Design, synthesis, biological activity evaluation and structure-activity relationships of new steroidal aromatase inhibitors. The case of C-ring and 7β substituted steroids.

In this work, new steroidal aromatase inhibitors (AIs) were designed, synthesized, and tested. In one approach, C-ring substituted steroids namely those functionalized at C-11 position with an α or β hydroxyl group or with a carbonyl group as well as C-9/C-11 steroidal olefins and epoxides were studied. It was found that the carbonyl group at C-11 is more beneficial for aromatase inhibition than the hydroxyl group, and that the C-ring epoxides were more potent than the C-ring olefins, leading to the discovery of a very strong AI, compound 7, with an IC of 0.

Effects of PI3K inhibition in AI-resistant breast cancer cell lines: autophagy, apoptosis, and cell cycle progression.

Introduction: Breast cancer is the leading cause of cancer death in women. The aromatase inhibitors (AIs), Anastrozole (Ana), Letrozole (Let), and Exemestane (Exe) are a first-line treatment option for estrogen receptor-positive (ER) breast tumors, in postmenopausal women. Nevertheless, the development of acquired resistance to this therapy is a major drawback.

Differential biological effects of aromatase inhibitors: Apoptosis, autophagy, senescence and modulation of the hormonal status in breast cancer cells.

Estrogen receptor-positive (ER) breast carcinomas are the most common subtype, corresponding to 60% of the cases in premenopausal and 75% in postmenopausal women. The third-generation of aromatase inhibitors (AIs), the non-steroidal Anastrozole (Ana) and Letrozole (Let) and the steroidal Exemestane (Exe), are considered a first-line endocrine therapy for postmenopausal women. Despite their clinical success, the development of resistance is the major setback in clinical practice.

The anti-cancer potential of crotoxin in estrogen receptor-positive breast cancer: Its effects and mechanism of action.

Estrogen receptor-positive (ER) breast cancer is the most diagnosed subtype of breast cancer. Currently, aromatase inhibitors (AIs) are used as first-line treatment option in this type of tumors, however they cause several side effects, which is why new therapeutic approaches are demanding. The South American rattlesnake Crotalus durissus terrificus produces a venom enriched in several bioactive substances, like phospholipases A (PLA).

Discovery of a multi-target compound for estrogen receptor-positive (ER) breast cancer: Involvement of aromatase and ERs.

Despite intense research, breast cancer remains the leading cause of cancer-related death in women worldwide, being estrogen receptor-positive (ER) the most common subtype. Nowadays, aromatase inhibitors (AIs), the selective estrogen receptor modulator (SERM) tamoxifen and the selective estrogen receptor down-regulator (SERD) fulvestrant are used as therapeutic options for ER breast cancer, since they interfere directly with the production of estrogens and with the activation of estrogen-dependent signaling pathways. Despite the success of these treatments, the occurrence of resistance limits their clinical efficacy, demanding the development of novel therapies.

The potential clinical benefit of targeting androgen receptor (AR) in estrogen-receptor positive breast cancer cells treated with Exemestane.

The development of acquired resistance to the aromatase inhibitors (AIs) used in clinic is being considered the major concern in estrogen-receptor positive (ER) breast cancer therapy. Recently, androgen receptor (AR) has gained attention in the clinical setting, since it has been implicated in AIs-resistance, although, different roles for AR in cell fate have been described. In this work, our group elucidates, for the first time, the oncogenic role of AR in sensitive and resistant ER breast cancer cells treated with the potent third-generation steroidal AI Exemestane (Exe).

Effects of new C6-substituted steroidal aromatase inhibitors in hormone-sensitive breast cancer cells: Cell death mechanisms and modulation of estrogen and androgen receptors.

Estrogen receptor-positive (ER) breast cancers require estrogens for their growth. Aromatase inhibitors (AIs) are considered the first-line therapy for this type of tumours. Despite the well-established clinical benefit of this therapy, the search for novel potent AIs that present higher efficacy and fewer side effects is still demanded.

A novel GC-MS methodology to evaluate aromatase activity in human placental microsomes: a comparative study with the standard radiometric assay.

Estrogens are key factors in the development of the estrogen receptor-positive (ER) breast cancer. Estrogens, estrone (E), and estradiol (E) production is achieved by aromatase, a cytochrome P450 enzyme that has androgens, androstenedione (AD), and testosterone (T) as substrates. Nowadays, third-generation aromatase inhibitors (AIs) are considered the gold-standard treatment for ER breast cancer in postmenopausal women as well as in premenopausal women with ovary ablation.

Hormone-dependent breast cancer: Targeting autophagy and PI3K overcomes Exemestane-acquired resistance.

The leading cause of cancer death in women around the world is breast cancer. The aromatase inhibitors (AIs) are considered - as first-line treatment for estrogen receptor-positive (ER) breast tumors, in postmenopausal women. Exemestane (Exe) is a powerful steroidal AI, however, despite its therapeutic success, Exe-acquired resistance may occur leading to tumor relapse.

Acquired resistance to aromatase inhibitors: where we stand!

Aromatase inhibitors (AIs) are one of the principal therapeutic approaches for estrogen receptor-positive (ER) breast cancer in postmenopausal women. They block estrogen biosynthesis through aromatase inhibition, thus preventing tumour progression. Besides the therapeutic success of the third-generation AIs, acquired resistance may develop, leading to tumour relapse.