HighlightsThe expression of two genes TRAIL, death receptor, and Caspase-8, associated with extrinsic pathway, up-regulated upon treating with P. harmala L.’s seed extract suggesting that the extract induces mainly on apoptosis extrinsic pathway.The pro-apoptotic genes, BH3 multidomain, Bax (Bcl-2-associated X protein) and Bak (Bcl-2 homologous antagonist/killer) caused permeability in mitochondrial membrane which was inhibited by anti-apoptotic proteins, Bcl-2, Bcl-xl.As a consequence of binding BH3-only proteins (BID, BIM (Bcl-2-like protein 11), BAD (Bcl-2-associated death promoter), and PUMA to anti-apoptotic proteins, their activities were inhibited.Both p53 and p21 were up-regulated in treated cells with P. harmala’s seed extract, hence p53 as transcription regulator up-regulated Bax, Puma and TRAIL.As long as the expression of anti-apoptosis Bcl-2 gen reduced dramatically, an over-expression in apoptosis genes, Bax and Puma, was monitored indicating activation of intrinsic apoptosis pathway.The results confirm the positive effect of P. harmala L.’s extract in inducing apoptosis in MDA-MB-231 cell line in both intrinsic/extrinsic apoptosis pathways and also in blocking cell cycle life.