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| 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↓">NRF2↓, TrxR↓**, SOD↓, GSH↓ Catalase↓ GPx4↓ - Raises AntiOxidant defense in Normal Cells: ROS↓, NRF2↑">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
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| Source: TCGA |
| Type: Antiapoptotic |
| Nrf2 is responsible for regulating an extensive panel of antioxidant enzymes involved in the detoxification and elimination of oxidative stress. Thought of as "Master Regulator" of antioxidant response. -One way to estimate Nrf2 induction is through the expression of NQO1. NQO1, the most potent inducer: SFN 0.2 μM, quercetin (2.5 μM), curcumin (2.7 μM), Silymarin (3.6 μM), tamoxifen (5.9 μM), genistein (6.2 μM ), beta-carotene (7.2μM), lutein (17 μM), resveratrol (21 μM), indol-3-carbinol (50 μM), chlorophyll (250 μM), alpha-cryptoxanthin (1.8 mM), and zeaxanthin (2.2 mM) 1. Raising Nrf2 enhances the cell's antioxidant defenses and ↓ROS. This strategy is used to decrease chemo-radio side effects. 2. Downregulating Nrf2 lowers antioxidant defenses and ↑ROS. In cancer cells this leads to DNA damage, and cell death. 3. However there are some cases where increasing Nrf2 paradoxically causes an increase in ROS (cancer cells). Such as cases of Mitochondial overload, signal crosstalk, reductive stress -In some cases, Nrf2 is overexpressed in cancer cells, which can lead to the activation of genes involved in cell proliferation, angiogenesis, and metastasis. This can contribute to the development of resistance to chemotherapy and targeted therapies. -Increased Nrf2 expression: Lung, Breast, Colorectal, Prostrate. Decreased Nrf2 expression: Skine, Liver, Pancreatic. -Nrf2 is a cytoprotective transcription factor which demonstrated both a negative effect as well as a positive effect on cancer - "promotes Nrf2 translocation from the cytoplasm to the nucleus," means facilitates the movement of Nrf2 into the nucleus, thereby enhancing the cell's antioxidant and cytoprotective responses. -Major regulator of Nrf2 activity in cells is the cytosolic inhibitor Keap1. Nrf2 Inhibitors and Activators Nrf2 Inhibitors: Brusatol, Luteolin, Trigonelline, VitC, Retinoic acid, Chrysin Nrf2 Activators: SFN, OPZ EGCG, Resveratrol, DATS, CUR, CDDO, Api - potent Nrf2 inducers from plants include sulforaphane, curcumin, EGCG, resveratrol, caffeic acid phenethyl ester, wasabi, cafestol and kahweol (coffee), cinnamon, ginger, garlic, lycopene, rosemany Nrf2 plays dual roles in that it can protect normal tissues against oxidative damage and can act as an oncogenic protein in tumor tissue. – In healthy tissues, NRF2 activation helps protect cells from oxidative damage and maintains cellular homeostasis. – In many cancers, constitutive activation of NRF2 (often through mutations in NRF2 itself or loss-of-function mutations in KEAP1) leads to an enhanced antioxidant capacity. – This upregulation can promote tumor cell survival by enabling cancer cells to thrive under oxidative stress, resist chemotherapeutic agents, and sustain metabolic reprogramming. – Elevated NRF2 levels have been implicated in promoting tumor growth, metastasis, and resistance to therapy in various malignancies. – High or sustained NRF2 activity is frequently associated with aggressive tumor phenotypes, poorer prognosis, and decreased overall survival in several cancer types. – While its activation is essential for protecting normal cells from oxidative stress, aberrant or sustained NRF2 activation in tumor cells can lead to enhanced survival, therapeutic resistance, and tumor progression. NRF2 inhibitors: (to decrease antioxidant defenses and increase cell death from ROS). -Brusatol: most cited natural inhibitors of Nrf2. -Luteolin: luteolin can reduce Nrf2 activity in specific cancer models and may enhance cell sensitivity to chemotherapy. However, luteolin is also known as an antioxidant, and its influence on Nrf2 can sometimes be context dependent. -Apigenin: certain studies to down‑regulate Nrf2 in cancer cells: Dose and context dependent . -Oridonin: -Wogonin: although its effects might be cell‑ and dose‑specific. - Withaferin A |
| 1346- | SK, | An Oxidative Stress Mechanism of Shikonin in Human Glioma Cells |
| - | in-vitro, | GBM, | U87MG | - | in-vitro, | GBM, | Hs683 |
| 1280- | SK, | Shikonin Induces Apoptotic Cell Death via Regulation of p53 and Nrf2 in AGS Human Stomach Carcinoma Cells |
| - | in-vitro, | GC, | AGS |
| 2201- | SK, | Shikonin promotes ferroptosis in HaCaT cells through Nrf2 and alleviates imiquimod-induced psoriasis in mice |
| - | in-vitro, | PSA, | HaCaT | - | in-vivo, | NA, | NA |
| 2198- | SK, | Shikonin suppresses proliferation of osteosarcoma cells by inducing ferroptosis through promoting Nrf2 ubiquitination and inhibiting the xCT/GPX4 regulatory axis |
| - | in-vitro, | OS, | MG63 | - | in-vitro, | OS, | 143B |
| 2197- | SK, | Shikonin derivatives for cancer prevention and therapy |
| - | Review, | Var, | NA |
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
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