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Invest New Drugs (2011) 29:562573 DOI 10.1007/s10637-010-9390-x
PRECLINICAL STUDIES
Cribrostatin 6 induces death in cancer cells througha reactive oxygen species (ROS)-mediated mechanism
Mirth T. Hoyt & Rahul Palchaudhuri &
Paul J. Hergenrother
Received: 23 October 2009 /Accepted: 13 January 2010 /Published online: 20 February 2010 # Springer Science+Business Media, LLC 2010
Summary Cribrostatin 6 is a quinone-containing natural product that induces the death of cancer cell lines in culture, and its mechanism of action and scope of activity are unknown. Here we show that cribrostatin 6 has broad anticancer activity, potently inducing apoptotic cell death that is not preceded by any defined cell cycle arrest. Consistent with this data, we find that cribrostatin 6 treated cells have large amounts of reactive oxygen species (ROS) and, based on transcript profiling experiments and other data, this ROS generation is likely the primary mechanism by which cribrostatin 6 induces apoptosis. Given the success of certain ROS producers as anticancer agents, cribrostatin 6 has potential as a novel chemotherapeutic agent.
Keywords Cribrostatin 6 . ROS . Quiescent 3T3 . Quinone .
HMOX1 . Apoptosis . Cancer stem cells . Transcript profile . Quiescent cells . Drug-resistant cell lines
Introduction
Certain quinone-containing small molecules have utility as anticancer agents, as demonstrated by FDA-approved drugs such as mitoxantrone, mitomycin C (MMC), and doxoru-
bicin (Fig. 1a). Most investigations into the mode of action for anticancer quinones focus on some combination of DNA intercalation, topoisomerase inhibition, DNA alkylation, and reduction/oxidation-cycling properties. Indeed, several quinones appear to induce death via topoisomerase inhibition [1], others through covalent alkylation of DNA (sometimes proceeded by bioreductive activation) [24], and others generate cellular reactive oxygen species (ROS), leading to cell death [57].
In many cases, the data suggests more than one of the above mechanisms of death being operational in cells treated with anticancer quinones. For example, doxorubicin both inhibits topoisomerase II and generates ROS through a 1-electron reduction pathway [1, 8]. There is also evidence that doxorubicin forms covalent adducts with DNA in cell culture as well as in carcinomas of human patients [9, 10]. MMC can be activated to a cytotoxic species through both 1- and 2-electron reduction pathways to give the MMC semi-quinone and hydroquinone, respectively [11].
The cribrostatins are a family of cytotoxic...