Brief report: RRx-001 is a c-Myc inhibitor that targets cancer stem cells.

Bryan Oronsky,Tony R Reid,Scott Caroen,Pedro Cabrales,Arnold Oronsky,Corey A Carter

doi:10.18632/oncotarget.25211

Bryan Oronsky, Tony R Reid + Show 4 more

Open Access

https://doi.org/10.18632/oncotarget.25211

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Abstract

The goal of anticancer therapy is to selectively eradicate all malignant cells. Unfortunately for the majority of patients with metastatic disease, this goal is consistently thwarted by the nearly inevitable development of therapeutic resistance; the main driver of therapeutic resistance is a minority subpopulation of cancer cells called cancer stem cells (CSCs) whose mitotic quiescence essentially renders them non-eradicable. The Wnt signaling pathway has been widely implicated as a regulator of CSCs and, therefore, its inhibition is thought to result in a reversal of therapeutic resistance via loss of stem cell properties.RRx-001 is a minimally toxic redox-active epi-immunotherapeutic anticancer agent in Phase III clinical trials that sensitizes tumors to radiation and cytotoxic chemotherapies. In this article, as a potential mechanism for its radio- and chemosensitizing activity, we report that RRx-001 targets CD133+/CD44+ cancer stem cells from three colon cancer cell-lines, HT-29, Caco-2, and HCT116, and inhibits Wnt pathway signalling with downregulation of c-Myc.

Highlights

The c-Myc (Myc) oncoprotein is a well-established driver of breast, lung, colorectal and prostate cancers that is currently considered “undruggable” [1,2,3,4]
As a potential mechanism for its radio- and chemosensitizing activity, we report that RRx-001 targets CD133+/CD44+ cancer stem cells from three colon cancer cell-lines, HT-29, Caco-2, and HCT116, and inhibits Wnt pathway signalling with downregulation of c-Myc
As a potential mechanism for its radio- and chemosensitizing activity, we demonstrate for the first time that RRx-001 targets cancer stem cells (CSCs) and that it decreases the expression levels of Wnt pathway components and target genes, such as TCF4, Pygo2, Axin2 and c-Myc, which are known to govern stem cell renewal and differentiation [7, 8]

Summary

INTRODUCTION

The c-Myc (Myc) oncoprotein is a well-established driver of breast, lung, colorectal and prostate cancers that is currently considered “undruggable” [1,2,3,4]. Myc overexpression is associated with cancer stem cell maintenance [5] and, by extension, with therapeutic resistance since cancer stem cells are thought to be the primary mediators of tumor resistance and progression. RRx-001 is a first-in-class minimally toxic epiimmunotherapeutic agent in Phase III clinical trials as a chemosensitizer to reverse resistance in small cell lung cancer (SCLC), high-grade neuroendocrine carcinomas (HGNEC) and colorectal cancers [6]. As a potential mechanism for its radio- and chemosensitizing activity, we demonstrate for the first time that RRx-001 targets cancer stem cells (CSCs) and that it decreases the expression levels of Wnt pathway components and target genes, such as TCF4, Pygo, Axin and c-Myc, which are known to govern stem cell renewal and differentiation [7, 8]

RESULTS

MATERIALS AND METHODS

CONCLUSIONS