This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Whibley, C. E. Articles by Hendricks, D. T. Search for Related Content PubMed PubMed Citation Articles by Whibley, C. E. Articles by Hendricks, D. T.

Research Articles: Therapeutics, Targets, and Development

Reactive oxygen species mediated apoptosis of esophageal cancer cells induced by marine triprenyl toluquinones and toluhydroquinones

¹ Institute of Infectious Diseases and Molecular Medicine, Division of Medical Biochemistry, University of Cape Town, Faculty of Health Sciences, Cape Town, South Africa; ² Department of Chemistry, Rhodes University, Grahamstown, South Africa; and ³ Cell and Cancer Biology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland

Requests for reprints: Denver Hendricks, Division of Medical Biochemistry, University of Cape Town, Faculty of Health Sciences, Private Bag X3, Observatory, Cape Town, 7935, South Africa. Phone: 27-21-406-6266; Fax: 27-21-406-6061. E-mail: Denver.Hendricks{at}uct.ac.za

Abstract

Marine invertebrates, algae, and microorganisms are prolific producers of novel secondary metabolites. Some of these secondary metabolites have the potential to be developed as chemotherapeutic agents for the treatment of a wide variety of diseases, including cancer. We describe here the mechanism leading to apoptosis of esophageal cancer cell lines in the presence of triprenylated toluquinones and toluhydroquinones originally isolated from the Arminacean nudibranch Leminda millecra. Triprenylated toluquinone–induced and toluhydroquinone-induced cell death is mediated via apoptosis after a cell cycle block. Molecular events include production of reactive oxygen species (ROS), followed by induction and activation of c-Jun (AP1) via c-Jun-NH₂-kinase–mediated and extracellular signal-regulated kinase–mediated pathways. Partial resistance to these compounds could be conferred by the ROS scavengers Trolox and butylated hydroxyanisol, a c-Jun-NH₂-kinase inhibitor, and inhibition of c-Jun with a dominant negative mutant (TAM67). Interestingly, the levels of ROS produced varied between compounds, but was proportional to the ability of each compound to kill cells. Because cancer cells are often more susceptible to ROS, these compounds present a plausible lead for new antiesophageal cancer treatments and show the potential of the South African marine environment to provide new chemical entities with potential clinical significance. [Mol Cancer Ther 2007;6(9):2535–43]

Grant support: Cancer Association of South Africa, South African National Research Foundation, South African Government Department of Environmental Affairs and Tourism, Rhodes University, and University of Cape Town.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 12/ 7/06; revised 5/18/07; accepted 8/ 1/07.