Resveratrol Inhibits Tumor Growth of Human Neuroblastoma and Mediates Apoptosis by Directly Targeting Mitochondria

Abstract

Purpose: Neuroblastoma is an aggressive childhood disease of the sympathetic nervous system.Treatments are often ineffective and have serious side effects. Because resveratrol, a natural plant product, has been reported to have limited toxicity at chemotherapeutic levels, we investigated its efficacy in the treatment of neuroblastoma as well as its underlying mechanism of action.Experimental Design: Resveratrol was tested in mouse xenograft models of human neuroblastoma and in vitro using human cell lines. Results: Resveratrol inhibited the outgrowth of tumors by as much as 80%.The bioavailability of the drug in serum was in the low micromolar range (2-10 Amol/L) and no accumulation was observed in tumor tissue. When resveratrol levels were increased by peritumor injection, rapid tumor regression occurred. Resveratrol decreased tumor cell viability in vitro by 75% to 90%, resulting from an inhibition of cell proliferation and an induction of apoptosis. Loss of mitochondrial membrane potential was an early response to resveratrol. In addition, resveratrol treatment of isolated mitochondria also led to depolarization, suggesting that the drug may target mitochondria directly. Following depolarization, resveratrol caused the release of cytochrome c and Smac/ Diablo from the mitochondria and subsequently the activation of caspase-9 (4-to 8-fold) and caspase-3 (4-to 6-fold). Conclusions: These studies indicate that, despite low bioavailability, resveratrol is effective at inhibiting tumor growth. Elevated levels of resveratrol enhance its antitumor potency leading to tumor regression, associated with widespread tumor cell death, the underlying mechanism of which involves the direct activation of the mitochondrial intrinsic apoptotic pathway.

The Effect of Resveratrol on the Quality of Extended Boar Semen During Storage at 17ºC

“…8;2013 potential than in RSV 20 µg/mL treated group (Silva et al, 2012). The decrease in the mitochondrial membrane potential caused by RSV has been widely described in somatic cells and has allowed its use in cancer treatment since RSV is able i) to regulate the mitochondrial permeability transition pore (Zunino & Storms, 2006), ii) to increase the mitochondrial superoxide production (Low et al, 2010), iii) to decrease the mitochondrial membrane potential (Sareen et al, 2006;van Ginkel et al, 2007) and iv) to disrupt the mitochondrial respiratory chain (Zheng & Ramirez, 2000;Zini et al, 1999). The ATP content diminution in RSV treated boar spermatozoa is very clear in our study, falling between 3-6 times when using 33 µM RSV and 10 to 20 times when using 100 µM RSV.…”

Resveratrol-loaded solid lipid nanoparticles versus nanostructured lipid carriers: evaluation of antioxidant potential for dermal applications

“…7 RSV induces promyelocytic leukemia cell differentiation, and exhibits anticancer properties by mediating apoptosis, arresting cell cycle progression, antiproliferation and inhibiting ribonucleotide reductase, ornithine decarboxylase, and cyclooxygenase through modulation of prostaglandin production. 8 Since their first description, solid lipid nanoparticles (SLNs) have attracted increasing attention as an efficient and nontoxic alternative lipophilic colloidal drug carrier, prepared either with physiological lipids or lipid molecules used as common pharmaceutical excipients. SLNs were developed in the early 1990s as an alternative carrier system to other colloidal formulations such as emulsions, liposomes, and polymeric nanoparticles.…”

Resveratrol Suppresses Cancer Cell Glucose Uptake by Targeting Reactive Oxygen Species–Mediated Hypoxia-Inducible Factor-1α Activation

“…The ability of resveratrol to inhibit cancer cell proliferation and survival has previously been reported (5)(6)(7)(8). For LLC cells, an antitumor effect was shown in mice treated with resveratrol (10).…”

“…Resveratrol, a natural polyphenol compound found in such fruits as grapes and berries, has particularly gained intense attention for its promising anticancer effects (2). Initially recognized for its ability to inhibit carcinogenesis at multiple stages (3,4), resveratrol has since been found to exert significant antitumor effects including inhibition of growth (5-7), induction of apoptosis (6)(7)(8), and suppression of metastatic potential (9,10).…”