The resveratrol analogue, 3,4,5,4′-trans-tetramethoxystilbene, inhibits the growth of A375 melanoma cells through multiple anticancer modes of action

Abstract

Resveratrol is a natural dietary product that has demonstrated multifaceted anticancer activity. Several analogues of resveratrol have been synthesized in an effort to enhance the pharmacological potency and improve the pharmacokinetic properties of the compound. 3,4,5,4'‑trans‑tetramethoxystilbene (3,4,5,4'‑TMS) is a methoxylated analogue of resveratrol that has demonstrated anti-proliferative activity in vitro (in cancer cell lines) and in vivo (in xenograft models). In the present study, the anticancer effects of 3,4,5,4'‑TMS in A375 human melanoma cells were examined. 3,4,5,4'‑TMS markedly inhibited the proliferation of A375 cells (IC50=0.7 µM), via a mechanism involving mitotic arrest at the prometaphase stage of cell division. This effect was accompanied by the upregulation of the expression of the mitogen activated protein kinases, JNK and p38, and the concomitant activation of p38, that was verified by the nuclear translocation of the phoshorylated form of the protein. The pharmacological inhibition of p38 by SB203580 (4 µM) attenuated the effects of 3,4,5,4'‑TMS, as demonstrated by decreased cell cycle progression at the mitotic phase. Furthermore, 3,4,5,4'‑TMS increased the total levels of Aurora A, while it inhibited the localization of the protein to the spindle poles. Finally, 3,4,5,4'‑TMS exhibited anti-metastatic activity, inhibiting A375 cell migration and the attachment of the cells to a collagen type IV-coated surface. Collectively, the data suggest that 3,4,5,4'‑TMS is an effective chemotherapeutic drug for the treatment of human melanoma and that it exerts its effects through multiple anticancer modes of action.

A Novel Quinolyl‐Substituted Analogue of Resveratrol Inhibits LPS‐Induced Inflammatory Responses in Microglial Cells by Blocking the NF‐κB/MAPK Signaling Pathways

“…In the recent years, considerable attention has been given to synthetic resveratrol derivatives, and numerous studies have reported that methoxylated, hydroxylated, and halogenated derivatives display more effective disease prevention characteristics than resveratrol . RV01 is the quinolyl‐substituted derivative of resveratrol.…”

“…Therefore, considerable attention has been given to the structural modification of resveratrol. In the recent years, many resveratrol derivatives have been developed to serve as functional food ingredients and supplements to promote health and prevent disease . ( E )‐5‐(2‐(Quinolin‐4‐yl) vinyl) benzene‐1,3‐diol (RV01), a novel quinolyl‐substituted derivative of resveratrol, was also designed and synthesized.…”

Insights on the Effects of Resveratrol and Some of Its Derivatives in Cancer and Autoimmunity: A Molecule with a Dual Activity

“…In several studies, the 3,4,5,4'-trans-tetramethoxystilbene (TMS) was reported as the most potent pro-apoptotic analog of resveratrol (reviewed in [75]).…”

Melanoma Chemoprevention: Current Status and Future Prospects

“…Thus far, the results from preclinical studies using resveratrol have failed to be replicated in humans, possibly due to the short half‐life, low bioavailability in vivo and lipophilic nature of resveratrol . To improve bioavailability and antimelanomagenesis activity, synthetic resveratrol derivatives and nanoformulations are now being explored as chemopreventive agents to prevent melanoma . A recent study by Sanna et al .…”

“…Thus far, the results from preclinical studies using resveratrol have failed to be replicated in humans, possibly due to the short half-life, low bioavailability in vivo and lipophilic nature of resveratrol (111,112). To improve bioavailability and antimelanomagenesis activity, synthetic resveratrol derivatives and nanoformulations are now being explored as chemopreventive agents to prevent melanoma (113)(114)(115)(116)(117). A recent study by Sanna et al found that chitosan-and anionic alginate-coated poly(d, l0lactide-co-glycolide (PLGA) nanoparticles were able to preserve bioactivity of resveratrol up to 6 months and allow for a controlled release formulation (118).…”