sildenafil-citrate and Breast-Neoplasms

Topics: Breast Neoplasms; Complementary Therapies; Exercise; Female; Humans; Immunization; Male; Nutritional Physiological Phenomena; Osteoporosis; Phosphodiesterase Inhibitors; Piperazines; Purines; Research; Sildenafil Citrate; Sulfones; Ultrasonography

Aromatase catalyses the conversion of androgens into estrogens and is a well-known target for breast cancer therapy. As it has been suggested that its activity is affected by inhibitors of phosphodiesterase-5, this work investigates the potential interaction of sildenafil with aromatase. This is carried out both at molecular level through structural and kinetics assays applied to the purified enzyme, and at cellular level using neuronal and breast cancer cell lines. Sildenafil is found to bind to aromatase with a K

Topics: Aromatase; Aromatase Inhibitors; Breast Neoplasms; Catalysis; Cyclic Nucleotide Phosphodiesterases, Type 5; Dose-Response Relationship, Drug; Electron Spin Resonance Spectroscopy; Female; Heme; Humans; Inhibitory Concentration 50; Iron; Kinetics; Ligands; MCF-7 Cells; Molecular Docking Simulation; Protein Binding; Recombinant Proteins; Sildenafil Citrate; Spectrophotometry; Spectrophotometry, Ultraviolet; Water

It has been demonstrated that aggressive in situ tumor destruction (ablation) could lead to the release of tumor antigens, which can stimulate anti-tumor immune responses. We developed an innovative method of tumor ablation based on intratumoral alpha-irradiation, diffusing alpha-emitters radiation therapy (DaRT), which efficiently ablates local tumors and enhances anti-tumor immunity. In this study, we investigated the anti-tumor potency of a treatment strategy, which combines DaRT tumor ablation with two approaches for the enhancement of anti-tumor reactivity: (1) neutralization of immunosuppressive cells such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) and (2) boost the immune response by the immunoadjuvant CpG. Mice bearing DA3 mammary adenocarcinoma with metastases were treated with DaRT wires in combination with a MDSC inhibitor (sildenafil), Treg inhibitor (cyclophosphamide at low dose), and the immunostimulant, CpG. Combination of all four therapies led to a complete rejection of primary tumors (in 3 out of 20 tumor-bearing mice) and to the elimination of lung metastases. The treatment with DaRT and Treg or MDSC inhibitors (without CpG) also resulted in a significant reduction in tumor size, reduced the lung metastatic burden, and extended survival compared to the corresponding controls. We suggest that the therapy with DaRT combined with the inhibition of immunosuppressive cells and CpG reinforced both local and systemic anti-tumor immune responses and displayed a significant anti-tumor effect in tumor-bearing mice.

Topics: Ablation Techniques; Adenocarcinoma; Alpha Particles; Animals; Antigens, Neoplasm; Brachytherapy; Breast Neoplasms; Cell Growth Processes; Cell Line, Tumor; Combined Modality Therapy; Cyclophosphamide; Female; Humans; Mice; Mice, Inbred BALB C; Myeloid-Derived Suppressor Cells; Oligodeoxyribonucleotides; Sildenafil Citrate; T-Lymphocytes, Regulatory; Tumor Burden

Sildenafil is the first phosphodiesterase-5 inhibitor used for the treatment of erectile dysfunction. However, recent studies have been suggesting an antitumor effect of sildenafil. The current study assessed the aforementioned activity of sildenafil in vivo and in vitro in solid-tumor-bearing mice and in a human cell line MCF-7, respectively. Moreover, we investigated the impact of sildenafil on cisplatin antitumor activity. The solid tumor was induced by inoculation of Ehrlich ascites carcinoma cells in female mice. The tumor-bearing mice were assigned randomly to control (saline), sildenafil (sildenafil 5 mg/kg/d, PO daily for 15 days), cisplatin (cisplatin 7.5 mg/kg, IP once on the 12th day of Ehrlich ascites carcinoma inoculation), and combination therapy (cisplatin and sildenafil) groups. The tumor volume was measured at the end of the treatment period along with the following parameters: angiogenin, vascular endothelial growth factor, tumor necrosis factor-α, Ki-67, caspase-3, DNA-flow cytometry analysis, and histopathological examination. The study results showed that sildenafil has significantly decreased the tumor volume by 30.4%, angiogenin and tumor necrosis factor-α contents, as well as vascular endothelial growth factor expression. Additionally, caspase-3 level significantly increased with sildenafil treatment, whereas Ki-67 expression failed to show any significant changes. Furthermore, the cell cycle analysis revealed that sildenafil was capable of improving the category of tumor activity from moderate to low proliferative. Sildenafil induced necrosis in the tumor. Moreover, the drug of interest showed cytotoxic activity against MCF-7 in vitro as well as potentiated cisplatin antitumor activity in vivo and in vitro. These findings shed light on the antitumor activity of sildenafil and its possible impact on potentiating the antitumor effect of conventional chemotherapeutic agents such as cisplatin. These effects might be related to antiangiogenic, antiproliferative, and apoptotic activities of sildenafil.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Biomarkers, Tumor; Breast Neoplasms; Carcinoma, Ehrlich Tumor; Cell Cycle; Cell Proliferation; Cisplatin; Dose-Response Relationship, Drug; Drug Synergism; Female; Humans; Inhibitory Concentration 50; MCF-7 Cells; Mice; Necrosis; Neovascularization, Pathologic; Signal Transduction; Sildenafil Citrate; Time Factors; Tumor Burden

Cancer multi-drug resistance is a major issue associated with current anti-tumoral therapeutics. In this work, Crizotinib an anti-tumoral drug approved for the treatment of non-small lung cancer in humans, and Sildenafil (Viagra(®)), were loaded into micellar carriers to evaluate the establishment of a possible synergistic anti-tumoral effect in breast cancer cells.. Micellar carriers comprised by PEG-PLA block co-polymers were formulated by the solvent displacement method in which the simultaneous encapsulation of Crizotinib and Sildenafil was promoted. Encapsulation efficiency was analyzed by a new UPLC method validated for this combination of compounds. Micelle physicochemical characterization and cellular uptake were characterized by light scattering and confocal microscopy. The bio- and hemocompatibility of the carriers was also evaluated. MCF-7 breast cancer cells were used to investigate the synergistic anti-tumoral effect.. Our results demonstrate that this particular combination induces massive apoptosis of breast cancer cells. The co-delivery of Crizotinib and Sildenafil was only possible due to the high encapsulation efficiency of the micellar systems (>70%). The micelles with size ranging between 93 and 127 nm were internalized by breast cancer cells and subsequently released their payload in the intracellular compartment. The results obtained demonstrated that the delivery of both drugs by micellar carriers led to a 2.7 fold increase in the anti-tumoral effect, when using only half of the concentration that is required when free drugs are administered.. Altogether, co-delivery promoted a synergistic effect and demonstrated for the first time the potential of PEG-PLA-Crizotinib-Sildenafil combination for application in cancer therapy.

Topics: Antineoplastic Agents; Breast; Breast Neoplasms; Cell Line, Tumor; Crizotinib; Drug Carriers; Drug Synergism; Female; Humans; Micelles; Piperazines; Polyethylene Glycols; Purines; Pyrazoles; Pyridines; Sildenafil Citrate; Sulfonamides; Vasodilator Agents

Studies were performed to determine the influence of the phosphodiesterase-5 inhibitor, sildenafil, on sensitivity to adriamycin (doxorubicin) in four human breast tumor cell lines and one murine breast tumor line. Sildenafil did not interfere with the effectiveness of adriamycin in any of the cell lines tested. Sildenafil also failed to protect MDA-MB231 cells against the cytotoxicity of cisplatin, taxol or camptothecin. Sildenafil enhanced sensitivity to adriamycin markedly in the p53 mutant MDA-MB231 and p53 null MCF-7/E6 cells and moderately in the MCF-7/caspase 3 and 4T1 cell lines. In the MDA-MB231 cells, sildenafil increased the extent of DNA damage induced by adriamycin as well as the extent of apoptotic cell death. Sildenafil did not influence sensitivity to adriamycin in bone marrow cells or macrophages. In an immunocompetent model of breast cancer (4T1 mammary carcinoma in Balb/c mice), sildenafil did not attenuate the antitumor effects of adriamycin; furthermore, the combination of sildenafil with adriamycin was no more toxic to the animals than adriamycin alone. Given that sildenafil has been shown to have the potential to protect the heart against the toxicity of adriamycin, these studies suggest that the inclusion of sildenafil with conventional chemotherapeutic protocols involving adriamycin (and possibly cisplatin, camptothecin and/or paclitaxel) should not compromise the antitumor effectiveness of these drugs nor enhance their toxicity to the patient.

Topics: Animals; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Camptothecin; Caspase 3; Cell Line, Tumor; Cisplatin; Dose-Response Relationship, Drug; Doxorubicin; Female; Heart Diseases; Humans; Mice; Mice, Inbred BALB C; Paclitaxel; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Time Factors; Tumor Suppressor Protein p53

Topics: Breast Neoplasms; Erectile Dysfunction; Female; Humans; Interpersonal Relations; Male; Piperazines; Purines; Sexual Partners; Sildenafil Citrate; Sulfones; Survivors; Vasodilator Agents