Oncotarget

Research Papers:

Autophagy-dependent apoptosis is triggered by a semi-synthetic [6]-gingerol analogue in triple negative breast cancer cells

Liany Luna-Dulcey, Rebeka Tomasin, Marina A. Naves, James A. da Silva and Marcia R. Cominetti _

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Oncotarget. 2018; 9:30787-30804. https://doi.org/10.18632/oncotarget.25704

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Abstract

Liany Luna-Dulcey1, Rebeka Tomasin1, Marina A. Naves1, James A. da Silva2 and Marcia R. Cominetti1

1Laboratory of Biology of Aging, Department of Gerontology, Federal University of São Carlos, CEP 13565-905, São Carlos, SP, Brazil

2Department of Pharmacy, Federal University of Sergipe, CEP 49400-000, São José, Lagarto, SE, Brazil

Correspondence to:

Marcia R. Cominetti, email: mcominetti@ufscar.br

Keywords: autophagy; breast cancer; caspase-independent apoptosis; cytotoxicity; natural products

Received: February 23, 2018     Accepted: June 12, 2018     Published: July 20, 2018

ABSTRACT

Triple negative breast cancer (TNBC) is very aggressive and lacks specific therapeutic targets, having limited treatment options and poor prognosis. [6]-gingerol is the most abundant and studied compound in ginger, presenting diverse biological properties such as antitumor activity against several types of cancer, including breast cancer. In this study, we show that the semi-synthetic analogue SSi6, generated after chemical modification of the [6]-gingerol molecule, using acetone-2,4-dinitrophenylhydrazone (2,4-DNPH) reagent, enhanced selective cytotoxic effects on MDA-MB-231 cells. Remarkably, unlike the original [6]-gingerol molecule, SSi6 enabled autophagy followed by caspase-independent apoptosis in tumor cells. We found a time-dependent association between SSi6-induced oxidative stress, autophagy and apoptosis. Initial SSi6-induced reactive oxygen species (ROS) accumulation (1h) led to autophagy activation (2-6h), which was followed by caspase-independent apoptosis (14h) in TNBC cells. Additionally, our data showed that SSi6 induction of ROS plays a key role in the promotion of autophagy and apoptosis. In order to investigate whether the observed cell death induction was dependent on preceding autophagy in MDA-MB-231 cells, we used siRNA to knock down LC3B prior to SSi6 treatment. Our data show that LC3B downregulation decreased the number of apoptotic cells after treatment with SSi6, indicating that autophagy is a key initial step on SSi6-induced caspase-independent apoptosis. Overall, the results of this study show that structural modifications of natural compounds can be an interesting strategy for developing antitumor drugs, with distinct mechanisms of actions, which could possibly be used against triple negative breast cancer cells that are resistant to canonical apoptosis-inducing drugs.


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