Oroxylin A is a naturally occurring flavonoid derived from the roots of Scutellaria baicalensis, a plant widely used in traditional Chinese medicine. Oroxylin A acts through multiple mechanisms against cancer cells, such as inhibiting glycolysis, modulating immune responses, targeting hypoxia-inducible factor-1α (HIF1α), and blocking vascular endothelial growth factor (VEGF) pathways. Its multitargeted approach and low toxicity to normal tissues make Oroxylin A a good option in cancer therapy.
Glycolysis Inhibition via SIRT3 and Hexokinase II (HKII) Dissociation: Oroxylin A disrupts cancer metabolism by inhibiting glycolysis. In breast carcinoma, it promotes the dissociation of HKII from mitochondria, mediated by SIRT3 activation. This mechanism reduces glucose uptake, lactate production, and overall energy supply in cancer cells, limiting proliferation.
Suppression of Hypoxia-Inducible Factor 1α (HIF1α) and Metabolic Reprogramming: Oroxylin A targets HIF1α to reduce glycolysis and promote fatty acid oxidation in hypoxic environments. This reprogramming is crucial in colorectal cancer cells, where HIF1α inhibition disrupts lipid accumulation and inactivates the Wnt pathway, leading to cell cycle arrest.
Modulation of Immune Microenvironment through NF-κB Pathway Inhibition: By inhibiting NF-κB signaling, Oroxylin A reduces the proliferation of tumor-associated regulatory T cells (Tregs) in non-small cell lung cancer, thereby enhancing the immune response against the tumor. This effect is partly achieved by reducing TGF-β1 secretion, which is vital for Treg induction.
Anti-Angiogenic Activity via VEGF Signaling Blockade: Oroxylin A inhibits angiogenesis by blocking VEGF-induced phosphorylation of KDR/Flk-1 in endothelial cells, which impedes the formation of new blood vessels essential for tumor growth. This mechanism has been demonstrated in models of breast and lung cancers.
Inhibition of Epithelial-Mesenchymal Transition (EMT) and Metastasis: Oroxylin A downregulates matrix metalloproteinase-2/9 (MMP-2/9) and upregulates TIMP-2, inhibiting the ERK1/2 signaling pathway. This action reduces the invasive capabilities of cancer cells, particularly in breast and lung cancers. Oroxylin A also suppresses the Notch pathway to inhibit hypoxia-induced invasion in MCF-7 breast cancer cells.
Induction of Caspase-Dependent Apoptosis: Oroxylin A promotes apoptosis through caspase activation, mainly targeting caspase-8 and caspase-3. This effect has been observed in hepatocellular carcinoma cells, where apoptosis is induced via the p62/SQSTM1 pathway, enhancing oxidative stress susceptibility in cancer cells.
Reversal of Multi-Drug Resistance (MDR): Oroxylin A reduces P-glycoprotein expression in hepatoma cells, enhancing the efficacy of chemotherapy drugs like 5-FU. This downregulation of MDR genes is achieved through NF-κB inhibition, which could potentially restore drug sensitivity in resistant cancer cells.
Inhibition of lactate dehydrogenase-a: By targeting LDH-A, Oroxylin A disrupts glycolysis in cancer cells, reducing lactate production and thereby hindering the energy supply necessary for cell proliferation and survival.
References
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