Recent developments in steroidal and nonsteroidal aromatase inhibitors for the chemoprevention of estrogen-dependent breast cancer

Ahmad, Irshad; Shagufta,

doi:10.1016/j.ejmech.2015.08.010

Cited by 98 publications

(44 citation statements)

References 91 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[28][29][30] The presence of high concentrations of estrogen in breast tissue increases the risk of developing breast cancer and the ability of immature breast tissue cells to strongly bind to carcinogens, decreasing their DNA repair capacity. 31,32) Aromatase, a CYP19 enzyme, is the rate-limiting enzyme in the conversion of testosterone and androstenedione to the estrogens, estrone and estradiol. [26][27][28][29][30][32][33][34] It is involved in the final step of the estrogen biosynthetic pathway and its selective inhibition will not affect the production of other steroids in the pathway.…”

Section: Resultsmentioning

confidence: 99%

“…[26][27][28][29][30][32][33][34] It is involved in the final step of the estrogen biosynthetic pathway and its selective inhibition will not affect the production of other steroids in the pathway. 32,[35][36][37] The source of estrogen production in breast cancer tissues is intratumoral aromatase, and thus, inhibition of aromatase may inhibit the growth stimulation effect of estrogens in breast cancer tissues. Therefore, aromatase is considered a useful therapeutic target in the treatment and prevention of estrogen-dependent breast cancer.…”

Section: Effects Of the Methanol Extract From The Flowers Of M Siamementioning

confidence: 99%

See 1 more Smart Citation

Aromatase Inhibitory Activity of Geranylated Coumarins, Mammeasins C and D, Isolated from the Flowers of <i>Mammea siamensis</i>

et al. 2016

View full text Add to dashboard Cite

Key words Mammea siamensis; mammeasin; aromatase inhibitor; geranylated coumarin; Calophyllaceae Mammea siamensis (MIQ.) T. ANDERS. is a species of flowering plant in the Calophyllaceae family and is widely distributed in Thailand, Laos, Cambodia, Vietnam, and Myanmar. The flowers of this plant have been used for preparing a heart tonic in Thai traditional medicine ("Sarapi" in Thai). [1][2][3][4][5][6][7][8][9][10] Several coumarins, [1][2][3][4][5][6][7] xanthones, 8,9) triterpenoids, 10) and steroids 10) have been isolated from the flowers, 1,2,6,7,10) seeds, 3,9) twigs, 4,8) and bark 5) of this plant. In the course of our characterization studies on bioactive constituents in Thai natural medicine, 1,[11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] we reported that the methanol extract of the flowers of M. siamensis and its coumarin constituents showed inhibitory effects on nitric oxide production in lipopolysaccharide-activated RAW264.7 cells.1) Further studies revealed that the methanol extract inhibited enzymatic activity against aromatase. Separation of the active constituents in the extract allowed us to isolate two new geranylated coumarins, mammeasins C (1) and D (2). This paper describes the isolation and structure elucidation of these new coumarins (1, 2) and the inhibitory effects of the coumarin constituents (1-26) on aromatase. 26) Results and Discussion Effects of the Methanol Extract from the Flowers of M. siamensis against Human Recombinant AromataseBreast cancer is one of the most common reasons for mortality in women. 26,27) Estrogens and estrogen receptors are well known to play an important role in the development and progression of hormone-dependent breast cancer; for this reason, estrogens and estrogen receptors are widely studied molecular targets. [28][29][30] The presence of high concentrations of estrogen in breast tissue increases the risk of developing breast cancer and the ability of immature breast tissue cells to strongly bind to carcinogens, decreasing their DNA repair capacity. 31,32) Aromatase, a CYP19 enzyme, is the rate-limiting enzyme in the conversion of testosterone and androstenedione to the estrogens, estrone and estradiol. [26][27][28][29][30][32][33][34] It is involved in the final step of the estrogen biosynthetic pathway and its selective inhibition will not affect the production of other steroids in the pathway. 32,[35][36][37] The source of estrogen production in breast cancer tissues is intratumoral aromatase, and thus, inhibition of aromatase may inhibit the growth stimulation effect of estrogens in breast cancer tissues. Therefore, aromatase is considered a useful therapeutic target in the treatment and prevention of estrogen-dependent breast cancer. 32)The dried flowers of M. siamensis (collected from Nakhonsithammarat Province, Thailand) were extracted with methanol under reflux (25.66% from the dried flowers). The methanol extract was partitioned into an EtOAc-H 2 O (1 : 1, v/v) mixture to furnish an EtOAc-soluble fraction (6.84%) and an aqueous ...

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Effects Of the Methanol Extract From The Flowers Of M Siamementioning

confidence: 99%

Aromatase Inhibitory Activity of Geranylated Coumarins, Mammeasins C and D, Isolated from the Flowers of <i>Mammea siamensis</i>

et al. 2016

View full text Add to dashboard Cite

show abstract

“…[49][50] The former, such as exemestane (EXE) or formestane, have similar structure to natural substrate ASD and hence they act as pseudo substrates of aromatase. In such a way, these inhibitors irreversibly bind the enzyme active site and thus are considered as a mechanism-based inactivators or suicidal inhibitors.…”

Section: Methodsmentioning

confidence: 99%

Theoretical Study of the Mechanism of Exemestane Hydroxylation Catalyzed by Human Aromatase Enzyme

Viciano

Martí

2016

J. Phys. Chem. B

View full text Add to dashboard Cite

Human aromatase (CYP19A1) aromatizes the androgens to form estrogens via a three-step oxidative process.The estrogens are necessary in humans, mainly in women, because of the role they play in the sexual and reproductive development. However, these also are involved in the development and growth of hormonedependent breast cancer. Therefore, inhibition of the enzyme aromatase, by means of drugs known as aromatase inhibitors, is the frontline therapy for these types of cancers. Exemestane is a suicidal third-generation inhibitor of aromatase, currently used in the breast cancer treatment. In this study, the hydroxylation of exemestane catalyzed by aromatase has been studied by means of hybrid QM/MM methods. The Free Energy Perturbation calculations provided a free energy of activation for the hydrogen abstraction step (rate-limiting step) of 17 kcal/mol. The results reveal that the hydroxylation of exemestane is not the inhibition stage suggesting a possible competitive mechanism between the inhibitor and the natural substrate androstenedione in the first catalytic subcycle of the enzyme. Furthermore, the analysis of the interaction energy for the substrate and the cofactor in the active site, shows that the role of the enzymatic environment during this reaction consists of a transition state stabilization by means of electrostatic effects.3

show abstract

“…In summary, a unique molecule, melatonin, has anti-estrogenic properties: It selectively counterbalances the actions of estrogens in both normal and tumor breast tissues, and provides a novel strategy to reduce the local biosynthesis of estrogens from androgens (which in turn, is one of the principal objectives of antitumor pharmacological therapy) (115). These cumulative actions of the pineal hormone point to its potential application as an anticancer molecule in both the prevention and treatment of estrogen-positive tumors, since, as it has been pointed above, this molecule acts at different levels by interfering with estradiol-dependent signaling pathways, both in tumor cells and in the surrounding endothelial cells and fibroblasts (116).…”

Section: Melatonin and Mammary Cancer: In Vitro And Animal Studiesmentioning

confidence: 99%

What is known about melatonin, chemotherapy and altered gene expression in breast cancer

et al. 2017

View full text Add to dashboard Cite

Melatonin, synthesized in and released from the pineal gland, has been demonstrated by multiple in vivo and in vitro studies to have an oncostatic role in hormone-dependent tumors. Furthermore, several clinical trials point to melatonin as a promising adjuvant molecule to be considered for cancer treatment. In the past few years, evidence of a broader spectrum of action of melatonin as an antitumor agent has arisen; thus, melatonin appears to also have therapeutic effects in several types of hormone-independent cancer, including ovarian, leukemic, pancreatic, gastric and non-small cell lung carcinoma. In the present study, the latest findings regarding melatonin molecular actions when concomitantly administered with either radiotherapy or chemotherapy in cancer were reviewed, with a particular focus on hormone-dependent breast cancer. Finally, the present study discusses which direction should be followed in the next years to definitely clarify whether or not melatonin administration could protect against non-desirable effects (such as altered gene expression and post-translational protein modifications) caused by chemotherapy or radiotherapy treatments. As treatments move towards personalized medicine, comparative gene expression profiling with and without melatonin may be a powerful tool to better understand the antitumor effects of melatonin, the pineal gland hormone.

show abstract

Recent developments in steroidal and nonsteroidal aromatase inhibitors for the chemoprevention of estrogen-dependent breast cancer

Cited by 98 publications

References 91 publications

Aromatase Inhibitory Activity of Geranylated Coumarins, Mammeasins C and D, Isolated from the Flowers of <i>Mammea siamensis</i>

Aromatase Inhibitory Activity of Geranylated Coumarins, Mammeasins C and D, Isolated from the Flowers of <i>Mammea siamensis</i>

Theoretical Study of the Mechanism of Exemestane Hydroxylation Catalyzed by Human Aromatase Enzyme

What is known about melatonin, chemotherapy and altered gene expression in breast cancer

Contact Info

Product

Resources

About