Anti-tumor research progress of Herba Hedyotidis Diffusae

Jin-Feng Liu Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China.

Abstract Cancer, as one of the major public health problems in the world, dramatically harms human health. In recent years,studies have found that Herba Hedyotidis Diffusae not only plays a huge role in anti-infection but also has a strong effect on anti-tumor. Several studies have shown that the components contained in Herba Hedyotidis Diffusae have different levels of antitumor results in multiple pathways. This article summarizes the antitumor elements in Herba Hedyotidis Diffusae, and describes the antitumor mechanism of Herba Hedyotidis Diffusae. Provide new ideas for further clinical use.

Keywords: Herba Hedyotidis Diffusae, Antitumor, Mechanism, Traditional Chinese medicine

Background

Herba Hedyotidis Diffusae is the whole herb of the Rubiaceae plant, Hedyotis diffusa. Hedyotis diffusa grows in a warm and humid environment and has a wide range of growth. But it is not resistant to drought and severe cold. Traditional Chinese medicine theory believes that Herba Hedyotidis Diffusae has a strong anti-inflammatory effect, and is mainly used to treat infectious diseases. Modern pharmacological studies have found that Herba Hedyotidis Diffusae can not only play a huge role in anti-infection but also has a strong effect in anti-tumor [1-3], regulating immunity[4] and antioxidant [5]. Especially in terms of antitumor effects, more and more evidence shows that Herba Hedyotidis Diffusae can effectively inhibit the development of tumors.

It is undeniable that cancer has become a disease that seriously threatens the survival of human beings and has become a publicly accepted fact. Currently, the main treatments for cancer are surgery, radiation, and chemotherapy. While these treatments treat cancer,they also bring about complications caused by adverse reactions. As one of the methods of adjuvant therapy,Chinese medicine is playing an increasingly important role in the clinic. This article summarizes the antitumor components and mechanism of Chinese medicine Herba Hedyotidis Diffusae, and provides new ideas for clinical treatment.

Active ingredients

With the emergence of some new instruments (E.g.liquid chromatography-mass spectrometer, nuclear magnetic resonance-mass spectrometer, time of flight-mass spectrometer) and the development of analytical techniques, research on the active ingredients of Herba Hedyotidis Diffusae is increasing.Herba Hedyotidis Diffusae mainly includes triterpenes,iridoids, polysaccharides, flavonoids, anthraquinones,phenolic acids, steroids, volatile oils, etc. The active ingredient also contains some trace elements and amino acids. However, not all active ingredients have antitumor effects. The following summarizes several types of active ingredients with relatively high antitumor activity.

Anthraquinones

Research on anthraquinones in Herba Hedyotidis Diffusae began in the 1980s. Anthraquinones are one of the three characteristic components of Herba Hedyotidis Diffusae, and the content of anthraquinones in medicinal materials is also high [6]. Among them,anthraquinone compounds having a significant tumor-suppressive effect include 2-hydroxy-3-methyl anthraquinone and 2-hydroxy-1-methoxy-3-methyl anthraquinone.

Iridoids

Iridoids are also an essential component of Herba Hedyotidis Diffusae. In addition to having various biological activities such as antioxidant,anti-inflammatory, and protecting the nervous system,they also have good anti-tumor activity [7]. And most of these ingredients have good anticancer activity.Iridoids mainly contain scandoside derivatives,geniposide derivatives, and asperuloside derivatives [8,9].

Triterpenoids

This ingredient is one of the main characteristic components of Herba Hedyotidis Diffusae, and has an obvious anti-cancer effect. At present, four triterpenoids have been isolated from Herba Hedyotidis Diffusae, including gypsogenicacid, lupeol acetate, oleanolic acid, and ursolic acid [10, 11].Among them, the content of ursolic acid and oleanolic acid is relatively high.

Flavonoids

Flavonoids are a class of compounds widely found in nature. The flavonoids in Herba Hedyotidis Diffusae are mainly quercetin, kaempferol, and the glycosides of both. These components have strong DNA cleavage activity [12]. Current pharmacological studies have found that flavonoids have antitumor, antioxidant, and scavenging effects [13].

Polysaccharides

The polysaccharide of Herba Hedyotidis Diffusae is a biological macromolecule composed of monosaccharides such as glucose, galactose, arabinose,and rhamnose [14]. As one of the essential active ingredients of Herba Hedyotidis Diffusae, Herba Hedyotidis Diffusae polysaccharide has anti-tumor,immune regulation, antioxidant, and anti-aging effects.

Other compounds

Organic acids are acidic organic compounds that are widely found in the leaves, roots, and fruits of traditional Chinese medicine. The organic acids in Herba Hedyotidis Diffusae are mainly ursolic acid,oleanolic acid, and ferulic acid. And some organic acids have antitumor effects. In addition, Herba Hedyotidis Diffusae also contains steroids, mainly sterols, and glycosides. Among them, there are compounds such as β-sitosterol and stigmasterol,which are one of the active antitumor ingredients of Herba Hedyotidis Diffusae [15].

Antitumor mechanism

Herba Hedyotidis Diffusae contains a variety of antitumor active ingredients. A large number of studies have found that these active ingredients mainly inhibit tumor cells through cytotoxic effects, inhibition of tumor cell proliferation, promotion of tumor cell apoptosis, enhancement of chemotherapeutic drugs,reduction of tumor cell drug resistance, and antioxidant.Especially in terms of inhibiting proliferation and promoting apoptosis, multiple studies have proven that Herba Hedyotidis Diffusae has practical effects on tumor cells in various locations.

Cytotoxicity

Priyadarsini et al. [16] studied the cytotoxic effect of quercetin on HeLa cells. Quercetin can cause changes in the nucleus morphology, chromosome condensation,and nuclear fragmentation. Studies by Ling et al. [17]showed that Herba Hedyotidis Diffusae has high selective toxicity. Herba Hedyotidis Diffusae is highly toxic to MCF7 breast cancer cells, but not significantly cytotoxic to normal breast epithelial cells MCF12A.Hu et al. [18] isolated three cyclic peptides (DC1, DC2,and DC3) from the leaves and roots of Herba Hedyotidis Diffusae. The results showed that all three had potent cytotoxicity to human prostate cancer cell lines PC3, DU145 and LNCaP, and DC3 had the most substantial effect.

Inhibit proliferation

Studies have shown that [19] quercetin can interfere with the PI3K/Akt signaling pathway, activate AMP-dependent protein kinases, inhibit the mTOR signaling pathway, and inhibit the growth of a variety of malignancies.

Li et al. [3] found that E-6-O-p-coumaroyl scandoside methyl ester and 10(S)-hydroxy-demagnesium chlorophyll in PC3 human androgen-independent prostate cancer cells Has a potent inhibition of proliferation. Besides,10(S)-hydroxide magnesium chlorophyll can also inhibit the proliferation of LNCa human androgen-sensitive prostate cancer cells. Chen et al.[20] showed that the water extract of Herba Hedyotidis Diffusae prevented the approach of the G0/G1 phase and delayed the S phase in the HepG2 cell cycle by down-regulating the expression of cdk2-e2f1 mRNA.Zhang et al. [21] found that some iridoids have inhibitory effects on cells such as SMMC7721,Bel7402, and HepG2. Li et al. [22] found that ethanol extract of Herba Hedyotidis Diffusae significantly inhibited the human colon cancer cell HCT-8/5-FU activity. Research suggests that this is achieved by down-regulating the expression of P-glycoprotein and ABCG2 protein. Zhang et al. [23] found that the water extract of Herba Hedyotidis Diffusae significantly inhibited the proliferation of cervical cancer HeLa cells and showed a dose- and time-dependent relationship.Also, Dong et al. [24] found that alkaloid/flavonoid extracts have antitumor activity on the human breast cancer cell line MCF7.

Promote apoptosis

Liu et al. [25] found that methyl anthraquinone can induce MCF-7 human breast cancer cell apoptosis.Methyl anthraquinone's antitumor mechanism is that it can up-regulate intracellular calcium levels, JNK phosphorylation and activation of calpain, release cytochrome C, and activate caspase-4, caspase-9, and caspase-7. Lee et al. [26] found that the ethanol extract of Herba Hedyotidis Diffusae can induce the death of human lung cancer cell H460, and the effect is dose-dependent, and this process depends on the caspase enzyme to achieve. Lin et al. [27] found that ethanol extract of Herba Hedyotidis Diffusae inhibited the growth and induced apoptosis of human colon cancer cell HT-29. This process caused the loss of mitochondrial potential, activated caspase-9 and caspase-3, and regulated the expression of anti-apoptotic genes Bcl-2 and pro-apoptotic genes Bax. Research by Young et al. [28] showed that ursolic acid, an extract of Herba Hedyotidis Diffusae,inhibited the growth of uterine cancer SK-OV-3 cells.Its mechanism of action is that ursolic acid can induce apoptosis in SK-OV-3 cells by activating caspase activity and phosphorylation of glycogen synthase kinase 3β (GSK3β). Zhang et al. [29] found that Herba Hedyotidis Diffusae injection can inhibit the growth of glioblastoma U87 and induce its apoptosis. This process is thought to be that the drug-induced mitochondrial apoptosis through the AKT/ERK signaling protein pathway.

In the treatment of non-solid tumors, Herba Hedyotidis Diffusae also has a robust apoptotic effect.Kuo et al. [30] thought that ethanol extract of Herba Hedyotidis Diffusae could induce cell cycle arrest and apoptosis of human leukemia cells HL-60, and this process depends on caspase-8, caspase-9, and caspase-3 activation. Wang et al. [31] found that 2-hydroxy-3-methyl anthraquinone can induce THP-1 cell apoptosis in a time and dose-dependent manner.The mechanism may be that 2-hydroxy-3-methyl anthraquinone triggers caspase-8 activation in THP-1 cells.

Other mechanisms

Herba Hedyotidis Diffusae can exert antitumor effects by enhancing the effects of chemicals. Cipak et al. [32]found that quercetin can enhance the apoptosis of HL-60 and L1210 leukemia cells by cisplatin. Ursolic acid and oleanolic acid are the two most useful and in-depth substances in antitumor research. These two substances not only inhibit the growth of breast cancer cells and can cause the up-regulation of p53 expression,but also can reduce the resistance of breast cancer MCF-7 cell lines to tamoxifen [33]. The occurrence and development of many human diseases are closely related to oxygen-free radicals. Kim et al. [34] reported that iridoids may inhibit the oxidation of low-density lipoproteins.

Summary

As one of the anti-inflammatory Chinese medicines,other functions of Herba Hedyotidis Diffusae have also been slowly tapped out. In recent years, more research has been done on the anticancer effect of Herba Hedyotidis Diffusae. These anti-cancer active ingredients mainly achieve tumor cell inhibition through cytotoxic effects, inhibition of tumor cell proliferation, promotion of tumor cell apoptosis,enhancement of chemotherapeutic drugs, reduction of tumor cell drug resistance, and anti-oxidation. By induction, it was found that the antitumor effect of Herba Hedyotidis Diffusae is mainly related to inhibiting tumor cell proliferation and promoting tumor cell apoptosis. Especially in terms of apoptosis,Herba Hedyotidis Diffusae is closely related to caspase,and the activation of caspase is beneficial to tumor cell apoptosis.

Some tests have proven that its side effects on normal cytotoxicity are minimal, which provides a basis for Herba Hedyotidis Diffusae to assist in the treatment of cancer and to replace chemotherapy.Thankfully, Herba Hedyotidis Diffusae has been used clinically as an anticancer drug. And it has been verified that Herba Hedyotidis Diffusae has a good effect on gastric cancer, liver cancer, lung cancer,esophageal cancer, and leukemia [35]. However, there is currently a single type of anticancer drug that contains Herba Hedyotidis Diffusae. And there is no drug type obtained by purifying the anticancer active ingredient of certain or certain types of Herba Hedyotidis Diffusae.