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Insights into free radicals scavenging, α-Amylase inhibition, cytotoxic and antifibrotic activities unveiled by Peganum harmala extracts

BMC Complementary Medicine and Therapies volume 24, Article number: 299 (2024) Cite this article

Abstract

Background

Peganum harmala L. is used in traditional medicine to treat several health ailments. Hence, the present work aimed to investigate the DPPH free radical scavenging, α-amylase, cytotoxic, and antifibrotic effects of the hydrophilic extract and fixed oil obtained from P. harmala seeds.

Methods

The hydrophilic extract and fixed oil of P. harmala were assessed for their abilities to scavenge DPPH free radicals and inhibit α-amylase using reference bioassays. The cytotoxicity was assessed on several cancer and normal cell lines, including B16F1, Caco-2, COLO205, HeLa, Hep 3B and Hep G2, MCF-7, and HEK-293 T cells. The MTS assay was used to evaluate the antifibrotic capabilities utilizing the human hepatic stellate (LX-2) cell line.

Results

P. harmala plant fixed oil has potent DPPH free radical scavenging activity with an IC50 dose of 79.43 ± 0.08 µg/ml. Besides, the hydrophilic extract has a poor anti-α-amylase effect compared with the antidiabetic drug Acarbose, with IC50 doses of 398 ± 0.59 and 25.11 ± 1.22 µg/ml, respectively. In addition, the growth of MCF-7, Hep3B, HepG2, HeLa, COLO205, CaCo2, B16F1, and HeK293t was inhibited by P. harmala hydrophilic extract with IC50 doses of 121.34 ± 1.71, 268.3 ± 0.75, 297.20 ± 1.00, 155.60 ± 1.14, 150.01 ± 0.51, 308.35 ± 0.53, 597.93 ± 1.36, and 5.38 ± 0.99 µg/ml, respectively. In addition, at 1000 µg/ml, 5-Fluorouracil reduced fibrosis cells by 0.089%, while the hydrophilic extract decreased the number of LX-2 cells by 5.81%.

Conclusion

P. harmala plant-fixed oil exhibits potential antioxidant properties. While the hydrophilic extract showed limited effectiveness as an anti-α-amylase agent and demonstrated notable cytotoxic effects against various tested cancer cell lines. Furthermore, this extract significantly reduces the number of LX-2 fibrotic cells. These findings emphasize the therapeutic potential of these products in managing various health disorders and warrant further investigation into their mechanisms of action and clinical applications.

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Background

Peganum harmala L., also known as “Suryin Rue” or “Harmal,” is a native plant of the Mediterranean and Central Asia, encompassing arid and semiarid regions such as Turkey, Iran, Mexico, the Middle East, and North Africa [1,2,3]. The P. harmala seeds contain alkaloids, phenolic acids, flavonoids, and glycosides [4,5,6]. Studies revealed that P. harmala seeds are effective in treating a variety of conditions, including respiratory problems [7], viral infections [8], knee osteoarthritis [9], gastric cancer [10], dermatoses [11], and skin ulcers. Additionally, studies have demonstrated that these seeds improve brain function [12, 13] and have an antidepressant effect [14,15,16].

The seeds contain phosphorylcholine, harmine, choline, asparagine, harmol, harmaline [3, 9], pegamine dimer, peganine, dexoypeganine, vasicinone, ruine, pegaline, tetrahydroharmin, pegamine, harmalol, deoxyvasicinone [4], peganumaline, ( ±)-peganumalines A–E, 2-oxoindole alkaloids [5], chlorogenic acid, hesperetin, catechin, rutin, p-coumaric acid [6], isorhamnetin-7-O-glucoside, quercetin-3-O-rutinoside, kaempferol-3-methyoxyl-5-O-rutinoside, kaempferol-3,5-dimethyxyl-7-O-glucoside, anthraquinone glucoside, 9,14-dihydroxy octadecanoic acid, quercetin-3-O-gentiobioside, isorhamnetin-3-O-rutinoside, and kaempferol-3-methoxyl-7-O-glucoside [17].

Oxidative stress is a prevalent issue in today’s society, causing normal cells to transform into malignant cells due to the buildup of a significant quantity of reactive oxygen species (ROS) [18]. Exploring oxidative stress is a primary focus for physicians and scientists because of its potential involvement in developing numerous health issues. When the production of reactive oxygen species surpasses the body’s antioxidant defenses, oxidative stress ensues. These reactive oxygen species (ROS) serve as crucial signaling molecules, aiding in maintaining cellular equilibrium with the external environment. However, elevated concentrations can lead to cellular death and function impairment [19,20,21].

Conversely, diabetes-related problems caused by long-term hyperglycemia may encompass stroke, neuropathy, retinopathy, and nephropathy [22, 23]. The IDF Diabetes Atlas estimates that 537 million adults aged 20–79 had diabetes in 2021. This number is expected to rise to 643 million by 2030 and is expected to reach 783 million by 2045. Indeed, according to data from 2021, this disease accounted for approximately 6.7 million fatalities [24]. α-Amylase facilitates the complex metabolic process of transforming starch (known as amylum in Latin) into sugars that are more readily digested. The enzyme is present in the saliva of humans and other mammals, initiating the process of chemical digestion. Alpha-amylase inhibitors have the ability to hinder the action of the enzyme alpha-amylase, hence impeding the breakdown of complex carbohydrates into simpler sugars. These inhibitors has the capacity to regulate blood sugar levels and are now being researched for their potential health advantages [25]

Cancer is the second leading cause of death in the United States and a major global public health concern [26]. According to the WHO, approximately 20 million new cases of cancer and 9.7 million fatalities were identified in 2022. Lung cancer constituted the most prevalent form of cancer on a global scale, comprising 2.5 million newly diagnosed cases or 12.4% of the total new cases. Colorectal cancer (1.9 million cases, 9.6%), prostate cancer (1.5 million cases, 7.3%), and gastric cancer (990,000 cases, 4.9%) ranked higher than female breast cancer (2.3 million cases, 11.6%) [27].

While the precise mechanisms connecting cancer and diabetes remain speculative, potential risk factors for both conditions may involve hyperglycemia leading to the formation of advanced glycated end products (AGEs) and oxidative stress, hyperinsulinemia resulting from insulin resistance or exogenous insulin administration, inflammatory processes, and obesity. Despite diabetes being recognized as a risk factor for cancer and its increasing prevalence, certain antidiabetic agents may exhibit beneficial effects in cancer management [28, 29].

Liver fibrosis, which results from chronic liver damage and the accumulation of extracellular matrix proteins, is a hallmark of a variety of chronic liver ailments. The lack of effective treatments underscores the urgent need for antifibrotic medication development. As a result, numerous studies targeting LX-2 cell lines have identified potential antifibrotic agents [30, 31]. In fact, alcohol addiction, chronic hepatitis C, and nonalcoholic steatohepatitis are the leading causes of liver fibrosis [32, 33]. In recent research, various phytochemicals have demonstrated antifibrotic effects on LX-2 cell lines. Researchers have observed curcumin, derived from turmeric, exhibiting antifibrotic properties on LX-2 cells. Additionally, researchers have found that green tea’s epigallocatechin gallate (EGCG) impedes LX-2 cell proliferation and fibrosis [34].

There is ample evidence supporting the therapeutic effects of P. harmala. Still, the α-amylase inhibitory and antifibrotic activities of its hydrophilic extract and oil remain unexplored in the existing literature. In addition, the free radical scavenging activity of the fixed oil of P. harmala seeds has not been explored before. Consequently, the present study aims to assess the free radicals scavenging, antidiabetic, antifibrotic, and cytotoxic attributes of the fixed oil and hydrophilic extract obtained from P. harmala seeds.

Material and methods

Processing of plant material

In June 2021, the seeds of the P. harmala plant were purchased from a herb shop in Nablus, Palestine (Latitude: 32° 13′ 16.00" N; Longitude: 35° 15′ 15.98" E). Dr. Nidal Jaradat, a pharmacognosist, recognized the seed sample in the Natural Products Laboratory, Department of Pharmacy at An-Najah National University. A voucher specimen was deposited in the abovementioned laboratory under the code (Pharm-PCT-2777).

Oil extraction

The current study used the cold pressing method to extract oil from the P. harmala seeds. This method exclusively uses mechanical methods, such as pressure, to extract (drain) oil from the prepared seeds. Cold pressing is a method that uses a low-temperature, continuous screw press to press raw or dried seeds. A screw press with a capacity of 4 kg/h of seeds and a 4.0 kW (Kern Kraft, Germany) machine was employed in this study.

Hydrophilic extract

A crude hydrophilic extract was obtained by steeping 400 g of dried P. harmala seeds in 4 Liters of boiling water for 3 h. After being filtered twice using filter paper, the extract was freeze-dried for 48 h in a vacuum (using a Stellar Laboratory Freeze Dryer from Millrock Technology, Inc., New York, United States). When it was time to store the dried extract, it was placed in a tightly sealed container and maintained at 4–6 ◦C.

Free radical scavenging activity

The same procedure as stated in [35, 36] was used to conduct the DPPH free radical scavenging activity, and a positive control consisting of Trolox was included. In contrast, solutions of tested substances (1 mg/ml) were prepared by dissolving 100 mg of each sample in 100 ml of methanol before further diluting the solution with methanol to reach the desired concentrations of 2, 5, 7, 10, 20, 50, and 80 μg/ml. At 517 nm, the absorbance was measured using a UV–Vis spectrophotometer. The reference standard Trolox was used at the same concentration as the plant extracts. The following formula was used to determine the DPPH-inhibiting activity of each sample.

$$\text{I }({\%})=\lbrack{\text{ABS}}_\text{blank} - {\text{ABS}}_\text{test}\rbrack/\lbrack{\text{ABS}}_\text{blank}\rbrack)\ast100{\%}$$

where I (%) is the percentage of free radical scavenging activity.

The BioDataFit version 1.02 (USA) was used to determine the free radical scavenging’s half-maximal inhibitory concentration (IC50) by the tested samples.

α-Amylase inhibitory method

The α-amylase inhibitory experiment was carried out as previously described [37], with the antidiabetic medication Acarbose which was used as a positive control. On the other hand, the concentrations of the examined substances were 10, 50, 70, 100, and 500 μg/ml. The plant extract working solution (1 mg/ml) was created by dissolving 25 mg of each plant extract in 10% Dimethyl sulfoxide (DMSO) and adding a buffer solution of up to 25 ml. Using a UV–Vis Spectrophotometer, the absorbance of the tested samples was estimated to be 540 nm. The positive control Acarbose used the same mentioned concentration for the plant fixed oil and hydrophilic extract. The α-amylase inhibitory potential was calculated using the formula below.

$$\text{I }({\%}) = [{\text{ABS}}_{\text{blank}} - {\text{ABS}}_{\text{test}}]/[ {\text{ABS}}_{\text{blank}}])\text{ X}100{\%}$$
(1)

where I (%) is the α-amylase inhibitory percentage.

Cytotoxic and antifibrotic assay

The colorectal adenocarcinoma (Caco-2, COLO205), human hepatic stellate (LX-2), human epithelial kidney (HEK-293 T), cervical adenocarcinoma (HeLa), melanoma skin cancer (B16F1), and breast cancer (MCF-7) cell lines were obtained from the American Type Culture Collection (ATCC; Manassas, VA, USA). Each cell line was authenticated by ATCC using short tandem repeat (STR) profiling and tested for mycoplasma contamination to ensure the reliability of experimental results. Cells were cultured in RPMI-1640 medium supplemented with 1% streptomycin and penicillin, 1% L-glutamine, and 10% fetal bovine serum (FBS) from ATCC (Rockville, MD, USA). The cell cultures were maintained in a humidified incubator at 37 °C with 5% CO2. For the cytotoxicity assays, cells were seeded in 96-well plates at a density of 2.6 × 104 cells per well and allowed to adhere for 48 h. Subsequently, cells were treated with extract concentrations of 1000, 800, 500, 300, and 100 µg/ml for 24 h. These concentrations were prepared from stock solutions of plant extracts (2 mg/ml) dissolved in 1% DMSO and media. The negative control consisted of 1% DMSO and media, which exhibited negligible activities. Doxorubicin served as a positive control to evaluate antiproliferative activity. Cell viability was assessed using the CellTiter 96® AQueous One Solution Cell Proliferation (MTS) Assay (Promega Corporation, Madison, WI, USA) according to the manufacturer’s instructions. After 24 h of treatment, 20 μL of the MTS solution was added to each well containing 100 μl of medium. The plates were incubated for 2 h at 37 °C, and absorbance was measured at 490 nm using a microplate reader.

Data normalization was performed by calculating the percentage of cell viability relative to the untreated control group. The reference standard 5-Fluorouracil (5-FU) was used for comparative analysis at identical concentrations to the plant extracts [38, 39]. Nevertheless, the present procedure adhered to the protocols outlined in Institutional Biosafety Committee approval number IBC-A0078-2021.

Statistical analysis

All the experiments were carried out in triplicates, and results were expressed as means ± standard deviation (SD).The SPSS software (IBM SPSS Statistics is 29.0.2, USA) was employed to determine statistical differences through a one-way analysis of variance (ANOVA) test for post hoc multiple comparisons. A p-value less than 0.05 was considered statistically significant.

Results

DPPH free radical scavenging effect

Figure 1 illustrates the inhibitory activity of DPPH free radicals exhibited by the hydrophilic extract and fixed oil derived from P. harmala seeds across various used concentrations. The trend observed indicates a direct correlation between the concentration of the extract and the percentage of DPPH inhibition. The findings indicated that the hydrophilic seed extract lacked free radical scavenging activity. In contrast, the fixed oil derived from P. harmala seeds exhibited potent free radical scavenging properties, with an IC50 dose of 79.43 ± 0.08 µg/ml compared with Trolox, which displayed an IC50 of 10.06 ± 0.05 µg/ml.

Fig. 1
figure 1

DPPH inhibitory effect by Peganum harmala hydrophilic extract, fixed oil, and positive control. The experiment was repeated in triplicate. P-value less than 0.05

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Porcine pancreatic α-amylase inhibitory effect

Acarbose was utilized as the positive control in the context of α-amylase inhibitory activity (Fig. 2). The obtained α-amylase inhibitory IC50 calculations indicated that the fixed oil derived from the plant exhibited inactivity. In contrast, the hydrophilic extract of P. harmala demonstrated a weak anti-α-amylase effect when compared to the antidiabetic drug Acarbose, with IC50 doses of 398 ± 0.59 and 25.11 ± 1.22 µg/ml, respectively.

Fig. 2
figure 2

Porcine pancreatic α-amylase inhibitory effect by Peganum harmala hydrophilic extract, fixed oil, and positive control (Acarbose). The experiment was repeated in triplicate. P-value less than 0.05

Full size image

Cytotoxic activity

Figure 3 shows the cytotoxic activity of the hydrophilic extract of P. harmala on different cell lines with the same concentrations of 100, 300, 500, 800, and 1000 µg/ml. When the P. harmala hydrophilic extract concentrations were applied to the MCF-7 cell line, the inhibition results were the following: 37.99, 73.24, 92.83, and 92.87%, respectively. The percentages of Hep3B inhibition were 22.13, 51.47, 74.69, and 89.95%, respectively, at the mentioned concentrations. The results on HepG2 were the following: 17.85, 50, 70, 88.01, and 93.73% in receptive concentrations. HeLa results were as follows using the same concentrations above: 37.28, 65.47, 80.96, 88.01, and 92.28%. The COLO205 cell line was affected as follows: 34.91, 48.64, 95.60, 96.91, and 96.73% in the respective concentrations. CaCo2 has been affected by the same concentrations as the following: 22.69, 45.18, 71.26, 83.87, and 91.98%, respectively. Moreover, the B16F1 cell line was affected by the hydrophilic extract as follows: 2.15, 3.78, 12.48, 91.18, and 93.9%, respectively. Finally, HeK293t was affected by the same respective concentrations: 66.13, 76.38, 93.85, 95.84, and 96.11%, respectively.

Fig. 3
figure 3

Percentage inhibition by hydrophilic extract of Peganum harmala against seven cancer cell lines and one normal cell line. The experiment was repeated in triplicate. P-value less than 0.05

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Besides, the results show the cytotoxic activity of the fixed oil of P. harmala (Fig. 4) on different cell lines with the same concentrations of 100, 300, 500, 800, and 1000 µg/ml, respectively. When the fixed oil concentrations were applied to the MCF-7 cell line, the inhibition results were the following: 2.33, 4.65, 6.25, 25.09, and 80%, respectively. The percentages of Hep3B inhibition were 7.76, 8.28, 10.02, 17.2, and 21.56, respectively. Moreover, the cytotoxicity results on HepG2 were 0.21, 0.55, 1, 10.16, and 13.96%, respectively. HeLa results were as follows using the same concentrations above: 1.02, 1.78, 1.88, 11.22, and 18.42%, respectively. The COLO205 cell line was affected as follows: 8.68, 9.17, 6.86, 36.66, and 79.77% in the respective concentrations. CaCo2 has been affected by the same concentrations as 1.37, 4.01, 6.15, 18.21, and 33.23%, respectively. Moreover, the B16F1 cell line was affected by the hydrophilic extract at the following levels: 1.4, 1.9, 3.02, 3.99, and 4.25%, respectively. Finally, HeK293t was affected by the same respective concentrations as 3.24, 7.17, 18.42, 20.63, and 25.65%.

Fig. 4
figure 4

Percentage inhibition by Peganum harmala fixed oil against seven cancer cell lines and one normal cell line. The experiment was repeated in triplicate. P-value less than 0.05

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The findings presented in Table 1 reveal a notable discrepancy in the antiproliferative properties between the hydrophilic extract and fixed oil of P. harmala. The hydrophilic extract consistently demonstrated superior activity across various cancer cell lines compared to the fixed oil. For instance, in MCF7 cells, the IC50 value for the hydrophilic extract was remarkably lower at 121.34 ± 1.71 µg/ml compared to 910.07 ± 1.61 µg/ml for the fixed oil. Similar trends were observed in COLO205, CaCo-2, B16F1, HeLa, Hep3B, HepG2, Hek293t, and LX-2 cell lines, where the hydrophilic extract consistently exhibited lower IC50 values compared to the fixed oil. These findings underscore the potential of hydrophilic extract as a promising candidate for further exploration in cancer therapeutics, potentially offering a more effective treatment option than fixed oil. Across most cell lines, the IC50 values of the hydrophilic extract were notably closer to the Doxorubicin values than fixed oil. For example, in MCF7 cells, the IC50 value for the hydrophilic extract was 121.34 ± 1.71 µg/ml, while Doxorubicin showed an IC50 of 0.330 ± 0.21 µg/ml. Similarly, in COLO205 cells, the hydrophilic extract’s IC50 value was 150.01 ± 0.51 µg/ml, considerably close to Doxorubicin’s IC50 of < 0.05 µg/ml. However, further studies would be necessary to fully elucidate its potential therapeutic utility and safety profile compared to standard chemotherapeutic agents like Doxorubicin.

Table 1 IC50 values (µg/ml) of the hydrophilic extract and fixed oils of P. harmala in comparison with positive control Doxorubicin against seven cancer cell lines and two normal cell lines
Full size table

Antifibrotic activity

Figure 5 demonstrates the antifibrotic activity of P. harmala fixed oil and hydrophilic extract using different concentrations. At 1000 µg/ml, P. harmala hydrophilic extract decreased LX-2 cell viability by 5.81%, while the fixed oil at the same concentration showed negligible activities, similar to the negative control DMSO. 5-Fluorouracil cell viability is reduced at this concentration to 0.89%.

Fig. 5
figure 5

The antifibrotic effects of Peganum harmala fixed oil and hydrophilic extract compared with DMSO and 5-Fluorouracil on LX-2 cell viability. The experiment was repeated in triplicate. P-value less than 0.05

Full size image

Pearson correlation is widely used in various fields, including biological activities and many others, to assess the relationship between variables [40]. Pearson correlation analysis was carried out to analyze the correlative relationships between the antioxidant activities of the P. harmala fixed oil and hydrophilic extract with their antifibrotic and antiproliferative effects. The analysis revealed that DPPH activities had a positive correlation with antifibrotic effect (r = 0.4959, P < 0.01 for Fixed oil; r = 0.9293, P < 0.05 for hydrophilic extracts) and good positive correlations with antiproliferative effect (r = 0.7480, P < 0.05 for fixed oil; r = 0.9128, P < 0.05 for hydrophilic extract), while weak correlation was observed between the DPPH activities of fixed oil and α-amylase inhibitory effect (r = 0.2364, P < 0.1) and good correlation between the DPPH activities of hydrophilic extract and α-amylase inhibitory effect (r = 0.7169, P < 0.05). Thus, the findings suggest that the DPPH activities of the hydrophilic extract were better correlated with other activities than fixed oil activities.

Discussion

Throughout human existence, individuals have employed medicinal plants to cure a wide range of diseases. Contemporary individuals exhibit great enthusiasm for traditional and alternative medicine to the extent that several countries have incorporated it into their healthcare policies [41]. P. harmala possesses medicinal properties, including antimicrobial effects and anti-inflammatory and analgesic qualities. Traditional medicine practices in North Africa and the Middle East have utilized P. harmala as both an emmenagogue and an abortifacient agent. A decoction made from P. harmala leaves has also been employed in treating rheumatism [42]. This plant also recently showed antidiabetic and antioxidant activities [43]. The diverse range of significant activities exhibited by Peganum harmala highlights its potential as a bioactive plant worthy of further investigation. Its antimicrobial, anti-inflammatory, analgesic, emmenagogue, abortifacient, and rheumatism-treating properties underscore this plant’s complexity and potential therapeutic value. Further research on P. harmala could uncover additional bioactive compounds and deepen our understanding of its medicinal properties, potentially leading to the development of novel therapeutic agents or complementary medicines.

Free radical scavenging activity

Multiple diseases and conditions in humans have been attributed to free radical accumulation. One way to mitigate their harmful effects is by using antioxidants to scavenge free radicals. Therefore, it is crucial to identify naturally occurring antioxidants in plants [44]. Among all the available methods for assessing antioxidant activity, the DPPH assay has been utilized most frequently to estimate free radicals scavenging activity. This method provides direct information on the sample’s overall free radical scavenging capacity and has the advantages of being quick, straightforward, and inexpensive [45].

The present study estimated the DPPH (1,1-diphenyl-2-picrylhydrazyl) free radical-scavenging effect of the hydrophilic extract and fixed oil of P. harmala. The results showed that the hydrophilic seeds extract was inactive as an antioxidant product, while the P. harmala seeds fixed oil has potent antioxidant activity with an IC50 dose of 79.43 ± 0.08 µg/ml, compared with the powerful antioxidant drug Trolox, which has a potent antioxidant effect (IC50 = 10.06 ± 0.05 µg/ml). In light of similar studies done on this plant species, Khlifi, et al.’s investigation showed that the P. harmala hydro-methanolic extract had a DPPH inhibitory effect with an IC50 value of 70.16 ± 3.30 mg/L [46]. Another study performed by Naziha et al. found that the P. harmala seeds ethanolic extract has antioxidant activity with an IC50 of 19.09 ± 3.07 mg/l [47].

Paul et al. stated that P. harmala seeds oil contains 21.5% oleic and 26.53% linoleic acids [48], and previous studies demonstrated that both oleic and linoleic acid had antioxidant properties, including their ability to scavenge free radicals [49, 50]. A significant correlation between antioxidant activity and phenolic content was also found, noting that halophytes exhibit particularly high levels of nutrients and phenolic metabolites. Key phenolic compounds identified in medicinal plants include syringic acid and gallic acid from Moringa oleifera, as well as gallic acid, vanillic acid, 4-hydroxybenzoic acid, and syringic acid from P. harmala [51]. Indeed, the DPPH scavenging activity displayed by the fixed oil of P. harmala represents a valuable contribution to the literature, particularly in light of the scarcity of information regarding the antioxidant properties of P. harmala fixed oil.

α-Amylase inhibitory activity

Blocking enzymes like α-amylase, which slows down starch digestion, is essential for diabetic management. By delaying the absorption of carbohydrates, pancreas α-amylase inhibitors reduce glucose uptake and postprandial blood sugar levels [52]. It was reported before that this plant has a weak α-amylase inhibitory effect compared to other plants’ extract [53].

This study is the first to demonstrate the anti-α-amylase activity of the hydrophilic extract and fixed oil from P. harmala seeds. The findings indicated that the plant’s fixed oil had no impact. The hydrophilic extract had a weaker effect than the antidiabetic drug Acarbose, with IC50 doses of 398 ± 0.59 and 25.11 ± 1.22 µg/ml, respectively. These findings are consistent with an in vivo investigation by Singh et al., which revealed that the P. harmala seed ethanolic extract significantly lowered blood glucose levels in normal and diabetic rats at variable dose levels (150 and 250 mg/kg). The plant seeds’ ethanolic extract significantly improved in controlling hyperglycemia [54].

Cytotoxic activity

The MTS assay results showed that cytotoxic effects varied against all cancer cell lines among the investigated P. harmala preparations. The hydrophilic extract showed potential activity against the screened cells, while the fixed oil showed the greatest activity against MCF7 and COLO205 cells. The alkaloids found in P. harmala, such as harmine and harmaline, demonstrate effectiveness against the human promyelocytic cell line (HL60 cells) previously [55]. Bournine et al. showed that the collective alkaloids extracted from various parts of P. harmala exhibited cytotoxic effects against A549, U373, Hs683, MCF7, B16F10, and SKMEL-28 cancer cell lines with IC50 values ranging from 1–52 μg/ml after 72 h of treatment, as assessed by the MTT assay [56]. An indole alkaloid named pegaharmine E was recently isolated from P. harmala, demonstrating noteworthy anticancer activities across a panel of cancer cell lines [57].

The results of the cytotoxicity tests showed that the growth of MCF-7, Hep3B, HepG2, HeLa, COLO205, CaCo2, B16F1, and HeK293t was inhibited by hydrophilic P. harmala extract with IC50 doses of 121.34 ± 1.71, 268.3 ± 0.75, 297.20 ± 1.00, 155.60 ± 1.14, 150.01 ± 0.51, 308.35 ± 0.53, 597.93 ± 1.36 and 5.38 ± 0.99, respectively. P. harmala fixed oil inhibited the growth of MCF-7 and COLO205 with IC50 values of 910.07 ± 1.61 and 870.51 ± 1.43 µg/ml, respectively. These results agree with a study by Sadaf et al., which found that the P. harmala seeds methanol extract inhibited crown gall tumors with an IC50 dose of 52.278 µg/ml [58].

The proliferation of cancer cells is slowed down. After exposing MDA-MB-231 breast cancer cells to P. harmala seed extract at several concentrations and for varying amounts of time, apoptosis was detected using Annexin-V-fluorescence. The growth rate was suppressed at 30 μg/ml, and apoptosis occurred in 50% of cells in just under 24 h. In addition, it was found that P. harmala seed extract promoted apoptosis via an extrinsic mechanism [59]. Even at the highest tested concentration of 40 µg/ml, the multidrug resistance inhibitory effects of deoxypeganine, harmine, and peganine on an MDR1 gene-transfected mouse lymphoma cell line were not observed [60].

Antifibrotic effect

The MTS test was used to measure the viability of LX-2 cells after treatment with different concentrations of P. harmala fixed oil and hydrophilic extract to investigate the antifibrotic effects of these preparations on the human hepatic stellate cell line LX-2 For 24 h. Compared to the chemotherapeutic drug 5-fluorouracil and the negative control, DMSO, the fixed oil, and the hydrophilic extract from P. harmala significantly decreased the number of living LX-2 cells. At 1000 µg/ml compared to 5-FU, which has a cell viability percentage of 0.089, P. harmala hydrophilic extract significantly decreased the number of LX-2 cells to 5.81%, while the fixed oil decreased the cell viability by 99.29%. These findings could be explained by Doha Beltagy and her colleagues’ study, which revealed that harmaline, one of the known components of P. harmala seeds, has a protective role against liver cirrhosis, which is the outcome of progressive liver fibrosis [61]. However, another plant, Zygophyllum album, belongs to the same Zygophyllaceae family and has been discovered to have a strong protective effect against cardiac fibrosis in rats [62].

Antifibrotic agents prevent or reduce the formation of fibrous scar tissue (fibrosis) in various organs. Fibrosis occurs due to chronic inflammation or tissue damage, leading to excessive collagen deposition and other extracellular matrix components. Some compounds possess both antiproliferative and antifibrotic properties. For instance, certain natural compounds like curcumin and resveratrol have been shown to inhibit the proliferation of cancer cells and reduce fibrosis in organs like the liver and kidneys. This dual action can be beneficial in conditions where excessive cell proliferation and fibrosis occur concurrently, such as in certain types of cancer and fibrotic diseases [63, 64].

In summary, compounds with antiproliferative, antifibrotic, antioxidant, and antidiabetic properties often exhibit overlapping mechanisms of action. They can offer synergistic benefits in preventing and managing various diseases, including cancer, fibrosis, and diabetes. Further research into these multifunctional compounds may lead to novel therapeutic approaches with broader efficacy and fewer side effects.

No previous studies have explored the antifibrotic properties of P. harmala hydrophilic extract and fixed oil. However, specific alkaloids, such as harmine, have been previously recognized as potential antifibrotic agents. Harmine has been demonstrated to inhibit DYRK1B, suppressing COL1A1 expression in the LX-2 cell line. These findings suggest harmine’s potential therapeutic efficacy in treating liver fibrosis [65]. The limitations of our study are in vivo experiments, which are crucial for understanding how P. harmala behaves within living organisms, providing insights into their potential effects, mechanisms of action, and safety profiles.

Conclusion

In light of these results, it is evident that fixed oil possesses modest free radical scavenging activity. It was observed that the hydrophilic extract of P. harmala displayed antidiabetic action and potential cytotoxic activity on various cancer cell lines employing in vitro models. These results demonstrate the efficacy of P. harmala hydrophilic extract in the treatment of numerous cancer types, including skin, colon, breast, liver, and cervical malignancies. Additionally, this extract has exceptional antifibrotic action. Therefore, it would be a good option for biopharmaceutical therapeutic products and nutraceuticals. Future preclinical and clinical research on P. harmala-derived compounds or extracts that influence carcinogenesis should focus on several important issues, such as elucidating the molecular targets and signaling pathways involved in anticancer, antidiabetic, and antioxidant activities and establishing an effective and non-toxic dose for humans.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

B16F1:

Melanoma skin cancer cells

Caco-2, COLO205:

Colorectal adenocarcinoma cells

HeLa:

Cervical adenocarcinoma cells

Hep 3B and Hep G2:

Hepatocellular carcinoma cells

MCF-7:

Breast cancer cells

HEK-293 T:

Human epithelial kidney cells

LX-2:

Human hepatic stellate cells

IC50:

Half maximal inhibitory concentration

5-FU:

5-Fluorouracil

MTS:

3-(4,5-Dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium

DPPH:

2,2-Diphenyl-1-picrylhydrazyl

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Acknowledgements

The authors wish to convey their acknowledgment to An-Najah National University.

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Authors and Affiliations

  1. Department of Pharmacy, Faculty of Medicine and Health Sciences, An-Najah National University, P.O. Box 7, Nablus, Palestine

    Nidal Jaradat, Mohammed Hawash, Fatima Hussein, Linda Issa, Sondos Hamamrhe, Eman Al-Sheikh & Alaa Naser Ibrahim

  2. Department of Range and Watershed Management, Faculty of Water and Soil, University of Zabol, Zabol, 98613-35856, Iran

    Majid Sharifi-Rad

  3. Department of Medicine, Faculty of Medicine and Health Sciences, An-Najah National University, P.O. Box 7, Nablus, Palestine

    Ali Shakhshir

  4. Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, An-Najah National University, P.O. Box 7, Nablus, Palestine

    Shorooq Sobuh

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  1. Nidal Jaradat
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Contributions

Conceptualization: N.J., M.S-R.; methodology: M.S-R.; software: M.H.; formal analysis: M.H., F.H., S.S.; investigation: L.I., S.H., E.A-S., A.N-I.; resources: N.J.; data curation: M.H., A.S, F.H., S.S.; writing original draft: N.J.; review and editing: N.J., M.H., A.S.; ; all authors have read and agreed with the final version of the manuscript.

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Correspondence to Nidal Jaradat or Majid Sharifi-Rad.

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Jaradat, N., Hawash, M., Sharifi-Rad, M. et al. Insights into free radicals scavenging, α-Amylase inhibition, cytotoxic and antifibrotic activities unveiled by Peganum harmala extracts. BMC Complement Med Ther 24, 299 (2024). https://doi.org/10.1186/s12906-024-04602-2

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BMC Complementary Medicine and Therapies

ISSN: 2662-7671

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