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

ABSTRACT: Aromatase is an enzyme that plays a crucial role in the biosynthesis of estrogens, which are hormones that contribute to the growth of certain types of breast cancer. In particular, aromatase catalyzes the conversion of androgens (male hormones) into estrogens (female hormones) in various tissues, including the adrenal glands, ovaries, and adipose tissue. Given the role of estrogen in promoting the growth of hormone-receptor-positive breast cancers, aromatase has become an important molecular target for the development of anticancer agents. Aromatase inhibitors can be classified into two main groups based on their chemical structure: steroidal and non-steroidal inhibitors. This work presents a review of the literature from the last ten years regarding the search for new aromatase inhibitors. We present the directions of search, taking into account the impact of structure modifications on anticancer activity.

SUBMITTER: Janowska S

PROVIDER: S-EPMC10819800 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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

Janowska Sara S Holota Serhii S Lesyk Roman R Wujec Monika M

Molecules (Basel, Switzerland) 20240110 2

Aromatase is an enzyme that plays a crucial role in the biosynthesis of estrogens, which are hormones that contribute to the growth of certain types of breast cancer. In particular, aromatase catalyzes the conversion of androgens (male hormones) into estrogens (female hormones) in various tissues, including the adrenal glands, ovaries, and adipose tissue. Given the role of estrogen in promoting the growth of hormone-receptor-positive breast cancers, aromatase has become an important molecular ta ...[more]

PMID: 38257259

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Project description:Background/Objectives: Endocrine therapies that comprise anti-estrogens and aromatase inhibitors (AIs) are the standard treatment for estrogen receptor-positive (ER+) (Luminal A) breast cancer-the most prevalent subtype. However, the emergence of resistance restricts their success by causing tumor relapse and re-growth, which demands a switch towards other therapeutic approaches in order to minimize or overcome resistance. Indeed, this clinical limitation highlights the search for new molecules to improve cancer treatment. Recently, strategies that address multiple targets have been emerging, and multi-target drugs have the potential to become the future anti-cancer molecules. Our group has been searching for new multi-target compounds, and as part of this, our study aims to understand the anti-cancer and multi-target potential of three new steroidal aromatase inhibitors (AIs): 7α-methylandrost-4-en-17-one (6), 7α-methylandrost-4-ene-3,17-dione (10a) and androsta-4,9(11)-diene-3,17-dione (13). Methods: Their in vitro actions and molecular mechanisms were elucidated in a sensitive ER+ aromatase-overexpressing breast cancer cell line, MCF-7aro cells, as well as in an AI-resistant ER+ breast cancer cell line, LTEDaro cells. Results: All the new AIs (10 µM) prevented the proliferation of MCF-7aro cells by arresting cell cycle progression. Interestingly, all AIs (10 µM) act as androgen receptor (AR) agonists and modulate ER levels, synthesis and signaling to induce the apoptosis of ER+ breast cancer cells. Additionally, these new AIs (10 µM) also re-sensitize resistant cells by promoting apoptosis, offering a therapeutic benefit. Conclusions: Overall, new steroidal polypharmacological compounds have been discovered that, by acting as AIs, ER modulators and AR agonists, impair ER+ breast cancer cell growth. Overall, this study is a breakthrough on drug discovery as it presents new molecules with appealing anti-cancer properties and multi-target action for the treatment of ER+ breast cancer.

Project description:BackgroundThe present study compares antiepileptic drugs and aromatase (CYP19) inhibitors for chemical and structural similarity. Human aromatase is well known as an important pharmacological target in anti-breast cancer therapy, but recent research demonstrates its role in epileptic seizures, as well. The current antiepileptic treatment methods cause severe side effects that endanger patient health and often preclude continued use. As a result, less toxic and more tolerable antiepileptic drugs (AEDs) are needed, especially since every individual responds differently to given treatment options.MethodsThrough a pharmacophore search, this study shows that a model previously designed to search for new classes of aromatase inhibitors is able to identify antiepileptic drugs from the set of drugs approved by the Food and Drug Administration. Chemical and structural similarity analyses were performed using five potent AIs, and these studies returned a set of AEDs that the model identifies as hits.ResultsThe pharmacophore model returned 73% (19 out of 26) of the drugs used specifically to treat epilepsy and approximately 82% (51 out of 62) of the compounds with anticonvulsant properties. Therefore, this study supports the possibility of identifying AEDs with a pharmacophore model that had originally been designed to identify new classes of aromatase inhibitors. Potential candidates for anticonvulsant therapy identified in this manner are also reported. Additionally, the chemical and structural similarity between antiepileptic compounds and aromatase inhibitors is proved using similarity analyses.ConclusionsThis study demonstrates that a pharmacophore search using a model based on aromatase inhibition and the enzyme's structural features can be used to screen for new candidates for antiepileptic therapy. In fact, potent aromatase inhibitors and current antiepileptic compounds display significant - over 70% - chemical and structural similarity, and the similarity analyses performed propose a number of antiepileptic compounds with high potential for aromatase inhibition.

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

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

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