Resveratrol inhibits tumor growth of human neuroblastoma and mediates apoptosis by directly targeting mitochondria

Paul R. Van Ginkel, Dhruv Sareen, Lalita Subramanian, Quintisha Walker, Soesiawati R. Darjatmoko, Mary J. Lindstrom, Amol Kulkarni, Daniel M. Albert, Arthur S. Polans

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129 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)5162-5169
Number of pages8
JournalClinical Cancer Research
Volume13
Issue number17
DOIs
StatePublished - Sep 1 2007

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Van Ginkel, P. R., Sareen, D., Subramanian, L., Walker, Q., Darjatmoko, S. R., Lindstrom, M. J., Kulkarni, A., Albert, D. M., & Polans, A. S. (2007). Resveratrol inhibits tumor growth of human neuroblastoma and mediates apoptosis by directly targeting mitochondria. Clinical Cancer Research, 13(17), 5162-5169. https://doi.org/10.1158/1078-0432.CCR-07-0347