In search of new anti-breast cancer agents, the present study envisaged the design and synthesis of a series of benzopyran-chalcones. All the synthesized compounds were assayed for their in-vitro ...anticancer activity against ER + MCF-7 and triple-negative MDA-MB-231 breast cancer cell lines using SRB assay. The synthesized compounds were found active against ER + MCF-7 cell lines. Based on the in-vitro data, in-silico analysis was performed using hormone-dependent breast cancer targets such as hER-α and aromatase because the compounds showed activity against MCF-7 cells and none was active against MDA-MB-231. The in-silico results supported the in-vitro anticancer activity suggesting the affinity of compounds toward hormone-dependant breast cancer. Compounds 4A1 to 4A3 were found to be most cytotoxic to MCF-7 cells with IC
50
values of 31.87, 22.95, and 20.34 μg/ml, respectively (Doxorubicin IC
50
: <10 μg/ml). In addition, they showed the interactions with the amino acid residues of a binding cavity of an hER-α. Furthermore, quantitative structure-activity relationship (QSAR) studies were performed to reveal the vital structural features required for anticancer activity against breast cancer. Molecular dynamic simulation studies of hER-α and 4A3 in comparison with the raloxifene complex ensure the appropriate refinement of compounds in the dynamic system. Additionally, a generated pharmacophore model explored the essential pharmacophoric features of the synthesized scaffolds with respect to clinically used drug molecules for optimal hormone-dependant anti-breast cancer activity.
Communicated by Ramaswamy H. Sarma
Communicated by Ramaswamy H. Sarma
p-Coumaric acid is derived from cinnamic acid and is one of the major compounds in the Brazilian green propolis extract. Studies have shown that both p-coumaric acid and cinnamic acid have promising ...antiproliferative effects. In this context, aiming to increase the complexity of these active natural products and their activities, we performed coupling reactions with propargylamine and benzylamine, as well as with threonine, phenylalanine and lysine amino acids, aiming to enhance their antiproliferative effects towards the hormone-dependent breast cancer MCF-7 cells. Overall, the p-coumaric acid coupling with L-threonine amino acid (compound 15) had the best selectivity index (SI = 5.1), with half-maximal inhibitory concentration of 39.6 ± 1 μM, showing a high selectivity against hormone-dependent breast cancer cell lines MCF-7 and low cytotoxicity against the normal breast cell lines MCF-10A. Thus, this new natural product derivative may represent a prototype for the future development of antiproliferative agents, especially against hormone-dependent breast cancer.
Breast cancer (BC) ranks first in the morbidity pattern among women in Russia. Adjuvant endocrinotherapy is an important step in the complex treatment of premenopausal patients with hormone-positive ...early breast cancer. The drug ovarian suppression with GnRH-agonists have supplanted surgical castration and radiation-based treatment of the ovaries in patients with hormone-positive early breast cancer. Today, several drugs authorised for the treatment of breast cancer are used in clinical practice: goserelin, buserelin and triptorelin. Buserelin-depo is an effective method for achieving ovarian suppression. The results obtained do not differ from similar indicators obtained in using imported LHRH analogues.
The prevalence of breast cancer is steadily increasing with metastasis and thromboembolic complications identified as the most common causes of death. The acquisition of an aggressive phenotype by ...hormone-dependent breast cancers is mediated by Transforming Growth Factor Beta 1 (TGF-β
1
) expression and is associated with epithelial-mesenchymal transition (EMT) and, potentially, increased propensity for thrombosis. We investigated this phenomenon by assessing the effect of platelet-rich plasma (PRP) and whole blood (WB) on parameters of EMT and hypercoagulation in vitro. MCF-7 breast cancer cells were cultured under standard conditions, followed by co-culture with PRP or WB. Cells were processed for real-time PCR (TGF-β
1
and vimentin), electron microscopy or immunocytochemistry (TGF-β
1
). Micrographs were qualitatively assessed, and real-time PCR data analyzed with PAST Statistical Software. The addition of blood components heightened TGF-β
1
immunolocalization and significantly increased corresponding gene expression. Both PRP and WB significantly increased vimentin expression and induced a shape change from a typical epithelial phenotype to a spindle-shape morphology, indicative of EMT. Fibrin fiber, network and plaque formation indicated a hypercoagulatory environment. The results thus show that in preparation for hematogenous metastasis, hormone-dependent breast cancer cells assume an aggressive phenotype associated with EMT, simultaneously increasing the propensity for the formation of thrombo-emboli.
Unravelling exemestane: From biology to clinical prospects Sobral, Ana Filipa; Amaral, Cristina; Correia-da-Silva, Georgina ...
The Journal of steroid biochemistry and molecular biology,
October 2016, 2016-10-00, 20161001, Letnik:
163
Journal Article
Recenzirano
•Biological effects of exemestane and its metabolites are reviewed.•Therapy resistance mechanisms to exemestane are described.•Clinical trials on exemestane are compiled.
Aromatase inhibitors (AIs) ...are anti-tumor agents used in clinic to treat hormone-dependent breast cancer. AIs block estrogens biosynthesis by inhibiting the enzyme aromatase, preventing tumor progression. Exemestane, a third-generation steroidal AI, belongs to this class of drugs and is currently used in clinic to treat postmenopausal women, due to its high efficacy and good tolerability. Here, its pharmacological and biological aspects as well as its clinical applications and comparison to other endocrine therapeutic agents, are reviewed. It is also focused the benefits and risks of exemestane, drawbacks to be overcome and aspects to be explored.
According with the present-day ideas, sequential lines of hormone therapy including those in patients with visceral metastases and multiple lesions form the basis of the treatment of HER2-negative ...metastatic hormone-dependent breast cancer. These measures make it possible to exercise the long-term control of the disease and maintain a good quality of life. In recent years, the clinical practice comprises the next-generation drugs that potentiate the effect of hormone therapy. These include cyclindependent kinases 4/6 inhibitors. Palbociclib (Ibransa, Pfizer) is the first representative of this class approved in Russia for the treatment of disseminated hormone-dependent breast cancer. The PALOMA-2 study demonstrated the high efficacy of the palbociclib combined with letrozole as a first-line hormone therapy. In the palbociclib and letrozole combination arm, the median time to progression was 27,6 months compared to 14,5 months in the letrozole monotherapy arm (p <0,001). The presented clinical case demonstrates the possibility of long-term successful control of the disease using palbociclib combined with letrozole hormone therapy.
Exemestane is a third-generation steroidal aromatase inhibitor that has been used in clinic for hormone-dependent breast cancer treatment in post-menopausal women. It is known that exemestane ...undergoes a complex metabolization, giving rise to some already identified metabolites, the 17β-hydroxy-6-methylenandrosta-1,4-dien-3-one (17-βHE) and the 6-(hydroxymethyl)androsta-1,4,6-triene-3,17-dione (6-HME). In this study, four metabolites of exemestane have been analyzed, three of them were synthesized (6β-spirooxiranandrosta-1,4-diene-3,17-dione (2), 1α,2α-epoxy-6-methylenandrost-4-ene-3,17-dione (3) and 17-βHE (4)) while one was acquired, the 6-HME (6). The stereochemistry of the epoxide group of 2 and 3 has been unequivocally elucidated for the first time on the basis of NOESY experiments. New structure–activity relationships (SAR) have been established through the observation that the substitution of the double bonds by epoxide groups led to less potent derivatives in microsomes. However, the reduction of the C-17 carbonyl group to a hydroxyl group originating 17-βHE (4) resulted in a significant increase in activity in MCF-7aro cells when compared to exemestane (IC50 0.25 μM vs 0.90 μM, respectively). All the studied metabolites reduced MCF-7aro cells viability in a dose and time-dependent manner, and metabolite 3 was the most potent one. Altogether our results showed that not only exemestane but also its main metabolites are potent aromatase inhibitors and reduce breast cancer cells viability. This suggests that exemestane efficacy may also be due to the active metabolites that result from its metabolic transformation. Our results emphasize the importance of performing further studies to expand our understanding of exemestane actions in breast cancer cells.
Display omitted
•Study of the anti-aromatase activity of four exemestane metabolites.•The stereochemistry of two metabolites was elucidated for the first time.•New structure–activity relationships for exemestane metabolites were established.•Metabolites strongly inhibit aromatase and reduced breast cancer cells viability.•Exemestane efficacy may also be due to the active metabolites.
Nuclear receptors such as the estrogen receptors (ERα and ERβ) modulate the effects of the estrogen hormones and are important targets for design of innovative chemotherapeutic agents for diseases ...such as breast cancer and osteoporosis. Conjugate and bifunctional compounds which incorporate an ER ligand offer a useful method of delivering cytotoxic drugs to tissue sites such as breast cancers which express ERs. A series of novel conjugate molecules incorporating both the ER ligands endoxifen and cyclofenil-endoxifen hybrids covalently linked to the antimitotic and tubulin targeting agent combretastatin A-4 were synthesised and evaluated as ER ligands. A number of these compounds demonstrated pro-apoptotic effects, with potent antiproliferative activity in ER-positive MCF-7 breast cancer cell lines and low cytotoxicity. These conjugates displayed binding affinity towards ERα and ERβ isoforms at nanomolar concentrations e.g., the cyclofenil-amide compound
is a promising lead compound of a clinically relevant ER conjugate with IC
in MCF-7 cells of 187 nM, and binding affinity to ERα (IC
= 19 nM) and ERβ (IC
= 229 nM) while the endoxifen conjugate
demonstrates antiproliferative activity in MCF-7 cells (IC
= 5.7 nM) and binding affinity to ERα (IC
= 15 nM) and ERβ (IC
= 115 nM). The ER binding effects are rationalised in a molecular modelling study in which the disruption of the ER helix-12 in the presence of compounds
,
and
is presented These conjugate compounds have potential application for further development as antineoplastic agents in the treatment of ER positive breast cancers.
Development of steroid sulfatase inhibitors Woo, L.W. Lawrence; Purohit, Atul; Potter, Barry V.L.
Molecular and cellular endocrinology,
07/2011, Letnik:
340, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Hydrolysis of biologically inactive steroid sulfates to unconjugated steroids by steroid sulfatase (STS) is strongly implicated in rendering estrogenic stimulation to hormone-dependent cancers such ...as those of the breast. Considerable progress has been made in the past two decades with regard to the discovery, design and development of STS inhibitors. We outline historical aspects of their development, cumulating in the discovery of the first clinical trial candidate STX64 (BN83495, Irosustat) and other sulfamate-based inhibitors. The development of reversible STS inhibitors and the design of dual inhibitors of both aromatase and STS is also discussed.
Treatment of choice of metastatic hormone-dependent breast cancer regardless of age is hormone therapy (HT) even with visceral metastases. Now we have a new class of drugs called inhibitors of ...cyclin-dependent kinases 4/6, which significantly increase effectiveness of HT and prevent development of resistance to HT. In MONALEESA-7 inhibitor of cyclin-dependent kinases 4/6 ribociclib was studied in combination with ovarian suppression and hormone therapy in young patients with preserved ovarian function, and found no differences in the efficacy and safety of these drugs compared with menopausal patients. Our clinical experience strongly demonstrates the safety and efficacy of ribociclib in combination with HT and ovarian suppression in premenopausal patient with visceral metastases.
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