Autophagy activation/inhibition by triterpenoids and the impact of membranes interaction: therapeutic implications on tumor response

Abstract

Human cancer is a significant global public health problem, particularly in cases where the cancer becomes refractory to chemotherapy, radiation therapy or photodynamic therapy. This is due to the apoptosis evasion, whose behavior increases cancer mortality. As a strategy to reverse this outcome, recently there have investigated the modulation of autophagy as a new antitumor approach. Autophagy is a biological process whose role in oncogenesis and tumor progression show a dichotomy by acting either as a pro-maintainer of tumor homeostasis regarded to intrinsic or extrinsic stresses and as a pro-cell death modulator. The idea of the project proposed here originally based on the modulation of autophagy by biochemical extrinsic stress triggered by pentacyclic triterpenoid isomers - Betulinic acid (BA) and Oleanolic (OA). The modulation of autophagy proposed here related to the concept of parallel damage of lysosomes and mitochondria membranes whose status of mitophagic flux ends up cell survival, death or aging of normal human keratinocytes. By modulating the autophagic flux in cells deficient in the gene related to autophagy ATG7, it will possible to evaluate if the biophysical intracellular damage mediated by AB may lead to cell death regardless or not activation of the autophagic mechanism. It is well known that ATG7 protein is required for mitophagy, and when it is silenced occurs tumor resistance to therapy such as photodynamic therapy and photoinduced lysosomal damage. Through biotechnology molecular and cellular tools, it will be possible to evaluate further the state of the art autophagy 's concept as proposed by Martins and colleagues. Thus, the effort of this project could in the near future contribute in antitumor drug development field as well raise knowledge in the pathophysiology of human disorders related to senescence and genomic instability, such as heart´s, Alzheimer's, Parkinson's and Huntington´s disease. (AU)