3,5-Dibenzyloxy-4'-hydroxystilbene induces early caspase-9 activation during apoptosis in human K562 chronic myelogenous leukemia cells

• Main Authors: Bunyamin, I. (Author), Chan, K.M (Author), Inayat-Hussain, S.H (Author), Kadir, S.A.I.A.S.A (Author), Majeed, A.B.A (Author), Myatt, G. (Author), Rajab, N.F (Author), Roslie, H. (Author), Thomas, N.F (Author), Velu, S.S (Author), Weber, J.-F.F (Author)
• Format: Article
• Language: English
• Subjects: 3' acetoxy 4 chlorostilbene; 3,5 dibezyloxy 4' hydroxystilbene; 4' hydroxy 3 methoxystilbene; 4' hydroxy 3,5 dimethoxystilbene; antineoplastic activity; antineoplastic agent; apoptosis; Apoptosis; article; caspase 3; caspase 9; Caspase 9; Caspase-3; Caspase-9; Cell Survival; chronic myeloid leukemia; drug synthesis; human; human cell; Humans; K562 cells; K562 Cells; leukemia cell; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Membrane Potential, Mitochondrial; Mitochondria; mitochondrial membrane potential; nonhuman; stilbene derivative; Stilbene derivatives; Stilbenes; structure activity relation; Structure-Activity Relationship; unclassified drug
• Online Access: View Fulltext in Publisher; View in Scopus

 A series of 22 stilbene derivatives based on resveratrol were synthesized incorporating acetoxy-, benzyloxy-, carboxy-, chloro-, hydroxy-and methoxy functional groups. We examined the cytotoxicity of these 22 stilbenes in human K562 chronic myelogenous leukemia cells. Only four compounds were cytotoxic namely 4'-hydroxy-3-methoxystilbene (15), 3'-acetoxy-4-chlorostilbene (19), 4'-hydroxy-3,5-dimethoxystilbene or pterostilbene (3) and 3,5-dibenzyloxy-4'-hydroxystilbene (28) with IC 50s of 78 μM, 38 μM, 67 μM and 19.5 μM respectively. Further apoptosis assessment on the most potent compound, 28, confirmed that the cells underwent apoptosis based on phosphatidylserine externalization and loss of mitochondrial membrane potential. Importantly, we observed a concentration-dependent activation of caspase-9 as early as 2 hr with resultant caspase-3 cleavage in 28-induced apoptosis. Additionally, a structure-activity relationship (SAR) study proposed a possible mechanism of action for compound 28. Taken together, our data suggests that the pro-apoptotic effects of 28 involve the intrinsic mitochondrial pathway characterized by an early activation of caspase-9.