Antineoplasm, antiproliferative and antioxidant effects
Since ancient times, P. harmala has been used by traditional healers to make various preparations in the treatment of cancers and tumors in some parts of the world.[13,55] For example, it has been so common in traditional medicine of Morocco to use powdered seeds of P. harmala to treat skin and subcutaneous tumors.[56] The seed extract of P. harmala is the main component of a very common ethnobotanical preparation used against different cancers and neoplasms in Iran, namely Spinal-Z.[57,58]
The antitumor activity of P. harmala and its active alkaloids (mainly beta-carbolines) have also drawn attentions of many researchers worldwide that has led to various pharmacological studies regarding this important effect of P. harmala.[23,56] Various authors have reported cytotoxicity of P. harmala on tumor cell lines in vitro and in vivo. In one study, the methanolic extract of P. harmala reduced significantly proliferation of three tested tumor cell lines (UCP-Med (a tumor cell line), Med-mek carcinoma, and UCP-Med sarcoma) in all concentrations. This anti-proliferative effect was produced by the alkaloid fraction of the extract in the first 24 h of the treatment. A cell lysis effect was observed in the next 24 h and thus, resulted in complete cell death within 48 to 72 h.[56] The same results were observed with the
Pharmacological and therapeutic effects of Peganum harmala and its main alkaloids
total extract of the plant in another study. The extract also showed cytotoxicity against artificially grafted subcutaneous Sp2/O cell- line in BALB-c (Albino) mice.[56] Administration of different beta-carboline alkaloids isolated from P. harmala showed inhibitory effect against Lewis Lung cancer sarcoma-180 or HepA tumor in mice at rates of 15.3-49.5%. Substitution of formate at R3 and aryl at R9 of the tricyclic skeleton respectively decreased neurotoxicity and increased the inhibitory effects of the alkaloids that made them ideal agents to be used as novel antitumor drugs with lesser side effects.[55] Several in vitro and in vivo studies have revealed that these cytotoxicity and antitumor effects of P. harmala are related to its interaction with RNA,[59] DNA and its synthesis,[56,60] and inhibition of human Topoisomerase.[58] In a study conducted in Iran, it was shown using the DNA relaxation assay that the extract of P. harmala inhibits human DNA Topoisomerase I. This effect was attributed to the beta-carboline content of the extract and potency of the alkaloids were determined as harmine >harmane >harmaline in a way that treatment with the total extract showed weaker inhibitory effect than treatment with every individual alkaloid.[58] Another study indicated that harmine and its derivatives have inhibitory effect on human Topoisomerase I activity but no effect on Topoisomerase II. Intercalation of several carbolines into eukaryotic DNA has also been reported by many authors.[58,61] This intraction of beta- carbolines cause significant structural changes in DNA and interfere with its synthesis.[56,61] The alkaloid-DNA binding affinity was ordered as harmine >harmalol >harmaline >harmane >tryptoline. There are also other suggested mechanisms for the anti-tumor activity of P. harmala alkaloids. In an in vitro study by Li et al., budding yeast was used as a model to investigate the anti-tumor activity of P. harmala. Results showed that DH334, a beta-carboline derivative and an anticancer drug, specifically inhibits cyclin dependent kinases (CDKs) and blocks the initiation of cell cycle at the G1 phase. It also inhibited the kinase activity of Cdk2/CyclinA (a member of the cyclin family) in vitro. This could be another possible mechanism for the antitumor activity of the drug.[56,93]
Many pharmacological studies suggest an antioxidant and free radical scavenging effect of P. harmala. This effect has been attributed to the increasing effect of P. harmala extract on E2 (17β-estradiol) level as an important antioxidant and reactive oxygen species (ROS) scavenger.[12,62,63] In another study, the effects of harmaline and harmalol were tested on Digoxin-induced cytochrome P450 1A1 (CYP1A1), a carcinogen-activating enzyme, in human hepatoma HepG2 cells. These alkaloids significantly inhibited the enzyme via both transcriptional and posttranslational mechanisms in a concentration-dependent manner.[3] Ethanol and chloroform extracts of P. harmala showed
Pharmacological and therapeutic effects of Peganum harmala and its main alkaloids
protective effects against thiourea-induced carcinogenicity by normalization of neuron-specific enolase and thyroglobulin levels in animal models.[64] Other effects of the plant extract such as anti-proliferative effect on Leukemic cell lines,[65] inhibitory action on the metastasis of melanoma cells, inducing apoptosis in melanoma cells,[66] tumor angiogenesis inhibition,[13] and binding to RNA[61] have also been reported by various authors. In some cases, P. harmala showed a higher selectivity towards malignant cells than common anticancer drugs like doxorubicin.[57] All of these data suggest that P. harmala and its alkaloids possess the potential to be used as novel antioxidant and anti-tumor agents in anti-cancer therapy.
