Abstract 1536 Evaluation of the Selective Cytotoxic Properties of Tigliane and Ingenane Macrocyclic Diterpene Esters Against Triple Negative Breast Cancer

Breast cancer is a serious worldwide disease and is the single most frequently diagnosed cancer in women.Among these, Triple-Negative Breast Cancer (TNBC) holds a higher morbidity than other Breast Cancer types due to its high molecular heterogeneity, limiting the development of targeted therapies which greatly benefit other types of breast cancer.We have previously shown that yuanhuacine, a 6-epoxy daphnane diterpene ester, displays potent selective cytotoxicity against the Basal-Like 2 (BL2) subtype of TNBC, one of the four molecularly distinct subtypes of TNBC.Yuanhuacine belongs to the daphnane diterpenoids sub-class macrocyclic diterpene esters which also encompasses sub-classes such as the tigliane and ingenane.But whether compounds belonging to the tigliane and ingenanes can mediate selective cytotoxicity against the BL2 subtype of TNBC like the daphnane has not been previously investigated.This premise prompted the hypothesis that due to the structural similarities between macrocyclic diterpenoids tiglianes and ingenanes will also mediate selective cytotoxicity against the BL2 TNBC cells lines.To test this hypothesis, the cytotoxic properties of tiglaines Phorbol 12, 13-Dibutyrate, Prostratin, and Phorbol and inganes Ingenol 3-angelate, Ingenol 3,20-Dibenzoate and Ingenol, were tested against cell lines representing all four TNBC subtypes using the SRB cytotoxicity assay.All six of the compounds tested have shown selective cytotoxicity against the BL2 cell lines albeit with different potencies.From these Phorbol 12, 13-Dibutyrate and Ingenol 3-angelate were the most potent derivatives in their respective groups.Collectively, these studies demonstrate the potential of macrocyclic diterpenoids to serve as future targeted therapy candidates for the treatment of BL2 TNBC.