An Exemestane Derivative, Oxymestane-D1, as a New Multi-Target Steroidal Aromatase Inhibitor for Estrogen Receptor-Positive (ER+) Breast Cancer: Effects on Sensitive and Resistant Cell Lines

Abstract

Around 70–85% of all breast cancer (BC) cases are estrogen receptor-positive (ER+). The third generation of aromatase inhibitors (AIs) is the first-line treatment option for these tumors. Despite their therapeutic success, they induce several side effects and resistance, which limits their efficacy. Thus, it is crucial to search for novel, safe and more effective anti-cancer molecules. Currently, multi-target drugs are emerging, as they present higher efficacy and lower toxicity in comparison to standard options. Considering this, this work aimed to investigate the anti-cancer properties and the multi-target potential of the compound 1α,2α-epoxy-6-methylenandrost-4-ene-3,17-dione (Oxy), also designated by Oxymestane-D1, a derivative of Exemestane, which we previously synthesized and demonstrated to be a potent AI. For this purpose, it was studied for its effects on the ER+ BC cell line that overexpresses aromatase, MCF-7aro cells, as well as on the AIs-resistant BC cell line, LTEDaro cells. Oxy reduces cell viability, impairs DNA synthesis and induces apoptosis in MCF-7aro cells. Moreover, its growth-inhibitory properties are inhibited in the presence of ERα, ERβ and AR antagonists, suggesting a mechanism of action dependent on these receptors. In fact, Oxy decreased ERα expression and activation and induced AR overexpression with a pro-death effect. Complementary transactivation assays demonstrated that Oxy presents ER antagonist and AR agonist activities. In addition, Oxy also decreased the viability and caused apoptosis of LTEDaro cells. Therefore, this work highlights the discovery of a new and promising multi-target drug that, besides acting as an AI, appears to also act as an ERα antagonist and AR agonist. Thus, the multi-target action of Oxy may be a therapeutic advantage over the three AIs applied in clinic. Furthermore, this new multi-target compound has the ability to sensitize the AI-resistant BC cells, which represents another advantage over the endocrine therapy used in the clinic, since resistance is a major drawback in the clinic.

In Vitro Effects of Combining Genistein with Aromatase Inhibitors: Concerns Regarding Its Consumption during Breast Cancer Treatment

“…In relation to aromatase, results showed that in the presence of E 2 , G significantly lost the ability to decrease MCF-7aro cell viability (Figure 4A) when compared with cells stimulated with T, which suggests an effect on cells that is aromatase-dependent. In accordance with previous studies [11,14,[34][35][36][37][38], Exe decreases the aromatase levels in MCF-7aro cells. Similarly to Exe, G at 10 µM was also able to significantly (p < 0.001) reduce the expression levels of aromatase (Figure 4B).…”

“…We have previously demonstrated that G decreases aromatase activity in human placental microsomes [ 29 ]. In addition, this study showed for the first time that G presents an aromatase-dependent effect on ER+ breast cancer cells, since G, at 10 µM, has the ability to decrease the expression levels of aromatase in MCF-7aro cells, an effect similar to Exe [ 11 , 14 , 34 , 35 , 36 , 37 , 38 ] and opposite to those already reported for Ana and Let [ 14 ]. Interestingly, only the combination with G at 10 µM prevented the degradation of aromatase detected for both G and Exe alone, which emphasizes that the loss of clinical benefit for the highest dose of G may be related to the lack of effect on aromatase.…”

Aromatase Inhibitors as a Promising Direction for the Search for New Anticancer Drugs

“…The tests showed that derivative 6 reduced the expression and activation of ERα and induced the overexpression of aromatase with an effect promoting cell death. Complementary transactivation assays showed that molecule 6 exhibited ER antagonist and AR agonist activity [ 15 ].…”

Switching from Aromatase Inhibitors to Dual Targeting Flavonoid-Based Compounds for Breast Cancer Treatment

“…In 2012, Lu et al [ 11 ] reported the first evidence of the ability of a single compound to interact with significant activities on two targets involved in the progression of ER+ BC. This discovery paved the way for the identification of new multitarget compounds capable of overcoming the limitations of current therapeutic strategies [ 12 ]; different series of compounds have been recently developed and/or evaluated for their multipotent activity [ 13 , 14 , 15 , 16 , 17 ].…”