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Talking About the Anti-tumor Mechanism of Curcumin

May 15, 2019

Talking About the Anti-tumor Mechanism of Curcumin


   Curcumin is a yellow pigment extracted from the roots of some plants of Zingiberaceae and Araceae. It is an acidic polyphenolic substance or a diketone compound. Curcumin acts as a synergist in traditional medicine. Medical research has found that curcumin has anti-oxidation and anti-cancer effects. Curcumin can directly inhibit tumor proliferation, and can also inhibit tumor by increasing the anti-cancer effect of other anti-cancer drugs.

   Why can curcumin fight cancer? In recent years, a large number of studies have been conducted on the mechanism of anti-cancer effects of curcumin at the molecular, cellular, and tissue levels. These studies have found that curcumin can be used as a target site for drug action and a signal of tumor cells. It plays a role in anti-cancer effects in the transmission and expression of certain genes and proteins in tumor cells, enzyme activity, tumor cell proliferation, apoptosis, angiogenesis, multi-drug resistance, and enhancement of NK cell lethality.

 

 

1. Curcumin enters tumor cells and effects target sites and signal transduction

 Curcumin works by first entering the cell. Once curcumin enters the cell, it can increase the target site of the drug and regulate the signal transduction in the cell, thereby regulating the gene, enzyme, and protein expression of the tumor cell.

 

Tumor cells take up curcumin

  Curcumin can enter cells through cell uptake and then acts as a cytotoxic effect. Hsu et al. used high performance liquid chromatography to determine the anti-proliferation mechanism of curcumin and quantitatively studied the function of cells to take curcumin. Chang et al. quantified the uptake of curcumin by human breast adenocarcinoma and ductal carcinoma by three human breast cancer cell lines MDA-MB-231, MDA-MB-435S and MCF-7 (Michigan Cancer Foundation-7). The results showed that with the increase of curcumin dose, the uptake of curcumin by cancer cells showed a dose-dependent inhibition of proliferation and promotion of apoptosis associated with cancer cells taking curcumin.

 

Increase the target site of drug action

  Anti-cancer drugs usually bind to tumor cell surface-specific antigens and destroy tumor cells. Curcumin can increase the target site of drug recognition on the surface of tumor cells, thereby increasing the anti-cancer effect of the drug. Wang Jiazhi found that the combination of irinotecan and curcumin inhibited human colon cancer cell LoVo more than irinotecan alone. The mechanism of action may be that curcumin causes LoVo cell topoisomerase I mRNA and protein. Increased expression increases the target site of irinotecan on LoVo cells.

 

Regulate the signal transmission of tumor cells

  The transforming growth factor-/Smad protein is a type of cellular signaling that is activated once the receptor binds to the ligand to form a complex. The receptor kinase phosphorylates directly in the cytoplasm and activates a special type of transcription factor Smad. Nuclear regulation of gene expression promotes protein expression such as peptide parathyroid hormone-related protein (PTHrP) and transcriptional regulator (ETwenty-Six-1, ETS-1). Curcumin inhibits the secretion of transforming growth factor TGF-stimulated PTHrP in tumor cells, phosphorylated Smad2/3 decreases in TGF-signaling, and ETS-1 interacts with p-38 mitogen-activated protein kinase , MAPK) mediated TGF-signal no response.

Wright et al treated mice inoculated with human breast cancer cell line MDA-MB-231 with curcumin and found that curcumin prevented the secretion of TGF-stimulated PTHrP and blocked the Smad signal of breast cancer cells. On the other hand, the study also found that curcumin can enhance the Nrf2 (nuclear transcription factor) signaling pathway and inhibit cancer.

An experimental study by Das et al found that curcumin prevents cancer by activating Nrf2 signaling. The study found that curcumin synergizes with other chemotherapeutic drugs to prevent tumors by increasing the original anticancer drug phosphoinositide-3-kinase/protein-serine threonine kinase (PI3K/AKT). Signal channel regulation is achieved. The PI3K/AKT signaling pathway is closely related to apoptosis, and the PI3K/AKT signal regulation of tumor cells often has abnormalities, which makes it have strong growth and proliferation ability. Both epirubicin and 5-fluorouracil (5-FU) are anticancer drugs. The use of curcumin in combination with 5-FU or epirubicin can greatly increase their anticancer ability.

Jin Meng was tested with HepG2 liver cancer cells using MTT [3-(4,5-dimethylthiazol-2-yl)-5diphenyl tetrazolium, tetramethylazozolium salt microenzyme reaction colorimetric assay], reverse transcription PCR and Western -Blot detects cell viability separately.

Wu Borong experimented with the same method and found that curcumin is a sensitizer for 5-FU and epirubicin inhibiting the growth of cancer cells. Curcumin combined with 5-FU or epirubicin reduced the expression level of AKT. Thus, regulation of the P13K/AKT signaling pathway in HepG2 cells is achieved.Wu Borong also determined that the most effective concentration ratio for reducing cell survival rate is curcumin (20 mo1/L) combined with epirubicin (2 mo1/m1). When curcumin enters the tumor cells and completes the signal transduction, it can regulate the activity of certain enzymes and the expression of proteins and genes in the cells.

 

 

2. Regulate the expression of certain enzyme activities, proteins and genes in tumor cells


  Protein is the main bearer of life activities, and enzymes are the catalysts for various biochemical reactions in cells. Excessive expression of certain enzymes or other proteins can promote the rapid proliferation of tumor cells. Curcumin can inhibit the expression of certain proteins and the activity of enzymes, and increase the activity of antioxidant enzymes.

 

Inhibit the expression of certain proteins and the activity of enzymes

  Over expression of histone demethylated JMJD2A, JMJD2B and JMJD2C is an important cause of growth in most colon tumors. Curcumin is capable of inhibiting the activity of the JMJD2 enzyme. Kim et al found that down-regulation of JMJD2C can reduce the growth of HCT-116 colon cancer cells. Curcumin, a derivative of an in vitro inhibitor of the JMJD2 enzyme, reduces the activity of the JMJD2 enzyme in vivo.

  Li Yan discovered through experiments that curcumin can inhibit the expression of hypoxia inducible factor-1 (HIF-1), matrix metallopeptide (MMP-9) and its promoter activity. It is indicated that curcumin can inhibit the transcription process of certain proteins and inhibit the expression of the protein, thereby inhibiting tumor growth.


  Drug metabolism enzymes can affect the body's absorption of drugs, drug metabolism and so on. Curcumin is used in combination with certain anticancer drugs to enter the body and be metabolized by drug metabolizing enzymes. It can also regulate or inhibit the expression level and metabolic activity of certain drug metabolizing enzymes, thereby increasing the therapeutic effect.

  In experiments, Liu et al. divided mice into normal controls, benzo (a) pyrene, BP, a carcinogen treatment, BP + curcumin treatment, BP + resveratrol treatment, and BP + curcumin + Resveratrol treatment of five groups. After a single dose treatment with BP, a significant increase in drug-metabolizing enzymes, cytochrome CYP and cytochrome b5 enzyme activity, was observed in the lungs of mice. Treatment of BP-treated mice with curcumin and resveratrol revealed a significant decrease in drug-metabolizing enzyme activity compared to the other groups.

  The experimental results of Liu et al also showed that the combination of curcumin and quercetin can significantly reduce the activity of drug-metabolizing enzymes, thereby inhibiting cancer. Carbonyl reductase 1 (CBR1) can reduce the metabolism of anti-tumor drugs such as Dau Norubicin Rubidomycin (DNR), Doxorubicin (DOX), etc., to reduce the efficacy of anti-tumor drugs, and CBR1 The amount of expression increases as the dose of the anti-tumor drug increases. The study found that curcumin is a CBR1 inhibitor that binds tightly to CBR1. Hintzpeter et al. found that curcumin occupied the cofactor binding site of CBR1 and inhibited the reductive cleavage ability of CBR1.

  The results showed that the combination of curcumin and daunorubicin can reduce the reductive cleavage of daunorubicin in A549 cells and increase its efficacy in cancerous tissues. Protein kinase (phosphatase b kinase, PBK) is a silk/threonine protein kinase that is highly expressed in tissues with abundant cell division and over expressed in tumor cells. Zhang Shengjun's in vitro and in vivo experiments showed that curcumin could bind to PBK and inhibit the activity of PBK, thus playing a role in the proliferation of colorectal cancer HCT116 cells. 

 

Increase activity of antioxidant enzymes

  Nuclear factor-B (NF-B) is a family of transcription factor proteins that play an important role in cell proliferation, apoptosis, and malignancy. Reactive oxygen species (ROS) is one of the most important regulators of NF-B. Intracellular reactive oxygen species are mainly regulated by an endogenous antioxidant defense system. Activation and signaling of NF-B in normal cells is inhibited by antioxidant enzymes and further induces activity of antioxidant enzymes. Increased metabolic activity in tumor cells results in oxidative stress, which further enhances the loss of the endogenous antioxidant defense system and causes activation of NF-B to facilitate transcription.

  Das et al. found through experiments that curcumin, through an endogenous antioxidant defense system, enhances antioxidant enzyme activity, regulates NF-B activity and oxidative stress, destroys the vicious cycle of ROS production, and destroys the highly oxidative micro-environment of tumor growth. Das et al also found that curcumin prevents cancer by increasing the activity of secondary antioxidant enzymes such as glutathione S-transferase (GST) and NQO1 (Quinone oxidoreductase).