IN VITRO AND IN VIVO STUDIES FOR THE TREATMENT OF BASAL LIKE BREAST CANCER (BLBC) WITH AZOLATE/PHOSPHANE GOLD(I) COMPOUNDS

IN VITRO AND IN VIVO STUDIES FOR THE TREATMENT OF BASAL LIKE BREAST CANCER (BLBC) WITH AZOLATE/PHOSPHANE GOLD(I) COMPOUNDS Rossana Galassia, Alfredo Burinia, Oumarou Camille Simona, Anna Teresa Ramadoria, Stefania Pucciarelli,b Albana Hisy,c Manuela Iezzi,c Valentina Gambini b, Martina Tiliob, Cristina Marchini b, Augusto Amicib a School of Science and Technology, Chemistry Division, Camerino University, Via Sant’ Agostino, I-62032 Italy. b Department of Biosciences and Veterinary, University of Camerino, Via Gentile III da Varano, I-62032, Italy c Aging Research Centre, G. d’Annunzio University, Chieti, 66100, Italy e-mail: annateresa.ramadori@unicam.it Breast cancer is a heterogeneous disease classified into molecular subtypes with distinctive gene expression signatures. Of all the molecular subtypes, BLBC has the worst negative outcome and prognosis. BLBCs are generally estrogen receptor (ER-) and progesterone receptor (PR)-negative and also lack high expression/amplification of HER2, limiting targeted therapeutic options. Thus, to date, Cisplatin remains the only possible therapeutic choice in the adjuvant or metastatic setting in the BLBC. Considering also several and serious side effects, new therapies are therefore an urgent unmet medical need for this patient population. Azolate gold(I) phosphane compounds have become good candidate for anticancer applications.[1] It was highlighted that azolate gold(I) phosphane compounds were mostly very active in the regards of many panel of cancer cells, in addition to cis-platin resistant cells. They show a mechanism of action involving the inhibition of seleno dependent ThioredoxinaReductase (TrxR), but they inhibit with IC50 in the micromolar scale also many other enzymes such as DeHydroFolateReductase.[1][2] In order to study the effectiveness of these new azolate gold(I) phosphane compounds as potential anticancer agents, different cell viability assays (MTT assays) were performed on a human in vitro model of HER2-overexpressing breast cancer: SKBR-3 cells.[3] After this preliminary screening, the most promising and effective compounds were selected to extend the study on A17 cell line, a murine preclinical model of Basal Like Breast Cancer (BLBC).[4] Hence, their efficacy in suppressing BLBC growth in vivo was tested and IHC analysis on explanted tumors were carried on. Overall, in vitro assays demonstrated a remarkable activity for those compounds having the Ph3PAu+ moiety and substituted imidazolate as co-ligands. Concerning the in vivo study the compounds act significantly delaying tumor growth. Accordingly, IHC analysis revealed a remarkable anti-angiogenic activity associated with a lower expression of proliferative markers and a higher level of apoptotic markers in treated tumours in comparison with controls. Moreover, respect to cisplatin these compounds displayed a lower nephrotoxicity, although their liver toxicity was higher. These promising results open the way to further investigations in order to understand the mechanism of action of these new azolate gold (I) posphane complexes. References [1] R. Galassi et al., Dalton Trans., 2012, (41), pp 5307-5318. [2] R. Galassi et al., Dalton Trans., 2015, (44), pp 3043-3056. [3] Fogh, J., Fogh J. M., Orfeo T, J Natl Cancer Inst. , 1977, (59), pp 221-6; [4] M. Galiè et al., Carcinogenesis , 2005, (11), pp 1868-1878