Targeting mitochondria in cancer therapy could provide a basis for the selective anticancer activity

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere0205623
JournalPloS one
Volume14
Issue number3
DOIs
StatePublished - Mar 1 2019

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Mitochondria
Assays
mitochondria
therapeutics
neoplasms
Poisons
assays
structure-activity relationships
Neoplasms
toxic substances
Cells
cells
Apoptosis
Lead compounds
apoptosis
Structure-Activity Relationship
viability
quantitative structure-activity relationships
quinoline
Therapeutics

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Targeting mitochondria in cancer therapy could provide a basis for the selective anticancer activity. / Rozanov, Dmitri; Cheltsov, Anton; Nilsen, Aaron; Boniface, Christopher; Forquer, Isaac; Korkola, James; Gray, Joe; Tyner, Jeffrey; Tognon, Cristina E.; Mills, Gordon; Spellman, Paul.

In: PloS one, Vol. 14, No. 3, e0205623, 01.03.2019.

Research output: Contribution to journalArticle

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