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

• Published in: Clinical cancer research Vol. 13; no. 17; pp. 5162 - 5169
• Main Authors: VAN GINKEL, Paul R, SAREEN, Dhruv, SUBRAMANIAN, Lalita, WALKER, Quintisha, DARJATMOKO, Soesiawati R, LINDSTROM, Mary J, KULKARNI, Amol, ALBERT, Daniel M, POLANS, Arthur S
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-09-2007
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents, Phytogenic - therapeutic use; apoptosis; Apoptosis - drug effects; Biological and medical sciences; Biological Availability; Cell Line, Tumor; Humans; Medical sciences; Membrane Potentials - drug effects; Mice; mitochondria; Mitochondria - drug effects; Mitochondria - physiology; Neoplasm Transplantation; neuroblastoma; Neuroblastoma - drug therapy; Neuroblastoma - pathology; Neurology; Pharmacology. Drug treatments; resveratrol; Stilbenes - pharmacokinetics; Stilbenes - pharmacology; Stilbenes - therapeutic use; Transplantation, Heterologous; Tumors of the nervous system. Phacomatoses; xenograft model; Human; Nervous system diseases; Targeting; Neuroblastoma; Malignant tumor; Stilbene derivatives; Target; Mitochondria; Polyphenol; Tumor growth; Cell death; Phytoalexin; Resveratrol; Phenols; Inhibitor; Autonomic neuropathy; Apoptosis
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-07-0347

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 μmol/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.