RESUMO
BACKGROUND: Studies indicate that extracts and purified components, including carnosic acid, from the herb rosemary display significant growth inhibitory activity on a variety of cancers. PURPOSE: This paper examines the ability of rosemary/carnosic acid to inhibit the growth of human breast cancer cells and to synergize with curcumin. MATERIALS AND METHODS: To do this, we treated human breast cancer cells with rosemary/carnosic acid and assessed effects on cell proliferation, cell cycle distribution, gene expression patterns, activity of the purified Na/K ATPase and combinations with curcumin. RESULTS: Rosemary/carnosic acid potently inhibits proliferation of ER-negative human breast cancer cells and induces G1 cell cycle arrest. Further, carnosic acid is selective for MCF7 cells transfected for Her2, indicating that Her2 may function in its action. To reveal primary effects, we treated ER-negative breast cancer cells with carnosic acid for 6h. At a low dose, 5 µg/ml (15 µM), carnosic acid activated the expression of 3 genes, induced through the presence of antioxidant response elements, including genes involved in glutathione biosynthesis (CYP4F3, GCLC) and transport (SLC7A11). At a higher dose, 20 µg/ml, carnosic acid activated the expression of antioxidant (AKR1C2, TNXRD1, HMOX1) and apoptosis (GDF15, PHLDA1, DDIT3) genes and suppressed the expression of inhibitor of transcription (ID3) and cell cycle (CDKN2C) genes. Carnosic acid exhibits synergy with turmeric/curcumin. These compounds inhibited the activity of the purified Na-K-ATPase which may contribute to this synergy. CONCLUSION: Rosemary/carnosic acid, alone or combined with curcumin, may be useful to prevent and treat ER-negative breast cancer.
Assuntos
Abietanos/uso terapêutico , Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Curcuma/química , Curcumina/uso terapêutico , Fitoterapia , Extratos Vegetais/uso terapêutico , Rosmarinus/química , Abietanos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Apoptose/genética , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Proliferação de Células/efeitos dos fármacos , Curcumina/farmacologia , Sinergismo Farmacológico , Feminino , Expressão Gênica/efeitos dos fármacos , Glutationa/genética , Glutationa/metabolismo , Humanos , Proteínas Inibidoras de Diferenciação/metabolismo , Células MCF-7 , Proteínas de Neoplasias/metabolismo , Extratos Vegetais/farmacologia , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismoRESUMO
BACKGROUND: Numerous studies have suggested that digitalis derivatives promise to be superior to existing adjuvant therapy for breast cancer as to effects and side-effects. In the present study, we have used gene expression analysis to determine the molecular action of digitoxin on breast cancer cells and assessed digitoxin's ability to synergize with the chemotherapy agent paclitaxel with respect to inhibition of cell proliferation MATERIALS AND METHODS: We treated (Her2 overexpressing, ER low) MDA-MB-453 human breast cancer cells with digitoxin at four doses {20 ng/ml (26 nM) to 1 µg/ml} and collected RNA at 6 h and 24 h for gene expression analysis. To examine the effects on ER positive cells, we treated MCF7 cells with digitoxin at 1 µg/ml and collected RNA for RT-PCR analysis. In addition, we assayed the growth inhibitory effect of low doses of digitoxin combined with paclitaxel and determined combination index values. RESULTS: To reveal primary effects, we examined digitoxin's effect 6 h post-treatment with the highest dose, 1µg/ml, and found upregulation of the stress response genes EGR-1 and NAB2, lipid biosynthetic genes and the tumor suppressor gene p21, and downregulation of the mitotic cell cycle gene CDC16 and the replication gene PolR3B. RT-PCR analysis validated effects on stress response, apoptotic and cell cycle genes on MDA-MB-453 and MCF7 cells. Western blot analysis confirmed induction of EGR1 protein at 1 h and ATF3 at 24 h. Paclitaxel, as well as digitoxin, inhibited the in vitro activity of the purified Na(+)-K(+)-ATPase; digitoxin enhanced the growth inhibitory effects of paclitaxel on Her2 overexpressing breast cancer cells. CONCLUSIONS: Our studies show the potential of digitoxin to prevent and treat breast cancer and indicate that the combination of digitoxin and paclitaxel is a promising treatment for ER negative breast cancer. These findings are the first to alert physicians to the possible dangers to patients who take a combination of digitoxin and paclitaxel. The potential dangers ensuing when paclitaxel and digitoxin are combined are dependent on the dose of digitoxin.
RESUMO
One of the major classes of adenosine diphosphate (ADP) receptor antagonists are thienopyridines. Thienopyridines compose a subcategory of antiplatelet medications, known as ADP receptor inhibitors, used commonly for the treatment of atherosclerotic cardiovascular disease. Thienopyridines, including ticlopidine, clopidogrel and prasugrel, are prodrugs administered orally that are further metabolized by hepatocytes to create active metabolites that irreversibly bind ADP receptors located on the platelet membrane. Thus, these selected drugs have an inhibitory effect for the duration of the platelet's lifespan of 7-10 days. The goal of this manuscript is to review the currently available ADP receptor blockers with emphasis on chemical structure, mode of action and clinical use.
Assuntos
Antagonistas do Receptor Purinérgico P2 , Piridinas/química , Piridinas/farmacologia , Doenças Cardiovasculares/tratamento farmacológico , Humanos , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/farmacologia , Inibidores da Agregação Plaquetária/uso terapêutico , Piridinas/uso terapêutico , Trombose/prevenção & controleRESUMO
The Na+K+-ATPase is a known target of cardiac glycosides such as digitoxin and ouabain. We determined that the enzyme also is a target of the structurally-related triterpene glycoside actein, present in the herb black cohosh. Actein's inhibition of Na+-K+-ATPase activity was less potent than that of digitoxin, but actein potentiated digitoxin's inhibitory effect on Na+-K+-ATPase activity and MDA-MB-453 breast cancer cell growth. We observed different degrees of signal amplification for the two compounds. Actein's inhibitory effect on ATPase activity was amplified 2-fold for cell growth inhibition, whereas digitoxin's signal was amplified 20-fold. Actein induced a biphasic response in proteins downstream of ATPase: low dose and short duration of treatment upregulated NF-kappaB promoter activity, p-ERK, p-Akt and cyclin D1 protein levels, whereas higher doses and longer exposure inhibited these activities. Actein and digitoxin may be a useful synergistic combination for cancer chemoprevention and/or therapy.
Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/enzimologia , Digitoxina/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Inibidores Enzimáticos/farmacologia , Saponinas/farmacologia , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores , Triterpenos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , NF-kappa B/genética , Regiões Promotoras Genéticas/efeitos dos fármacos , Interferência de RNARESUMO
Glycoprotein (GP) IIb/IIIa receptor antagonists compose a subcategory of antiplatelet medications that reduce thrombus formation through the blockade of key binding sites needed to stabilize the forming platelet aggregate. The GP IIb/IIIa receptors have been identified as a therapeutic target in reducing the occurrence of platelet-dependent thrombus formation. One advantage of GP IIb/IIIa receptor antagonists is that because GP IIb/IIIa is platelet-specific, inhibition of this receptor does not affect platelet adhesion. This may contribute to hemostasis without leading to ischemic damage. The platelet-specific pharmacological activity of GP IIb/IIIa receptor antagonists has allowed for its broad use in clinical settings. Based on clinical trials, GP IIb/IIIa receptor antagonists have been extensively studied and used in patients with acute coronary syndrome or during percutaneous coronary interventions. The goal of the present article is to provide a detailed review of the chemical structures and mode of action of currently used Food and Drug Administration-approved GP IIb/IIIa receptor antagonists in the United States.