Pharmacological Evaluation of Novel Chloroquine Analogues in Breast Cancer Cells

Abstract

Targeting autophagy, a conserved cellular process required for the degradation and recycling of proteins and cellular organelles, has emerged as a potential therapeutic approach for cancer treatment. Although, its role in cancer progression remains controversial, autophagy inhibition has been shown to be potentially beneficial in pre‐clinical studies. Constitutively active autophagy due to cellular stress has been implicated in tumor progression and therapeutic resistance. Pharmacological inhibition of autophagy using chloroquine, an approved antimalarial agent, has been investigated in preclinical cancer models and is currently being investigated in several ongoing clinical trials. However, several problems may prevent the translation of preclinical findings into the clinic such as the potential adverse events associated with chloroquine. Additionally, most preclinical studies utilize high chloroquine concentrations to inhibit autophagy which may not be achieved clinically. Therefore, we hypothesized that the design and synthesis of novel chloroquine polyamine conjugates may result in compounds that inhibit autophagy in breast cancer cells at lower concentrations due to enhanced cellular uptake through the polyamine transporter. Assessment of the biological activity of the chloroquine analogs using MTT assay demonstrates the chloroquine polyamine conjugates induce cell death at lower concentrations relative to chloroquine. Additionally assessment of the ability of these compounds to inhibits autophagy indicate that they inhibit autophagy at lower concentrations as indicated by the accumulation of LC3B‐II and p62, a protein known to undergo autophagy‐dependent degradation. Future studies will aim at investigating the mechanism of the enhanced cytotoxic activity of these compounds.Support or Funding InformationD'Youville College and D'Youville College School of PharmacyThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.