Introduction
The African rue (Espand in Persian), with the scientific name Peganum harmala, is from the Zygophyllaceae family. This plant is found in most parts of the world, including Africa, the Mediterranean, Europe, and Asian countries, including Turkey, Iraq and Iran [1-3]. For a long time, African rue has been used in traditional medicine as an important drug in various fields [1, 2, 4].
The medical history and treatment with African rue in Iran dates back to about 7000 BC, and the first medical herbs in the world's most important civilizations, such as ancient Persia, Egypt, the Middle East, ancient Greece, India and China date back to 3000 BC. Among the most famous and widely-documented authors who published and approved herbal therapies as a science, Hippocrates can be named for the writings, and in particular his medical certificate, as well as Abu Ali Sina who owns the "Law on Medicine" reference book, which contains materials on the recognition of diseases and their treatment. One of the most important medicinal plants that has been studied on its effective ingredient is African rue plant [5]. In folk medicine, African rue is used to improve diabetes, asthma, colic, dysmenorrhea, fever, bladder stones, hysteria, jaundice, laryngitis, malaria, Parkinson and rheumatism [5, 6]. The use of this plant in different countries varies according to their customs; for example, in India, African rue is used to treat syphilis and in North Africa is used to reduce fever. In Egypt, the plant is used to treat infectious diseases and is used as a strong microbial disease. Also, African rue seeds oil is used to prepare "Ziyat al-Harmal" which is used to enhance libido [5, 7].
In World War II, the harmala alkaloid in African rue was used as a true serum [5]. In the Middle East, India as well as in Africa, the plant has been used for abortion [4]. In Iran, the plant is also widely used as a popular herb for reducing blood sugar, vitality, removal of bladder stones, and after new research in treating cancer cells [5, 8]. The purpose of this paper is to identify the plant of African rue as one of the natural potential of the country in relation to its pharmacological effects, especially in the field of research on the treatment of cancer cells, which today is one of the concerns of the medical community in Iran.
This study was conducted by reviewing more than 30 articles published in Internet information science databases. All articles were selected from Elsivier, Pubmed and Google Scholar sites by Peganum harmala, pathway of betacarbolins in human body, betacarbolins, Toxicity and Anti-cancer keywords. Also, in Persian articles, the anticancer effects of African rue plant, family of the betacarbolins, alkaloids of the betacarbolin family, etc. were the keywords for our selection. The search for articles was categorized according to the mechanism of effective substance on cancer cells. Unrelated or less effective articles were deleted. Of the resources reviewed, 28 articles were carefully reviewed and information was extracted from them.

Figure 1) Chemical structure of the important alkaloids of African rue

The African rue contains important alkaloids which include Harmaline, Harmine, Harmane, Harmol, Tetrahydroharmine and opioid [5, 9, 10], as well as other substances including peganin, isopaganin, dopamine, gamma-aminobutyric acid, hydroxytryptamine, Benzodiazepine, Imidazoline, and aromatic aldehydes, including benzaldehyde and methoxybenzaldehyde [3-5, 11]. The important alkaloids of African rue are seen in different parts of the plant, including seeds, roots, stems, leaves and even flowers [7, 12]. A large part of the reserve is the major alkaloids of this plant, including Harmonium and Harmalin, in the seeds of spandan [12]. The most important characteristic of alkaloids in African rue belongs to the betacarbolin family. The formulation of the important Alkaloids of African rue is given in Figure 1 [14]. The components of African rue include Harmin, Harmalin, Harmol, Harmalol, Tetrahydroharmin and quinoamine. In addition, there are other compounds called imidazoline and opioid-benzodiazepine in the African rue extract [9, 13]. Investigations have shown that two important alkaloids of African rue, Harmin and Harmalin, have the highest amounts in seeds and roots, and very insignificant amount in the flowers [9] (Table 1).

Table 1) Amount of alkaloids present in different parts of the African rue

Beta-Carboline family
Beta-Carbolines are one of the most important synthetic materials of plants with pyrido indole B structure [15]. Structurally, beta-Carbolines are composed of five or six ring of amines. In fact beta-Carbolinens, are the heterocyclic indole alkaloids [16]. The building of the beta-Carboline ring is very similar to tryptamine [17], which is found in grilled meat, alcoholic beverages, coffee and smoke. In the human body, these compounds are derived from the amino acids of phenylalanine, tyrosine and tryptophan as endogenous and present in the body fluids, platelets, milk, urine and some body tissues, including the brain [18]. The most important effect of beta-carbolines is the stopping of cancer cells growth.
Effect of Alkaloids of Beta-Carboline family on cancer cells
Cancer is a major problem in today's medical world. According to the latest global statistics, about 12.6 million cases of cancer have been reported. The most common cancer treatments are surgery, radiation therapy and chemotherapy. Besides imposing extraordinary costs, they also have a lot of side effects. Therefore, most cancer patients have come up with a new approach to medicine. Medicinal herbs that can be effective in preventing disease progression are available and can be extracted easily, and on the other hand, herbal remedies are almost unaffected [19]. In recent years, there has been a lot of research on the effects of African rue extract on cancer cells, which all confirm the anticancer and inhibitory effects of the alkaloids in the African rue extract. For many years, African rue has been used as an anticancer drug in traditional Chinese medicine in northwest China [20]. In Morocco, African rue powder is also used to treat subcutaneous tumors [14]. Due to the high healing properties of African rue in traditional medicine, many scientific studies have been done on its therapeutic properties. Nearly 26 types of beta-Carboline have been found, which can be used as a pure extract or in combination with other plants to treat cancer cells [21]. 7 mechanisms of the effect of these compounds on the body and their effects on cancer cells have been investigated in this study:
1. Preventing the growth of cancer cells through the phenomenon of apoptosis
In many organs and tissues of plants and animals, the balance between cell renewal and death persists. Different types of adult cells have a certain life span and, with their death, new cells are produced by multiplying and differentiating different types of stem cells. The process of apoptosis or scheduled cell death, as a protected method, is controlled by genes. Planned cell death is used to remove unwanted or unnecessary cells in living organisms. This process is very important in regulating growth, cell proliferation, evolution and body health, and the incidence of many autoimmune diseases, cancers and viral infections is a result of poor performance or a controlled cell death phenomenon [22]. Cancer occurs as a result of uncontrolled cell division, which is rooted in the effects of environmental factors and genetic disorders. Four categories of key genes involved in the guidance of cancer cells include oncogenes, tumor suppressor genes, DNA repair genes, and scheduled death genes [23]. In a study on acute leukemia cancer cells, it has been shown that the alkaloid derivatives of African rue, Harmine and Harmalin, reduce and stop cancer cells, depending on the amount (dose) and growth time. This occurs through the induction of apoptosis in cancer cells [8]. In 2011, Hasma et al. carried out studies on the effects of Harmala alkaloid in African rue on melanoma cancer cells, in which the melanoma cells were placed under laboratory culture conditions in the presence and absence of African extract containing harmin, and changes in cell cycle and expression of various genes and induction effects of apoptosis were studied and analyzed. Morphological changes indicated the induction of apoptotic phenomena in treated cells with harmin. Also, placing the sample on the gel electrophoresis also indicates the fragmentation of the DNA and the impairment of the cellular division process [21]. In induction of apoptosis, caspases cause the release of apoptosis inducers with impaired cellular respiratory chain. These factors disrupt the topoisomerase enzymes 1 and 2, and disrupt DNA replication by replicating the DNA. By breaking down the structural nuclear protein, the nucleus membrane laminae are degraded by Caspase 6, which results in chromatin condensation and fragmentation in apoptotic cells. A recent set of events causes the cell to stop cell growth and replication and ultimately leads to cell death [19]. P53 molecule is one of the most important cell proliferation inhibitors that interrupts the G2 stage by inhibiting the cell cycle and prevent the tumor by induction. Harmin alkaloid in African rue plant induces apoptosis in the cell by activating P53 cells inside cancer cells and prevents the growth and progression of cancer cells by stopping cell division and destroying tumor cells [24, 25]. In 2015, Chun Hawang et al. used African rue plant alkaloids against cancer cell growth, and the results of the study showed that among the 12 different types of alkaloids used on cancer cells, harmaline alkoloid had the highest induction and effect on stopping and death in the cancer cells and in the apoptosis induced by compounds of the African rue plant, membrane potential, and mitochondrial ATP levels has been significantly reduced [26].
2. Impairment of replication
The use of African rue alkaloids inhibits the growth of K562 erythema leukemic cells by preventing the formation of DNA and cell division. Harmin in these compounds also prevents the function of the enzyme topomerase 1 [8]. In 2007, a study was conducted on the effects of African rue alkaloids with ATRA (All-Trans Retinoic Acid) and vitamin D3 and arsenic trioxide on cancer cells [15]. ATRA is a known differentiator for the treatment of cancer cells [8]. Studies have shown that ARTA and vitamin D3 differentiate malignant and immature malignant cells into the differentiation of neutrophil and monocyte cells and clarify the anti-leukemic effects of plant alkaloids [8].
In another study, the cancer cells of Pc12, B65 and B19 were evaluated using African rue seed extracts, especially beta-carbolins in African rue seeds against these cells. In that study, the interaction of Xanthomicrol with noscapine, which are alkaloids, was used in conjunction with alkaloids in African rue against Pc12 and B65 cells. The results showed that Harmalin in the African rue extract exhibits a small toxic effect on animals and humans, and shows strong inhibitory effects on cancer cells.
Another study was conducted in 2004 on the effects of beta-Carbolines in dried seed extract of African rue plant. The results showed that beta-carbolines inhibit the growth and inhibition of cancer cells in mice by inhibiting the synthesis of DNA and intercalate DNA Helix and inhibition of DNA of topomerase1 and.
In another study, the effect of African rue extract on Vcp-med, Med-mec carcinoma and Vcp-med sarcoma cancer cells was investigated. The results indicated that the death of cancer cells occurred within 48 to 72 hours after the effects of these alkaloids. In that study, also, African rue alkaloids had inhibitory effects on the synthesis of ANA and DNA by inhibiting the topomerase 1 enzyme as well as inhibitory effect on cyclin-dependent kinase (CDKS) in the G1 phase in cell division [4].
In another study, by involving the effect of thiourea, cancer cells were produced in mice. Then these cells were affected by alkaloids in the African rue plant. The results showed the inhibitory effect of compounds present in the African rue plant on cancer cells in thyroid cells, liver enzymes (ALT, AST, BILL, and ALK) and cancer cells in blood cancer [2].
3- Angiogenesis
Studies have shown that Harmin is a potent angiogenic inhibitor that can significantly reduce vascular endothelial cell proliferation and reduce the expression of genes associated with various factors affecting angiogenesis, such as KB, ATP-2, and so on. Mechanism of harmine effect can be used to inhibit the growth of cancer cells because Harminn reduces the production of other factors that are involved in the angiogenesis of tumor cells and thereby inhibits angiogenesis in the tumor [27, 28].
4- The antioxidant effect of African rue plant
A study by Berrougui et al. (2006) found that Harmin and Harmalin in African rue seed extract have antioxidant effects on LDL and prevent its oxidation in the laboratory. In this process, the effect of Harmalin is more than Harmin. Concerning the antioxidant mechanism of these alkaloids, studies have shown that these two alkaloids have a high capacity to remove free radicals in comparison with the control substance (vitamin E) and the effect of harmalin is triple more than harmin [25]. These compounds, in addition to beta-carbolin acids, contain phenolic flavonoids that have antioxidant activity and prevent the formation of free radicals and the formation of cancer cells.
In a study conducted in 2010, the effect of alkaloids in African rue on laryngeal and hep-2 cells was investigated. The method used was that the methanolite extract of the African rue plant, whose main alkaloid, was harmalole, was used at different doses for the development of cancer cells in mice. The results indicated that a dose of 312 μg / ml of extract had a significant inhibitory effect compared ot the other doses [3].
5- Effects on the immune system
Studies have shown that beta-carbolines alkaloids have a balancing effect on immune function. Extract of African rue has a significant anti-inflammatory effect through inhibition of some inflammatory mediators such as prostaglandin (one microgram / 100 milligrams). In cancerous conditions, the immune system is weakened by its immune response; it can have modulating and boosting effects on the immune system [14].
6- Pain killer
Research on some of the African rue compounds, such as Harmen and Harmin, and their inhibitory effect on naloxone induced exclusion syndrome have been done in morphine-dependent mice. The findings of this study have shown that these compounds can stimulate opioid receptors [14]. Opioids have complex and contradictory effects on epileptic activities, so that depending on the type and conditions of the trial, anti-epileptic effects and epilepsy exacerbation effects have been reported for them [14, 31]. Since opioid substances have analgesic effects and they have the most well-known role of quaternary morphine in the spinal cord, Harman and Harmin at the synapse site between the enkephalinergic interstitial neurons (located on the posterior horn of the spinal cord gray material) affect the peripheral nerve terminals, which give pain information to the spinal cord [32].
7- Effects on the monoamine oxidase enzyme (MAO)
As it was said earlier, beta-Carbolins are produced in the body as endogenous and measurable at a level of 1 Ng in animal protein [15]. Harman and Norharman are considered as biological indicators in alcoholism and dependence on opioids. Harman and other beta-carbolines act as reversible agonists on the site ω of GABA-A receptors and cause a wide range of reverse effects of benzodiazepines, such as inducing anxiety, stimulating CNS, and seizure. Beta-Carbolines increase the concentration of norapinephrine, serotonin and dopamine in various neuropsychiatric synapses by inhibiting the activity of monoamine oxidase B (MAO-B) and monoamine oxidase A (MAO-A). These results indicate the modulating effect of beta-carbolines on dopaminergic steroidal behaviors. In fact, beta-Carbolines act like antidepressants [14, 18]. Accordingly, the properties of these compounds have been described by inhibiting monoamine oxidase enzyme, binding to benzodiazepine receptors, seizure and anticonvulsant effects, anxiety, oxidative antidotes, and immunosuppressive agents. Benzodiazepine drugs have anti-anxiety and amorphous properties, while beta-carbolins as reverse agonists exhibit anxiety and increased levels of learning. Researchers at one of Japan's research centers managed to detect an enzyme in the brain that adjusts all emotional states. This enzyme is called Rines and is the most important monoamine oxidase A regulator. This protein is the only factor regulating the emotions and mood of individuals. This protein breaks down serotonin, neurotransmitters and dopamine. Changing this gene is one of the most important factors in increasing the level of violence and antisocial behavior. Although the association between this protein and emotional patterns has been proven, the root cause of this mechanism is still unclear. The most important use of this enzyme is to achieve the latest treatment of various types of neurological disorders and mental disorders. Another application of this achievement is the ability to control various levels of excitement and stress in individuals. Researchers believe that after completing the necessary tests, the enzyme can be used in the pharmaceutical industry, especially sedative and refreshing drugs. The full results of this research are published in the recent issue of the journal Neuroscience [21].

Conclusion
African rue plant is one of the most widely used herbs in Iran. This plant grows wild and does not require much farming. Therefore, due to the high pharmacological effects of the African rue plant, and given the talent of the Iranian land for the growth of this plant, it can be used in the field of medicine. African rue, with numerous medicinal properties and valuable alkaloids from the beta-carboline family, produces an effective agent against cancer cells and is capable of treating cancer. At the same time, there are grounds for further research on the effects of this plant.
Regarding the mechanism of the effect of the compounds in this plant on cancer cells, African rue compounds can be used in anticancer drug formulation, individually or in combination. This goal requires highly precise pharmacological research to track the location of the compound's effects.

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Contribution of authors: Zahra Roostai (First author), All affairs of the article has been carried out by her (100%).