New steroidal aromatase inhibitors: Suppression of estrogen-dependent breast cancer cell proliferation and induction of cell death

<p>Abstract</p> <p>Background</p> <p>Aromatase, the cytochrome P-450 enzyme (CYP19) responsible for estrogen biosynthesis, is an important target for the treatment of estrogen-dependent breast cancer. In fact, the use of synthetic aromatase inhibitors (AI), which induce suppression of estrogen synthesis, has shown to be an effective alternative to the classical tamoxifen for the treatment of postmenopausal patients with ER-positive breast cancer. New AIs obtained, in our laboratory, by modification of the A and D-rings of the natural substrate of aromatase, compounds <b>3a </b>and <b>4a</b>, showed previously to efficiently suppress aromatase activity in placental microsomes. In the present study we have investigated the effects of these compounds on cell proliferation, cell cycle progression and induction of cell death using the estrogen-dependent human breast cancer cell line stably transfected with the aromatase gene, MCF-7 aro cells.</p> <p>Results</p> <p>The new steroids inhibit hormone-dependent proliferation of MCF-7aro cells in a time and dose-dependent manner, causing cell cycle arrest in G₀/G₁phase and inducing cell death with features of apoptosis and autophagic cell death.</p> <p>Conclusion</p> <p>Our <it>in vitro </it>studies showed that the two steroidal AIs, <b>3a </b>and <b>4a</b>, are potent inhibitors of breast cancer cell proliferation. Moreover, it was also shown that the antiproliferative effects of these two steroids on MCF-7aro cells are mediated by disrupting cell cycle progression, through cell cycle arrest in G₀/G₁phase and induction of cell death, being the dominant mechanism autophagic cell death. Our results are important for the elucidation of the cellular effects of steroidal AIs on breast cancer.</p

Synthesis and biochemical studies of 17-substituted androst-3-enes and 3,4-epoxyandrostanes as aromatase inhibitors

http://www.sciencedirect.com/science/article/B6TC9-4T0WJXG-2/2/58305e64e3c068f352293a693f168db

Plant derived and dietary phenolic antioxidants: Anticancer properties

n this paper, a review of the literature on the phenolic compounds with anticancer activity published between 2008 and 2012 is presented. In this overview only phenolic antioxidant compounds that display significant anticancer activity have been described. In the first part of this review, the oxidative and nitrosative stress relation with cancer are described. In the second part, the plant-derived food extracts, containing identified phenolic antioxidants, the phenolic antioxidants isolated from plants and plant-derived food or commercially available and the synthetic ones, along with the type of cancer and cells where they exert anticancer activity, are described and summarized in tables. The principal mechanisms for their anti-proliferative effects were also described. Finally, a critical analysis of the studies and directions for future research are included in the conclusion

The Structural Diversity and Biological Activity of Steroid Oximes

Steroids and their derivatives have been the subject of extensive research among investigators due to their wide range of pharmacological properties, in which steroidal oximes are included. Oximes are a chemical group with the general formula R1R2C=N−OH and they exist as colorless crystals and are poorly soluble in water. Oximes can be easily obtained through the condensation of aldehydes or ketones with various amine derivatives, making them a very interesting chemical group in medicinal chemistry for the design of drugs as potential treatments for several diseases. In this review, we will focus on the different biological activities displayed by steroidal oximes such as anticancer, anti-inflammatory, antibacterial, antifungal and antiviral, among others, as well as their respective mechanisms of action. An overview of the chemistry of oximes will also be reported, and several steroidal oximes that are in clinical trials or already used as drugs are described. An extensive literature search was performed on three main databases—PubMed, Web of Science, and Google Scholar

The Structural Diversity and Biological Activity of Steroid Oximes

Steroids and their derivatives have been the subject of extensive research among investigators due to their wide range of pharmacological properties, in which steroidal oximes are included. Oximes are a chemical group with the general formula R1R2C=N&minus;OH and they exist as colorless crystals and are poorly soluble in water. Oximes can be easily obtained through the condensation of aldehydes or ketones with various amine derivatives, making them a very interesting chemical group in medicinal chemistry for the design of drugs as potential treatments for several diseases. In this review, we will focus on the different biological activities displayed by steroidal oximes such as anticancer, anti-inflammatory, antibacterial, antifungal and antiviral, among others, as well as their respective mechanisms of action. An overview of the chemistry of oximes will also be reported, and several steroidal oximes that are in clinical trials or already used as drugs are described. An extensive literature search was performed on three main databases&mdash;PubMed, Web of Science, and Google Scholar

Lipophilic Caffeic and Ferulic Acid Derivatives Presenting Cytotoxicity against Human Breast Cancer Cells

In the present work, lipophilic caffeic and ferulic acid derivatives were synthesized, and their cytotoxicity on cultured breast cancer cells was compared. A total of six compounds were initially evaluated: caffeic acid (CA), hexyl caffeate (HC), caffeoylhexylamide (HCA), ferulic acid (FA), hexyl ferulate (HF), and feruloylhexylamide (HFA). Cell proliferation, cell cycle progression, and apoptotic signaling were investigated in three human breast cancer cell lines, including estrogen-sensitive (MCF-7) and insensitive (MDA-MB-231 and HS578T). Furthermore, direct mitochondrial effects of parent and modified compounds were investigated by using isolated liver mitochondria. The results indicated that although the parent compounds presented no cytotoxicity, the new compounds inhibited cell proliferation and induced cell cycle alterations and cell death, with a predominant effect on MCF-7 cells. Interestingly, cell cycle data indicates that effects on nontumor BJ fibroblasts were predominantly cytostatic and not cytotoxic. The parent compounds and derivatives also promoted direct alterations on hepatic mitochondrial bioenergetics, although the most unexpected and never before reported one was that FA induces the mitochondrial permeability transition. The results show that the new caffeic and ferulic acid lipophilic derivatives show increased cytotoxicity toward human breast cancer cell lines, although the magnitude and type of effects appear to be dependent on the cell type. Mitochondrial data had no direct correspondence with effects on intact cells suggesting that this organelle may not be a critical component of the cellular effects observed. The data provide a rational approach to the design of effective cytotoxic lipophilic hydroxycinnamic derivatives that in the future could be profitably applied for chemopreventive and/or chemotherapeutic purposes

New steroidal 17b-carboxy derivatives present anti-5a-reductase activity and anti-proliferative effects in a human androgen-responsive prostate cancer cell line

The androgens testosterone (T) and dihydrotestosterone (DHT), besides playing an important role in prostate development and growth, are also responsible for the development and progression of benign prostate hyperplasia (BPH) and prostate cancer. Therefore, the actions of these hormones can be antagonized by preventing the irreversible conversion of T into DHT by inhibiting 5a-reductase (5a-R). This has been a useful therapeutic approach for the referred diseases and can be achieved by using 5areductase inhibitors (RIs). Steroidal RIs, finasteride and dutasteride, are used in clinic for BPH treatment and were also proposed for chemoprevention of prostate cancer. Nevertheless, due to the increase in bone and muscle loss, impotency and occurrence of high-grade prostate tumours, it is important to seek for other potent and specific molecules with lower side effects. In the present work, we designed and synthesized steroids with the 3-keto-D4 moiety in the A-ring, as in the 5a-R substrate T, and with carboxamide, carboxyester or carboxylic acid functions at the C-17b position. The inhibitory 5a-R activity, in human prostate microsomes, as well as the anti-proliferative effects of the most potent compounds, in a human androgen-responsive prostate cancer cell line (LNCaP cells), were investigated. Our results showed that steroids 3, 4 and 5 are good RIs, which suggest that C-17b lipophylic amides favour 5a-R inhibition. Moreover, these steroids induce a decrease in cell viability of stimulated LNCaP cells, in a 5a-R dependent-manner, similarly to finasteride.The authors are grateful to Fundação para a Ciência e Tecnologia (FCT) for the strategic project PEst-OE/SAU/UI0177/2011 and for the PhD grants attributed to Cristina Amaral and Carla Varela (SFRH/ BD/48190/2008 and SFRH/BD/44872/2008, respectively). Sara C. Cunha is grateful to “Subprograma Ciência e Tecnologia do 3 Quadro Comunitário de Apoio” for grant SFRH/BPD/41854/2007. We also acknowledge the “Rede Nacional de RMN” (REDE/1517/ RMN/2005) for access to the facilities. This work was funded by FEDER Funds through the Operational Competitiveness Program- COMPETE and by National Funds through FCT under the project FCOMP-01-0124-FEDER-020970 (PTDC/QUI-BIQ/120319/2010)

Lipophilic Caffeic and Ferulic Acid Derivatives Presenting Cytotoxicity against Human Breast Cancer Cells

In the present work, lipophilic caffeic and ferulic acid derivatives were synthesized, and their cytotoxicity on cultured breast cancer cells was compared. A total of six compounds were initially evaluated: caffeic acid (CA), hexyl caffeate (HC), caffeoylhexylamide (HCA), ferulic acid (FA), hexyl ferulate (HF), and feruloylhexylamide (HFA). Cell proliferation, cell cycle progression, and apoptotic signaling were investigated in three human breast cancer cell lines, including estrogen-sensitive (MCF-7) and insensitive (MDA-MB-231 and HS578T). Furthermore, direct mitochondrial effects of parent and modified compounds were investigated by using isolated liver mitochondria. The results indicated that although the parent compounds presented no cytotoxicity, the new compounds inhibited cell proliferation and induced cell cycle alterations and cell death, with a predominant effect on MCF-7 cells. Interestingly, cell cyle data indicates that effects on nontumor BJ fibroblasts were predominantly cytostatic and not cytotoxic. The parent compounds and derivatives also promoted direct alterations on hepatic mitochondrial bioenergetics, although the most unexpected and never before reported one was that FA induces the mitochondrial permeability transition. The results show that the new caffeic and ferulic acid lipophilic derivatives show increased cytotoxicity toward human breast cancer cell lines, although the magnitude and type of effects appear to be dependent on the cell type. Mitochondrial data had no direct correspondence with effects on intact cells suggesting that this organelle may not be a critical component of the cellular effects observed. The data provide a rational approach to the design of effective cytotoxic lipophilic hydroxycinnamic derivatives that in the future could be profitably applied for chemopreventive and/or chemotherapeutic purposes.info:eu-repo/semantics/publishedVersio

New steroidal aromatase inhibitors: Suppression of estrogen-dependent breast cancer cell proliferation and induction of cell death-1

for 72 hr. Wright staining shows that cells treated with 4a have condensed and marginalized chromatin (arrowheads) and cytoplasm vacuolization (arrows) (C) in comparison to the control cells (A). Nuclear morphological changes in MCF-7aro cells were demonstrated by Hoechst 33258 staining under the fluorescence microscope. Untreated cells exhibited normal nuclear morphology and the presence of abundant mitotic figures (open arrows) (B). Treatment with 4a induced chromatin condensation (arrows) (D).<p><b>Copyright information:</b></p><p>Taken from "New steroidal aromatase inhibitors: Suppression of estrogen-dependent breast cancer cell proliferation and induction of cell death"</p><p>http://www.biomedcentral.com/1471-2121/9/41</p><p>BMC Cell Biology 2008;9():41-41.</p><p>Published online 24 Jul 2008</p><p>PMCID:PMC2515307.</p><p></p

New steroidal aromatase inhibitors: Suppression of estrogen-dependent breast cancer cell proliferation and induction of cell death-3

H the indicated concentrations of the compounds in medium containing 1 nM T. Cells cultured with testosterone represented maximum cell proliferation and were considered as control. 3a and 4a induced a decrease in cell proliferation, evaluated by the thymidine incorporation assay, in a time- and dose-dependent manner. Results are the mean ± SE of three independent experiments whereas cultures were performed in triplicate. Significant inhibition relative to the control level is denoted by * (< 0.001), ** (P < 0.01) and θ (P < 0.05).<p><b>Copyright information:</b></p><p>Taken from "New steroidal aromatase inhibitors: Suppression of estrogen-dependent breast cancer cell proliferation and induction of cell death"</p><p>http://www.biomedcentral.com/1471-2121/9/41</p><p>BMC Cell Biology 2008;9():41-41.</p><p>Published online 24 Jul 2008</p><p>PMCID:PMC2515307.</p><p></p