Targeting mitochondria in cancer therapy could provide a basis for the selective anti-cancer activity.

Dmitri Rozanov,Cristina E Tognon,Isaac Forquer,James Korkola,Gordon B Mills,Aaron Nilsen,Christopher Boniface,Joe Gray,Anton Cheltsov,Jeffrey Tyner,Paul Spellman,Aamir Ahmad

doi:10.1371/journal.pone.0205623

Abstract

To determine the target of the recently identified lead compound NSC130362 that is responsible for its selective anti-cancer efficacy and safety in normal cells, structure-activity relationship (SAR) studies were conducted. First, NSC13062 was validated as a starting compound for the described SAR studies in a variety of cell-based viability assays. Then, a small library of 1,4-naphthoquinines (1,4-NQs) and quinoline-5,8-diones was tested in cell viability assays using pancreatic cancer MIA PaCa-2 cells and normal human hepatocytes. The obtained data allowed us to select a set of both non-toxic compounds that preferentially induced apoptosis in cancer cells and toxic compounds that induced apoptosis in both cancer and normal cells. Anti-cancer activity of the selected non-toxic compounds was confirmed in viability assays using breast cancer HCC1187 cells. Consequently, the two sets of compounds were tested in multiple cell-based and in vitro activity assays to identify key factors responsible for the observed activity. Inhibition of the mitochondrial electron transfer chain (ETC) is a key distinguishing activity between the non-toxic and toxic compounds. Finally, we developed a mathematical model that was able to distinguish these two sets of compounds. The development of this model supports our conclusion that appropriate quantitative SAR (QSAR) models have the potential to be employed to develop anti-cancer compounds with improved potency while maintaining non-toxicity to normal cells.

Highlights

We showed that its combination with different oxidative stress inducers, such as arsenic trioxide (ATO), myricetin (Myr), and buthionine sulfoximine (BSO), caused cell death in a variety of breast, pancreatic, prostate, and lung carcinoma cell lines as well as in human melanoma MDA-MB-435 and acute myeloid leukemia (AML) cells from patients
We published that NSC130362 inhibits GSR and, as a consequence, induces reactive oxygen species (ROS) and subsequent apoptosis in cancer cells but not in normal human hepatocytes as a model for hepatotoxicity [7]
A goal for ROS-based cancer therapy will be the ability to either target the antioxidant proteins that are used by tumor cells to detoxify from ROS or affect ROS producing pathways that result in increased ROS production

Summary

Introduction

One promising strategy for successful cancer therapy is to induce oxidative stress and followed by apoptosis in cancer cells but not in normal cells. Instead of targeting specific oncogenes and tumor suppressors, exploiting common biochemical alterations in cancer cells, such as an increased ROS stress, could provide the basis for developing selective and potent therapeutic agents. Targeting any of these components can potentially induce oxidative stress which can result in cell death. We recently reported the discovery of 1,4-naphthoquinine (1,4-NQ) derivative, NSC130362, which inhibits GSR and, as a consequence, induces oxidative stress and subsequent apoptosis in cancer cells but not in normal human primary hepatocytes. In addition to inhibiting GSR, 1,4-NQs can be reduced by NADH/NADPH dehydrogenase followed by autoxidation, which results in the formation of ROS and potential oxidative stress. Based on the obtained results, we were able to construct a mathematical model that could distinguish toxic NSC130362 analogs from analogs that were non-toxic to normal cells

Materials and methods

Results

39 NSC4285

Discussion