RRx-001 is a novel aerospace-derived compound currently under investigation in several ongoing Phase II studies. In a Phase I trial, it demonstrated anti-
cancer activity and evidence of resensitization to formerly effective
therapies in heavily pre-treated patients with relapsed/refractory solid
tumors.
RRx-001 generates reactive
oxygen and
nitrogen species (ROS and RNS) and
nitric oxide (NO), elicits changes in intracellular redox status, modulates
tumor blood flow,
hypoxia and vascular function and triggers apoptosis in
cancer cells. We investigated the effect of
RRx-001 on the epigenome of SCC VII
cancer cells.
RRx-001 at 0.5 and 2 μM significantly decreased global DNA methylation, i.e.,
5-methylcytosine levels, in SCC VII cells. Consistently, 0.5-5 μM
RRx-001 significantly decreased Dnmt1 and
Dnmt3a protein expression in a dose- and time-dependent manner. In addition, global methylation profiling identified differentially methylated genes in SCC VII cells treated with 0.5, 2, and 5 μM
RRx-001 compared to control cells. Twenty-three target sites were hypomethylated and 22 hypermethylated by >10% in the presence of at least two different concentrations of
RRx-001. Moreover,
RRx-001 at 2 μM significantly increased global acetylated
histone H3 and H4 levels in SCC VII cells after 24 hour treatment, suggesting that
RRx-001 regulates global acetylation in
cancer cells. These results demonstrate that, in contrast to the traditional "one drug one target" paradigm,
RRx-001 has multi(epi)target features, which contribute to its anti-
cancer activity and may rationalize the resensitization to previously effective
therapies observed in clinical trials and serve as a unifying mechanism for its anticancer activity.