title: 3,5-dibenzyloxy-4'-hydroxystilbene induces early caspase-9 activation during apoptosis in human K562 chronic myelogenous leukemia cells.
abstract: 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(50)s 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.
authors.affiliation: Faculty of Pharmacy, Universiti Teknologi MARA, Puncak Alam Campus, 42300 Selangor, Malaysia.
authors.forename: Haslan
authors.initials: H
authors.lastname: Roslie
authors.forename: Kok Meng
authors.initials: KM
authors.lastname: Chan
authors.forename: Nor Fadilah
authors.initials: NF
authors.lastname: Rajab
authors.forename: Saraswathi S
authors.initials: SS
authors.lastname: Velu
authors.forename: Syed Abd Illah Alyahya Syed Abd
authors.initials: SA
authors.lastname: Kadir
authors.forename: Irmaizatussyehdany
authors.initials: I
authors.lastname: Bunyamin
authors.forename: Jean-Frédéric Faizal
authors.initials: JF
authors.lastname: Weber
authors.forename: Noel F
authors.initials: NF
authors.lastname: Thomas
authors.forename: Abu Bakar Abdul
authors.initials: AB
authors.lastname: Majeed
authors.forename: Glenn
authors.initials: G
authors.lastname: Myatt
authors.forename: Salmaan Hussain
authors.initials: SH
authors.lastname: Inayat-Hussain
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D053453:Caspase 9 / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D013267:Stilbenes / Q000138:chemical synthesis / Q000633:toxicity*; D013329:Structure-Activity Relationship
chemical_list: D013267:Stilbenes; D053453:Caspase 9