INHIBITION OF TUMOR GROWTH, STEROIDOGENESIS, HORMONE AND DRUGS RESISTANCE BY AN ACYL-COA SYNTHETASE 4 NEW INHIBITOR

CASTILLO AF; ORLANDO UD; MALOBERTI PM; PRADA JG; DATTILO MA; SOLANO AR; SZAJNMAN S; LORENZANO MENNA P; GOMEZ DE; RODRIGUEZ JD; PODESTA EJ

Ciudad de Salta

Congreso; Reunión anual conjunta de las sociedades SAIB- PABMB 2019; 2019

SAIB- PABMB

Acyl-CoA synthetase 4 (ACSL4) is an isoenzyme of the fatty acid ligase-coenzyme A ligase family that takes part in arachidonic acid metabolism.This enzyme is involved in cancer development, particularly in breast and prostate cancers, where a correlation between its high expression andtumor cell aggressiveness has been found. Functionally, it was shown that ACSL4 is part of the mechanism responsible for increased breast andprostate cancer cell proliferation, invasion, and migration. ACSL4 is involved in the regulation of several signal transduction mechanisms,including the mTOR pathway, and furthermore increases the expression of proteins involved in drug resistance. Another relevant property of thisenzyme is its participation as an essential protein in the activation of cholesterol transport from the external to the internal mitochondrial membrane,the regulatory and rate-limiting step in the syntheses of all steroids. The development of selective inhibitors for ACSL4, which may inhibit tumorgrowth and steroidogenesis, may be an important tool in the prevention and treatment of breast and prostate cancers expressing ACSL4. In thiswork, we have developed and characterized a new ACSL4 inhibitor, PRGL493. An ACSL4 homology model was generated by MODELLER, anda docking based virtual screening was performed. The selected compound was modified to improve particularly solubility properties and fullycharacterized by nuclear magnetic resonance and mass spectroscopy. We demonstrated that PRGL493 was effective in reducing AA-CoA levels,as a product of ACSL4 activity, in a cell-free assay system using recombinant protein and in intact cells using cell models for steroidogenesis andtumor growth. Our compound inhibited cell proliferation and migration of highly aggressive human breast and prostate cancer cell lines (MDAMB-231 and PC-3 respectively) and in vivo using the Chick Embryo Chorioallantoic Membrane model assay. In addition, PRGL493 inhibitedsteroid synthesis both in vitro in Leydig, adrenal, and PC-3 prostate cancer cells and in vivo in a mouse model, inhibiting cholesterol transport tothe inner mitochondrial membrane and thus preventing steroid accumulation. Moreover, the inhibitor produced sensitization to hormonal andchemotherapeutic treatment. The combination of PRGL493 with tamoxifen, cisplatin, doxorubicin, or paclitaxel in MDA-MB-231 cells, or withdocetaxel in PC-3 cells, showed a synergistic effect on the inhibition of cell proliferation. The results show that ACSL4 is an essential target forbreast and prostate cancer therapy. These findings open an important route to treat these tumors that may lead to the development of rational cancertreatment and continue to lead to the introduction of the combination of chemotherapy to specific other agents.