, cl-PARP↑, HSP↓,
- Lowers AntiOxidant defense in Cancer Cells: NRF2↓, TrxR↓**, SOD↓, GSH↓ Catalase↓ GPx4↓
- Raises AntiOxidant defense in Normal Cells: ROS↓, NRF2↑, SOD↑, GSH↑, Catalase↑,
- lowers Inflammation : NF-kB↓, COX2↓, p38↓, Pro-Inflammatory Cytokines : NLRP3↓, IL-1β↓, TNF-α↓, IL-6↓, IL-8↓
- inhibit Growth/Metastases : TumMeta↓, TumCG↓, EMT↓, MMPs↓, MMP2↓, MMP9↓, IGF-1↓, uPA↓, VEGF↓, FAK↓, NF-κB↓, TGF-β↓, ERK↓
- cause Cell cycle arrest : TumCCA↑, cyclin D1↓, cyclin E↓, CDK2↓, CDK4↓,
- inhibits Migration/Invasion : TumCMig↓, TumCI↓, FAK↓, ERK↓, EMT↓,
- inhibits glycolysis /Warburg Effect and ATP depletion : HIF-1α↓, PKM2↓, cMyc↓, GLUT1↓, LDH↓, LDHA↓, HK2↓, PFKs↓, PDKs↓, ECAR↓, OXPHOS↓, GRP78↑, GlucoseCon↓
- inhibits angiogenesis↓ : VEGF↓, HIF-1α↓, EGFR↓, Integrins↓,
- Others: PI3K↓, AKT↓, JAK↓, STAT↓, β-catenin↓, AMPK, ERK↓, JNK, P53↑,
- Synergies: chemo-sensitization, chemoProtective, RadioSensitizer, Others(review target notes), Neuroprotective, Cognitive, Renoprotection, Hepatoprotective, CardioProtective,

- Selectivity: Cancer Cells vs Normal Cells


selectivity, selectivity: Click to Expand ⟱
Source:
Type:
The selectivity of cancer products (such as chemotherapeutic agents, targeted therapies, immunotherapies, and novel cancer drugs) refers to their ability to affect cancer cells preferentially over normal, healthy cells. High selectivity is important because it can lead to better patient outcomes by reducing side effects and minimizing damage to normal tissues.

Achieving high selectivity in cancer treatment is crucial for improving patient outcomes. It relies on pinpointing molecular differences between cancerous and normal cells, designing drugs or delivery systems that exploit these differences, and overcoming intrinsic challenges like tumor heterogeneity and resistance

Factors that affect selectivity:
1. Ability of Cancer cells to preferentially absorb a product/drug
-EPR-enhanced permeability and retention of cancer cells
-nanoparticle formations/carriers may target cancer cells over normal cells
-Liposomal formations. Also negatively/positively charged affects absorbtion

2. Product/drug effect may be different for normal vs cancer cells
- hypoxia
- transition metal content levels (iron/copper) change probability of fenton reaction.
- pH levels
- antiOxidant levels and defense levels

3. Bio-availability
Scientific Papers found: Click to Expand⟱
2230- SK,    Shikonin induces ROS-based mitochondria-mediated apoptosis in colon cancer
- in-vitro, CRC, HCT116 - in-vivo, NA, NA
TumCG↓, shikonin suppressed the growth of colon cancer cells in a dose-dependent manner in vitro and in vivo
Bcl-2↓, Shikonin induced mitochondria-mediated apoptosis, which was regulated by Bcl-2 family proteins.
ROS↑, found that shikonin dose-dependently increased the generation of intracellular ROS in colon cancer cells
Bcl-xL↓, generation of ROS, down-regulated expression of Bcl-2 and Bcl-xL, depolarization of the mitochondrial membrane potential and activation of the caspase cascade
MMP↓,
Casp↑,
selectivity↑, shikonin presented minimal toxicity to non-neoplastic colon cells and no liver injury in xenograft models
cycD1↓, Cyclin D expression was decreased with shikonin treatment
TumCCA↑, induced cell growth inhibition by the induction G1 cell cycle arrest.
eff↓, NAC or GSH could block the shikonin-dependent burst of intracellular ROS

2227- SK,    Shikonin induces mitochondria-mediated apoptosis and enhances chemotherapeutic sensitivity of gastric cancer through reactive oxygen species
- in-vitro, GC, BGC-823 - in-vitro, GC, SGC-7901 - in-vitro, Nor, GES-1
selectivity↑, In vitro, SHK suppresses proliferation and triggers cell death of gastric cancer cells but leads minor damage to gastric epithelial cells.
TumCP↓,
TumCD↑,
ROS↑, SHK induces the generation of intracellular reactive oxygen species (ROS), depolarizes the mitochondrial membrane potential (MMP) and ultimately triggers mitochondria-mediated apoptosis.
MMP↓,
Casp↑, SHK induces apoptosis of gastric cancer cells not only in a caspase-dependent manner which releases Cytochrome C and triggers the caspase cascade
Cyt‑c↑,
Endon↑, nuclear translocation of AIF and Endonuclease G
AIF↑,
eff↓, NAC and GSH significantly inhibited SHK-induced death
ChemoSen↑, SHK enhances chemotherapeutic sensitivity of 5-fluorouracil and oxaliplatin
TumCCA↑, SHK caused S-phase cell cycle arrest in SGC-7901 and BGC-823 gastric cancer cells
GSH/GSSG↓, We found that the GSH/GSSG ratio was significantly decreased when treated with SHK.
lipid-P↑, SHK increases lipid peroxidation and induces apoptosis in vivo

2226- SK,    Shikonin, a Chinese plant-derived naphthoquinone, induces apoptosis in hepatocellular carcinoma cells through reactive oxygen species: A potential new treatment for hepatocellular carcinoma
- in-vitro, HCC, HUH7 - in-vitro, HCC, Bel-7402
selectivity↑, shikonin induced apoptosis of Huh7 and BEL7402 but not nontumorigenic cells.
ROS↑, ROS generation was detected
eff↓, ROS scavengers completely inhibited shikonin-induced apoptosis, indicating that ROS play an essential role
Akt↓, downregulation of Akt and RIP1/NF-κB activity was found to be involved in shikonin-induced apoptosis
RIP1↓,
NF-kB↓,

3048- SK,    Shikonin inhibits triple-negative breast cancer-cell metastasis by reversing the epithelial-to-mesenchymal transition via glycogen synthase kinase 3β-regulated suppression of β-catenin signaling
- in-vitro, BC, MDA-MB-231 - in-vitro, BC, 4T1 - in-vitro, Nor, MCF12A - in-vivo, NA, NA
tumCV↓, results revealed that shikonin potently decreased the viabilities of TNBC MDA-MB-231 and 4T1 cells but showed less cytotoxicity to normal mammary epithelial MCF-12A cells
selectivity↑,
EMT↓, shikonin reversed the epithelial-to-mesenchymal transition (EMT) in MDA-MB-231 and 4T1 cells.
TumCMig↓, Shikonin depressed cell migration and invasion, upregulated E-cadherin levels, downregulated N-cadherin, vimentin, and Snail levels, and reorganized the cytoskeletal proteins F-actin and vimentin.
TumCI↓,
E-cadherin↑,
N-cadherin↓,
Vim↓,
Snail↓,
β-catenin/ZEB1↓, Shikonin reversed EMT by inhibiting activation of β-catenin signaling through attenuating β-catenin expression
GSK‐3β↑, shikonin upregulated glycogen synthase kinase 3β (GSK-3β) levels, leading to enhanced phosphorylation and decreased levels of β-catenin.

2185- SK,    Shikonin Inhibits Tumor Growth in Mice by Suppressing Pyruvate Kinase M2-mediated Aerobic Glycolysis
- in-vitro, Lung, LLC1 - in-vitro, Melanoma, B16-BL6 - in-vivo, NA, NA
Glycolysis↓, confirming the inhibitory effect of shikonin on tumor aerobic glycolysis
GlucoseCon↓, shikonin dose-dependently inhibited glucose uptake and lactate production in Lewis lung carcinoma (LLC) and B16 melanoma cells
lactateProd↓,
PKM2↓, suppression of cell aerobic glycolysis by shikonin is through decreasing PKM2 activity
selectivity↑, shikonin treatment significantly promoted tumor cell apoptosis compared to untreated control cells.
Warburg↓, agreement with previous findings of shikonin as a Warburg effect inhibitor
TumVol↓, A significant reduction of tumor size (Fig. 7B) and weight (Fig. 7C) was observed when shikonin was injected at concentration of 1 or 10 mg/kg.
TumW↓,

2010- SK,    Shikonin inhibits gefitinib-resistant non-small cell lung cancer by inhibiting TrxR and activating the EGFR proteasomal degradation pathway
- in-vitro, Lung, H1975 - in-vitro, Lung, H1650 - in-vitro, Nor, CCD19
EGFR↓, Shikonin is a potent inhibitor of EGFR
selectivity↑, Shikonin exhibited selective cytotoxicity among two NSCLC cell lines (H1975 and H1650) and one normal lung fibroblast cell line (CCD-19LU).
Casp↑, Shikonin significantly increased the activity of caspases and poly (ADP-ribosyl) polymerase (PARP), which are indicators of apoptosis
PARP↑,
Apoptosis↑,
ROS↑, intensity of ROS by greater than 10-fold
eff↓, NAC, an inhibitor of ROS, completely blocked apoptosis, caspase and PARP activation induced by Shikonin.
selectivity↑, the IC50 value of Shikonin in CCD19 (normal cells) is approximately 4-fold higher than that of HCC827, H1650 and H1975.

2009- SK,    Necroptosis inhibits autophagy by regulating the formation of RIP3/p62/Keap1 complex in shikonin-induced ROS dependent cell death of human bladder cancer
- in-vitro, Bladder, NA
TumCG↓, shikonin has a selective inhibitory effect on bladder cancer cells
selectivity↑, and has no toxicity on normal bladder epithelial cells
*toxicity∅,
Necroptosis↑, shikonin induced necroptosis and impaired autophagic flux via ROS generation
ROS↑,
p62↑, accumulation of autophagic biomarker p62 elevated p62/Keap1 complex and activated the Nrf2 signaling pathway to fight against ROS
Keap1↑,
*NRF2↑, activated the Nrf2 signaling pathway to fight against ROS
eff↑, we further combined shikonin with late autophagy inhibitor(chloroquine) to treat bladder cancer and achieved a better inhibitory effect.

2008- SK,  Cisplatin,    Enhancement of cisplatin-induced colon cancer cells apoptosis by shikonin, a natural inducer of ROS in vitro and in vivo
- in-vitro, CRC, HCT116 - in-vivo, NA, NA
ChemoSen↑, combination of shikonin and cisplatin exhibited synergistic anticancer efficacy
selectivity↑, and achieved greater selectivity between cancer cells and normal cells.
i-ROS↑, By inducing intracellular oxidative stress, shikonin potentiated cisplatin-induced DNA damage, followed by increased activation of mitochondrial pathway.
DNAdam↑,
MMP↓,
TumCCA↑, induction of G2/M cell cycle arrest
eff↓, NAC and GSH were used in our experiment. The MTT results revealed that scavenging of ROS fully attenuated combined treatment-induced cell growth inhibition against HCT116 cell
*toxicity↓, combined treatment showed less cytotoxicity toward NCM460 normal human colon mucosal epithelial cells

2007- SK,    Shikonin Directly Targets Mitochondria and Causes Mitochondrial Dysfunction in Cancer Cells
- in-vitro, lymphoma, U937 - in-vitro, BC, MCF-7 - in-vitro, BC, SkBr3 - in-vitro, CRC, HCT116 - in-vitro, OS, U2OS - NA, Nor, RPE-1
tumCV↓, We found that shikonin has strong cytotoxic effects on 15 cancer cell lines, including multidrug-resistant cell lines.
selectivity↑, structure of mitochondria show marked differences between cancer cells and normal cells
Dose↝, Shikonin inhibited proliferation by 50% in nearly all cancer cell lines at concentrations below 10 μM after 24 h.
other↑, mitochondrion itself is a possible target of the compound
MMP↓, Breakdown of the Mitochondrial Membrane Potential
ROS↑, ROS production shortly after cellular shikonin uptake, and ROS levels continuously increased for at least 1 h after exposure to shikonin
DNAdam↑, Induction of ROS, oxidative DNA damage, and elevated intracellular Ca2+ levels by shikonin
Ca+2↑,
Casp9↑, Caspase 9 is activated after the release of cytochrome c from the mitochondria
Cyt‑c↑,
*toxicity↓, RPE-1-GFP-EB3 (normal) cells were treated with 25 μM shikonin. shikonin treatment did cause a strong slowdown and finally a complete disappearance of EB3 particles within 3 min of application

977- SK,    A novel antiestrogen agent Shikonin inhibits estrogen-dependent gene transcription in human breast cancer cells
- in-vitro, BC, T47D - in-vitro, BC, MDA-MB-231 - in-vitro, BC, MCF-7 - in-vitro, Nor, HMEC
TumCG↓, SK inhibits tumor cell growth in estrogen receptor alpha (ERalpha)-positive, but not ERalpha-negative breast cancer cells.
ERα↓, SK inhibits ERa expression, and suppresses ERa signaling
selectivity↑, non-malignant HME cells show undetectable ERa protein (Fig. 2a). Treatment with increased concentrations of SK for 72 h has no effect on cell growth
*toxicity↓, In addition, SK shows low cytoxicity in normal human mammary epithelia cells.


* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 10

Results for Effect on Cancer/Diseased Cells:
AIF↑,1,   Akt↓,1,   Apoptosis↑,1,   Bcl-2↓,1,   Bcl-xL↓,1,   Ca+2↑,1,   Casp↑,3,   Casp9↑,1,   ChemoSen↑,2,   cycD1↓,1,   Cyt‑c↑,2,   DNAdam↑,2,   Dose↝,1,   E-cadherin↑,1,   eff↓,5,   eff↑,1,   EGFR↓,1,   EMT↓,1,   Endon↑,1,   ERα↓,1,   GlucoseCon↓,1,   Glycolysis↓,1,   GSH/GSSG↓,1,   GSK‐3β↑,1,   Keap1↑,1,   lactateProd↓,1,   lipid-P↑,1,   MMP↓,4,   N-cadherin↓,1,   Necroptosis↑,1,   NF-kB↓,1,   other↑,1,   p62↑,1,   PARP↑,1,   PKM2↓,1,   RIP1↓,1,   ROS↑,6,   i-ROS↑,1,   selectivity↑,11,   Snail↓,1,   TumCCA↑,3,   TumCD↑,1,   TumCG↓,3,   TumCI↓,1,   TumCMig↓,1,   TumCP↓,1,   tumCV↓,2,   TumVol↓,1,   TumW↓,1,   Vim↓,1,   Warburg↓,1,   β-catenin/ZEB1↓,1,  
Total Targets: 52

Results for Effect on Normal Cells:
NRF2↑,1,   toxicity↓,3,   toxicity∅,1,  
Total Targets: 3

Scientific Paper Hit Count for: selectivity, selectivity
10 Shikonin
1 Cisplatin
Filter Conditions: Pro/AntiFlg:%  IllCat:%  CanType:%  Cells:%  prod#:150  Target#:1110  State#:%  Dir#:%
  wNotes=on  sortOrder:rid,rpid

 

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