Study on Pharmacological Effects of Harmine Hydrochloride

Yue TENG, Anqi WANG, Jiazhu LI, Qing ZHANG, Xue ZHAO, Yuwei WANG, Chenghao JIN

College of Life Science and Technology, Heilongjiang Bayi Agricultural University, Daqing 163319, China

Abstract Harmaine hydrochloride is an important alkaloid compound and mainly exists in the roots, stems, leaves and seeds of the plant Peganum harmala L. (family Zygophyllaceae). Harmaine hydrochloride not only has good anti-bacterial, anti-plasmodium, anti-Parkinson’s disease, anti-fungal, anti-oxidation and anti-tumor activities, but also has the characteristics of small adverse reactions and low toxicity, thus it has attracted wide attention from scholars and researchers. This paper reviews the pharmacological effects and mechanisms of harmine hydrochloride in recent years, and is intended to provide a theoretical basis for the clinical application of harmine hydrochloride.

Key words Harmaine hydrochloride, Pharmacological effects, Anti-Parkinson’s disease, Antibacterial activity, Anti-tumor activity

1 Introduction

Harmaine hydrochloride is a compound that mainly exists inPeganumharmalaL. (family Zygophyllaceae). It is soluble in water, ethanol, chloroform and ether. Its molecular formula is C13H12ClN2O, and its appearance is a pale yellow powder. Harmine hydrochloride has a variety of biological activities such as antibacterial and anti-tumor activities. It can be used in the treatment of clinical bacterial infections and cancer, and has broad medical prospects[1]. In this study, we reviewed the pharmacological effects and mechanisms of harmine hydrochloride in recent years, to provide a theoretical basis for the development of anti-tumor drugs.

2 Anti-Parkinson’s disease

Parkinson’s disease (PD) is a common neurodegenerative disease. In China, the prevalence of PD among people over 65 years of age is about 1.7%. It seriously threatens the health and lives of elderly people. Studies have found that harmine hydrochloride has a good protective effect on the nervous system. ZS Nurmaganbetovetal.[2]used mice to verify the anti-Parkinson effect of harmine hydrochloride, after treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), they observed the tremor, rigidity and exercise volume of the mice on the 1stand 7thday. The results show that harmine hydrochloride can increase acetylcholinesterase activity and protective effect, maintain the distribution of cholinergic fibers in the damaged area, and it also can protect cholinergic fibers in the parietal area of the cerebral cortex and reduce the duration and severity of Parkinson’s disease.

3 Antibacterial effect

Inflammation can cause acute systemic infections. It is clinically characterized by chills, high fever, skin rash, arthralgia, and hepatosplenomegaly, and some inflammations are characterized by septic shock and migratory lesions. Harmaine hydrochloride can play an antibacterial effect by inhibiting the activation of inflammatory signal pathways and the infiltration of inflammatory cells. According to findings of Sun Baoliangetal[3], harmaine hydrochloride has different degrees of antibacterial activities againstStaphylococcus,EnterobacterandStreptococcusinvitro.

Combined medication is an effective way to resist fungi. At present, there are limited varieties of antifungal drugs available in clinic, and most of them are expensive and have obvious side effects. Therefore, finding drug sensitizers to fight drug-resistant fungi has become a research hotspot at both home and abroad. Li Xiuyunetal.[4]conducted an experiment on drug-resistant Monilia albican Candida albicans method of Clinical and Laboratory Standards Institute 27-A3 (CLSIM 27-A3) and found that harmine hydrochloride combined with fluconazole can enhance the antibacterial activity of fluconazole on drug-resistant canidia Albicans, produce a synergistic antifungal effect, and can reverse the resistance of canidia Albicans to fluconazole. Combined medication for fluconazole-resistant canidia Albicans can significantly reduce its minimum inhibitory concentration, and the greater the concentration, the stronger the effect. The synergistic effect of harmine hydrochloride on fluconazole antifungal performance is to expand its application range, and reduce the minimum effective inhibitory concentration of fluconazole, reduce the dosage of the antifungal drug fluconazole, thereby reducing the occurrence of adverse drug reactions and overcoming the clinical problem of fungal drug resistance.

4 Anti-tumor effect

Cancer is a malignant tumor originating in epithelial tissues. It is the most common type of malignant tumors. It has biological characteristics such as abnormal cell differentiation and proliferation, loss of growth control, invasiveness and metastasis. Studies have shown that harmine hydrochloride has a good inhibitory effect on tumor cells. At present, the World Health Organization (WHO) has gradually deepened the research on the anti-tumor mechanism of harmine compounds, and four mechanisms have been better accepted.

4.1 Inhibiting cancer cell proliferation and cloningThe proliferation of cancer cells is an infinite proliferation. Cancer cells will rob nutrients of normal cells and promote their rapid spread. Zhang Xiaokaietal.[5]used the methylthiazolyldiphenyl-tetrazolium bromide (MTT) method to detect that after harmine hydrochloride acted on human pancreatic cancer AsPC-1 cells, compared with the blank control group, harmine hydrochloride of different concentrations had an inhibitory effect on the pancreas cancer cells (P<0.01), and with the increase of drug concentration, the inhibitory effect is enhanced in a significant dose-dependent manner. Further study found that as the concentration of drugs acting on pancreatic cancer cells increases, cell clones gradually decrease. When the concentration of harmine hydrochloride was 4 μmol/L, it produced obvious clonal formation inhibition. When the concentration reached 16 μmol/L, no clonal cell lines were formed. Through proliferation experiment, Lu Xianyuetal.[6]found that the ability of harmine hydrochloride to inhibit the proliferation of esophageal squamous cells increased significantly with the increase of its concentration. At the same time, they conducted cloning experiments to detect the inhibitory effect of harmine hydrochloride on the independent growth of esophageal squamous cell carcinoma cell lines. They found that harmine hydrochloride inhibited the cloning ability of esophageal squamous cell carcinoma cells and increased significantly as its concentration increased. Tan Biboetal.[7]also tested the apoptotic rate of gastric cancer cells by flow cytometry and found that the apoptotic rate of AGS cells was significantly increased after harmine hydrochloride treatment (P<0.01).

4.2 Inducing cancer cell apoptosis and autophagyFrom the perspective of cell apoptosis, the occurrence of tumors is caused by the obstruction of apoptosis. Therefore, inducing apoptosis of cancer cells is an effective way to treat cancer. Zhang Xiaokaietal.[5]used the MTT method to observe the inhibitory effect of harmine hydrochloride on the proliferation of pancreatic cancer AsPC-1 cells, and found that Caspase-3 was activated, PARP enzymatic digestion was inactivated, and the expression of protein P62 was reduced, and expression of autophagy marker protein LC3 II was increased. After different concentrations of harmine hydrochloride were treated, there were obvious late apoptosis and necrotic cell populations. Xiren Ayi Xirefuetal.[8]found that harmine hydrochloride can inhibit the Akt/mTOR signaling pathway and activate the endogenous apoptosis pathway of tumor cells to effectively inhibit the proliferation of human neuroblastoma SH-SY5Y cells and induce autophagy at the same time. Liu Huaileietal.[9]used flow cytometry to detect the effect of harmine hydrochloride on the apoptosis of glioma cells U87 and C6 and found that harmine hydrochloride can significantly reduce the activity of glioma cells and induce their apoptosis.

4.3 Inhibiting glycolytic function of cancer cellsAbout 50% of ATP in tumor cells is synthesized through glycolysis, and even in an aerobic environment, tumor cells still provide energy mainly through glycolysis. Through proteomics, Lu Xianyuetal.[6]found that harmine hydrochloride has the function of inhibiting the glycolysis of cancer cells. They established a PDX model of human esophageal squamous cell carcinoma, and intraperitoneally injected harmine hydrochloride (20 and 40 mg/kg), and performed immunohistochemical staining with KI67 antibody to verify the anti-tumor effect of harmine hydrochlorideinvivo. Through GO function enrichment and KEGG pathway analysis of differential proteins greater than 1.5 times, it is found that harmine hydrochloride can inhibit the occurrence of glycolysis; the growth of esophageal squamous cell carcinoma is inhibited by harmine hydrochloride. After treatment with harmine hydrochloride, the tumor volume and weight of the administration group were significantly smaller than those of the control group; the tumor growth rate of mice in the control group was significantly greater than that of the experimental group.

4.4 Inhibiting the migration of cancer cellsThe migration of tumor cells is one of the important reasons for increasing clinical mortality. Therefore, inhibiting tumor cell migration is an important means to increase the cure rate and maintain the lives of patients. Through experiments on xenograft tumors derived from cells such as MDA-MB-231, MCF-7, MCF-7 andinvitroexperiments, Ding Yuetal.[10]found that HM has a good inhibitory effect on breast cancer cells and inhibits cell migration, and the inhibition is dose-dependent and time-dependent. By studying the action and mechanism of harmine hydrochloride on gastric cancer cells, Tan Biboetal.[7]used the scratch test and Transwell test to measure the migration and invasion ability of GC cells and found that harmaine hydrochloride can reduce the expression of MMP-2, HIF-1α and PRDX1, thereby regulating the invasion and migration of GC cells to treat cancer.

5 Conclusions and prospects

As an alkaloid compound extracted from the plantP.harmalaL, harmine hydrochloride has the characteristics of wide source, low toxicity and small molecular weight. It is a drug with broad medical development prospects in scientific research and clinical research. However, as a traditional Chinese medicine compound, the research and clinical application of its function mechanism is still in its infancy. For example, the specific signal transduction pathways, pharmacological targets, and the interaction between the two are still unclear. The antibacterial mechanism of harmine hydrochloride and the way to inhibit tumor cells are not clear. These points need to be combined with related theories of traditional Chinese medicine to conduct in-depth research on harmine hydrochloride from the animal (such as the construction of nude mouse tumor models), cells (various cell experiments) and molecular levels, so as to provide a theoretical basis for clinical research.