Harmaline isolated from Peganum harmala suppresses growth of esophageal squamous cell carcinoma through targeting mTOR

Abstract

Harmaline is a naturally occurring β-carboline alkaloid that is isolated from Peganum harmala. It has shown efficacy in treating Parkinson's disease and has been reported to exhibit antimicrobial and anticancer properties. However, the molecular mechanism of harmaline in the context of esophageal squamous cell carcinoma (ESCC) has not been characterized. Here, we report that harmaline attenuates ESCC growth by directly targeting the mammalian target of rapamycin (mTOR). Harmaline strongly reduced cell proliferation and anchorage-independent cell growth. Additionally, harmaline treatment induced G2/M phase cell-cycle arrest through upregulation of p27. The results of in vitro and cell-based assays showed that harmaline directly inhibited the activity of mTOR kinase and the phosphorylation of its downstream pathway components. Depletion of mTOR using an shRNA-mediated strategy in ESCC cell lines indicated that reduced mTOR protein expression levels are correlated with decreased cell proliferation. Additionally, we observed that the inhibitory effect of harmaline was dependent upon mTOR expression. Notably, oral administration of harmaline suppressed ESCC patient-derived tumor growth in vivo. Taken together, harmaline is a potential mTOR inhibitor that might be used for therapeutically treating ESCC.

Promising Antifungal Activity of Encephalartos laurentianus de Wild against Candida albicans Clinical Isolates: In Vitro and In Vivo Effects on Renal Cortex of Adult Albino Rats

“…Our findings align with prior research on the antimicrobial properties of certain flavonoids or flavonoid glycosides, such as myricetin [ 57 , 58 ], apigenin derivatives [ 59 ], luteolin derivatives [ 60 ], epicatechin [ 57 ], anthocyanidin derivatives [ 61 , 62 ], biflavonoids derivatives [ 13 , 14 , 63 , 64 ], coumarines derivatives [ 65 , 66 ], harmaline alkaloid [ 67 ].…”

Anticancer Potential of β‐Carboline Alkaloids: An Updated Mechanistic Overview

“…[66] A549 and HepG-2 cells were moderately inhibited by norharmane, which had IC 50 values of 16.45 and 17.27 μM, respectively, whereas 3-(4hydroxyphenyl)quinoline, with an IC 50 value of 3.05 μM, showed strong antiproliferative activity against HepG-2 cell lines. [67] Jiménez, et al [68] used two in vitro human cell assays to determine the citoxicity of harmine and harmaline. These assays were the cytochalasin-B blocked micronucleus (CBMN) assay and the viability/colony formation assay with four different human cultured non-transformed (CCD).…”

“…The cell lines HL60 and K562 were cytotoxic to harmine [66] . A549 and HepG‐2 cells were moderately inhibited by norharmane, which had IC 50 values of 16.45 and 17.27 μM, respectively, whereas 3‐(4‐hydroxyphenyl)quinoline, with an IC 50 value of 3.05 μM, showed strong antiproliferative activity against HepG‐2 cell lines [67] . Jiménez, et al [68] .…”

Collection of Hairy Roots as a Basis for Fundamental and Applied Research

“…Peganum harmala L. (Zygophyllaceae) is a perennial herbaceous plant common in the Mediterranean region of Europe, Central Asia, and southern South America [90,91]. It refers to medicinal plants widely used in folk and traditional Chinese medicine for the treatment of various human diseases [90][91][92][93][94]. The therapeutic effect of extracts from seeds and vegetative parts of the plant is explained by the presence of two classes of alkaloids-quinazoline and indole β-carboline type.…”

“…Because the content of harmine in the hairy roots was predominant and only slightly inferior to its content in the roots of intact plants, the resulting hairy roots of Peganum harmala can be a source for obtaining an important group of pharmacologically valuable alkaloids which include harmine. According to the literature, Peganum harmala has antibacterial [95], anti-inflammatory [96], anti-fungal [97], and antitumor effects [92], and is used to treat hypertension [98], cough [99], diabetes [100], jaundice [94], malaria [101], tremor paralysis, Parkinson's disease, and Alzheimer's disease [92,102]. Despite the wide spectrum of action, the medicine uses peganin hydrochloride (ampoules and tablets) for the treatment of myopathy and myasthenia gravis and harmine hydrochloride for the treatment of encephalitis, tremor paralysis, and Parkinson's disease [103].…”