1. ¹Department of Chemistry and Chemical Biology, Center for Advanced Food Technology, Rutgers, The State University of New Jersey, Piscataway, NJ 08854-8087, USA
2. ²New Jersey Cancer Institute, New Brunswick, NJ 08901, USA

Correspondence: Dr KY Chen, Department of Chemistry and Chemical Biology, Rutgers University, 610 Taylor Road, Piscataway, NJ 08854-8087, USA. E-mail: kychen@rutchem.rutgers.edu

Revised 11 October 2004; Accepted 22 October 2004; Published online 25 January 2005.

Abstract

Resveratrol (R-3), a trihydroxy trans-stilbene from grape, inhibits multistage carcinogenesis in animal models. A resveratrol derivative 3,4,5,4'-tetrahydroxystilbene (R-4) exhibits potent growth inhibitory effect against transformed human cells. Here we report that 3,4,5,4'-tetramethoxystilbene (MR-4), converted from R-4, was more potent against cancer cell lines (WI38VA, IMR-90SV, HeLa, LNCaP, HT-29, and HepG2), but had almost no inhibitory effect on the growth of normal cells (WI38, IMR-90, BJ-T) at the concentrations tested. The IC₅₀ value of MR-4 on the growth inhibition of transformed WI38VA human cells was 0.5 M, as compared to the value of greater than 50 M for the normal WI38 cells. Resveratrol, however, did not exhibit such clear differential effect and the IC₅₀ value of R-3 for WI38VA cells was about 50 M. The growth inhibitory effect of MR-4 correlated with the induction of apoptosis in the transformed cells. When normal WI38 cells and transformed WI38VA cells were compared, MR-4 induced increases of the Bax/Bcl-2 mRNA ratio, p53 and Bax protein level, activation of caspases, and DNA fragmentation in transformed, but not in normal cells. Further analysis revealed that MR-4 caused a rapid appearance of perinuclear aggregation of mitochondria in WI38VA but not in WI38 cells, suggesting that the mitochondria could serve as an early target of MR-4. R-3 also induced apoptosis and mitochondrial clustering but only at a much higher concentration, close to 500 M. Taken together, the specific activation of the mitochondria-mediated apoptotic pathway could be a major reason for the striking differential growth inhibitory effect of MR-4.