Oxymestane, a cytostatic steroid derivative of exemestane with greater antitumor activity in non-estrogen-dependent cell lines

Pires, Ana Salomé; Varela, Carla; Marques, Inês; Abrantes, Ana Margarida; Gonçalves, Ana Cristina; Rodrigues, Tiago; Matafome, Paulo; Botelho, Maria Filomena; Roleira, Fernanda M.F.; Silva, E. J. Tavares da

doi:10.1016/j.jsbmb.2021.105950

Cited by 5 publications

(6 citation statements)

References 35 publications

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“…Several different mechanisms have been described for the interaction between mitochondria and caspase-8 activation [ 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 ], although this relationship is not totally elucidated. The ability of Oxy to impair cell cycle progression and activate apoptosis of cancer cells was also reported by our group, on lung, liver, colon and prostate cancer cell lines [ 31 ].…”

Section: Discussionsupporting

confidence: 60%

“…Considering all this, and as an attempt to discover a new steroidal compound with these key properties, the mechanism of action of Oxy —a potent steroidal AI, derivative of Exe, designed and synthesized by our group—was investigated [ 20 ]. For this AI, it was reported that it affects the viability of ER + breast cancer cells [ 20 ] and presents promising anti-cancer properties in lung, liver, colon and prostate cancer cell lines by inducing cell cycle arrest, apoptosis and necrosis as well as DNA damage, and also by inhibiting the DNA damage response [ 31 ]. In addition, we previously verified that this molecule is more potent than Exe, the reference steroidal AI used in clinic, with regard to the decrease in cell viability [ 20 , 31 ] and other conventional chemotherapeutic drugs [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

“…For this AI, it was reported that it affects the viability of ER + breast cancer cells [ 20 ] and presents promising anti-cancer properties in lung, liver, colon and prostate cancer cell lines by inducing cell cycle arrest, apoptosis and necrosis as well as DNA damage, and also by inhibiting the DNA damage response [ 31 ]. In addition, we previously verified that this molecule is more potent than Exe, the reference steroidal AI used in clinic, with regard to the decrease in cell viability [ 20 , 31 ] and other conventional chemotherapeutic drugs [ 31 ]. In this study, our results demonstrate that in sensitive MCF-7aro cells, Oxy dramatically affected the rate of DNA synthesis and impaired the progression of cell cycle by causing an arrest on G 0 /G 1 phase.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, it should be pointed that all these anti-cancer properties were observed at a dose ten times lower than the doses used in similar pre-clinical studies for the three AIs used in clinic [ 16 , 36 , 40 , 41 ]. Moreover, we had previously demonstrated that Oxy is more potent than Exe with regard to the decrease in cell viability [ 20 , 31 ] and even more potent than other conventional chemotherapeutic drugs [ 31 ]. In addition, this multi-target compound also has the ability to re-sensitize resistant breast cancer cells by activating apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…Actually, Oxy is a potent AI in human placental microsomes (IC 50 of 0.81 µM) and in ER + breast cancer cells (MCF-7aro) (IC 50 of 1.18 µM), reducing MCF-7aro cells viability in an aromatase-dependent manner, being in this last case more potent than Exe [ 20 ]. In addition, our group demonstrated that Oxy can also reduce the viability of lung, liver, colon and prostate cancer cell lines, even being considered to be a more potent anti-cancer molecule than other conventional chemotherapeutic drugs [ 31 ].…”

Section: Introductionmentioning

confidence: 99%

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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

et al. 2023

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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.

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