Anti-tumor fuction
1.1 Inhibit the proliferation of tumor cells
The inhibitory effect of Luteolin on tumor cell proliferation is mainly through inhibition of the activity of certain kinases in the cell and arrest of the cell cycle. Aurora B kinase, a member of the Aurora kinase family, is a protein serine/threonine kinase involved in many mitotic events and is an important mitotic regulator. Histone H3 is a specific substrate for Aurora B kinase, and phosphorylation at Ser10 reflects the activity of Aurora B kinase. Xie et al. pointed out that after administration of Luteolin, the phosphorylated histone H3 (Ser10) protein content in HeLa and SW20 cells decreased, and the protein content of Aurora B kinase and total histone H3 remained unchanged. This shows that Luteolin inhibits the proliferation of HeLa and SW20 cells by affecting the activity of laser kinase B without altering its content. Attrib et al. Research proved that Luteolin increased the expression of histone H3 and H4 acetylated proteins in LNM35 cells, and as an inhibitor of histone deacetylase, inhibited the proliferation of LNM35 cells. The mechanism which histone deacetylase inhibitors inhibit tumor cell proliferation is not well understood. Research shown that inhibition of histone deacetylation can slow down the replication fork, activate dormancy and induce DNA damage.
Luteolin can also block the cell cycle. Lee et al.research showed that Luteolin increased express of estrogen receptor (ER) for serine-threonine kinase (AKT) and in human breast cancer cell line MDA-MB-231 negative、 Polo-like kinase 1， PLK1、 cyclin B1、 cyclin A、 cell division cycle 2 (CDC2)、 and cyclin-dependent kinase 2 (CDK2) etc. and reduced the protein content of the cell cycle-dependent protein kinase inhibitor p21, and make the cell cycle stagnate in G2/M and S. When used in combination with epidermal growth factor (EGF), Luteolin can attenuate EGF induced PI3K/AKT and mitogen-activated protein kinase (MAPK) pathway activation, making EGFR、 AKT、 p38 and extracellular signal-regulated kinase (ERK) phosphorylation reduces, inhibit of EGFR-mediated cell survival. Shoulars et al. using chromatin immunoprecipitation-gene chip technology, screened the effect of Luteolin on the gene expression profile of human prostate cancer PC-3 cells. It was found that the increased gene expression of PLK1, proliferating cell nuclear antigen (PCNA) and cyclin E2 (CCNE2) involved in the cell cycle increased, and the expression of kinase inhibitor 1B, CDKN1B) was reduced and these changes were verified at the protein level by Western blot.
1.2 Induction apoptosis of tumor cell
Luteolin can induce apoptosis of tumor cells through the mitochondrial apoptosis pathway, endoplasmic reticulum stress, and death receptor apoptosis pathway.
Choi et al. used mouse brain neuroma cells (Neuro-2a) as a cell model to research the mechanism of Luteolin-induced apoptosis. After finding the action of luteolin, the expression of intracellular apoptosis promoting protein Bax and Bim increased, and the expression of anti-apoptotic protein Bcl-2 reduced. As time goes on, cytochrome
C in mitochondria gradually decreases, while cytochrome C in cytoplasm increases significantly, and caspase-specific proteases caspase-3, caspase-9, caspase-12 and poly(ADP-ribose) polymerase, PARP increased with increasing concentration of the drug. Luteolin activates the mitochondrial apoptotic pathway. Further studies have shown that luteolin affects both endoplasmic reticulum stress-related proteins and increases CCAAT/enhancer-binding protein homologous protein (CHOP) 、 (glucose- Regulated protein, GRP )94 and 78, etc., and induced activating transcription factor 6α, ATF6α. The mitochondrial apoptotic pathway and endoplasmic reticulum stress are not isolated from each other. The caspase-12 interference plasmid can reduce the expression of caspase-3 and CHOP, and the CHOP interference plasmid can also reduce the content of caspase-12. Luteolin acts within 10 min of the cell, and the three proteins of the MAPK pathway, ERK, p38 and c-Jun N terminal kinase (JNK) are activated and phosphorylated, and the MAPK inhibitor reduces the amount of cytochrome C in Bax and cytoplasm. Similarly, in a short period, reactive oxygen species (ROS) also appeared in the cells, and ROS inhibitors could not change the MAPK changes, nor could it affect the early mitochondrial membrane potential, but could attenuate the late mitochondrial membrane potential. This suggests that Luteolin through activating MAPK by first make Bax occur mitochondrial translocation, leading to early mitochondrial dysfunction, produce early ROS and early endoplasmic reticulum stress. Late mitochondrial dysfunction can aggravate ROS production and further lead to endoplasmic reticulum stress. Endoplasmic reticulum stress and mitochondrial apoptosis can ultimately activate the caspase cascade reaction and Induce cell apoptosis.
Lee et al. used proteomic analysis to demonstrate demonstrated that Luteolin induced apoptosis of CH27 cells was a process of a mitochondria and endoplasmic reticulum interact together, and ATP was involved. In the early stage of apoptosis, Luteolin induces ATP release and the content increases; in the late stage of apoptosis, α-enolase (α-enolase) and hydroxyalkyl-coenzyme A dehydrogenase (ATP synthase) damaged and ATP content decreases.
Luteolin can also induce cell apoptosis through the death receptor signaling pathway. In the mechanism of study of luteolin by HeLa cells, it was found that the caspase inhibitor zVAD-fmk and the caspase-10 inhibitor zAEVD-fmk significantly inhibited Luteolin-induced cell death. At the transcriptional level find, luteolin significantly increased the death receptor (DR) 5 mRNA content in cells, allowing Fas ligand, Fas, DR4 and tumor necrosis factor-related apoptosis-inducing ligand, (TRAIL) the content of mRNA also increased, but did not affect decoy receptors (DcR) 1 and 2. 10 μmol/L luteolin treatment increased the expression of DR5 protein in HeLa cells, resulting Bid cleavage cut, at the same time can activate caspase-3, caspase-8, caspase-9, caspase-10. When cells were transfected with DR5 interference plasmid, luteolin-induced apoptosis of HeLa cells was significantly reduced, and the activation of caspase-9 and caspase-3 was decreased. Recombinant human DR5/Fc also inhibited luteolin-induced apoptosis. Luteolin induces apoptosis in HeLa cells through the death receptor pathway, and DR5 plays an important role in Luteolin induced apoptosis.
This article details Luteolin's description of tumor changes, tumor growth and apoptosis are detailed records, What does luteolin do to the tumor, I believe everyone knows!
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