Abstract
Harmaline (HAR), a natural occurrence β-carboline alkaloid, was isolated from the seeds of Peganum harmala and exhibited potent antitumor effect. In this study, the anti-gastric tumor effects of HAR were firstly investigated in vitro and in vivo. The results strongly showed that HAR could inhibit tumor cell proliferation and induce G2/M cell cycle arrest accompanied by an increase in apoptotic cell death in SGC-7901 cancer cells. HAR could up-regulate the expressions of cell cycle-related proteins of p-Cdc2, p21, p-p53, Cyclin B and down-regulate the expression of p-Cdc25C. In addition, HAR could up-regulate the expressions of Fas/FasL, activated Caspase-8 and Caspase-3. Moreover, blocking Fas/FasL signaling could markedly inhibit the apoptosis caused by HAR, suggesting that Fas/FasL mediated pathways were involved in HAR-induced apoptosis. Interestingly, HAR could also exert on antitumor activity with a dose of 15 mg/kg/day in vivo, which was also related with cell cycle arrest. These new findings provided a framework for further exploration of HAR which possess the potential antitumor activity by inducing cell cycle arrest and apoptosis.
Highlights
Harmal (Peganum harmala L.) is a perennial, glabrous plant which grows spontaneously in semi-arid conditions, steppe areas and sandy soils, native to eastern Mediterranean region
The eukaryotic cell cycle progression is regulated by cyclin-dependent kinases (CDKs) and Cyclins
Progression through G1 into S phase is regulated by the Cyclin A-Cyclin-dependent kinases (Cdks)[2] and Cyclin E-Cdk[2] complexes, while Cyclin B-Cdc[2] plays a role in G2/M phase transition
Summary
HAR treatment significantly increased the expressions of p21, p-Cdc[2] accompanying by the reduction of p-Cdc25C These results strongly suggested that HAR might induce apoptosis through cell cycle arrest in vivo. Cdc25C is another critical regulator of Cdc2-Cyclin B1 kinase activity and control cell cycle progression by dephosphorylating and activating CDKs21–23 Consistent with these notions, we observed an increase in the protein level of inhibitory p21 in SGC-7901 cell. HAR suppressed tumor growth at a dose of 15 mg/kg/day without any significant changes of the mice body weight and the possible mechanism was cell cycle arrest owning to the up-regulating P21 and p-Cdc[2] Side effects, such as hair loss, lethargy, dysphoria, or other macroscopical visceral pathogenic changes were not observed. The induction of P21 at early stage, along with the increased p-Cdc[2] as a result of the downregulation of Cdc25c, lies at the base of the mechanism through which HAR induced G2/M arrest and the activation Fas/FasL pathway (Fig. 7)
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