RESUMEN
Globally, breast cancer is the most common cause of cancer deaths. In Taiwan, it is the most prevalent cancer among females. Since San-Huang-Xie-Xin-Tang (SHXXT) exerts not only an anti-inflammatory but an immunomodulatory effect, it may act as a potent anti-tumor agent. Herein, the study aimed to explore the influence of SHXXT and its constituents on the mortality rate among breast cancer patients in Taiwan regarding the component effect and the dose-relationship effect. By using the Taiwan National Health Insurance (NHI) Research Database (NHIRD), the study analyzed 5387 breast cancer patients taking Chinese herbal medicine (CHM) and 5387 breast cancer patients not using CHM. CHM means SHXXT and its constituents in the study. The Kaplan-Meier method was utilized to determine the mortality probabilities among patients. Whether the CHM influences the mortality rate among patients was estimated by Cox proportional hazard regression analysis. The use of CHM could lower the cancer mortality rate by 59% in breast cancer patients. The protective effect was parallel to the cumulative days of CHM use and the annual average CHM dose. In addition, the mortality rate was lower in patients who used SHXXT compared to those who only used one of its constituents. SHXXT and its constituents were all promising therapeutic weapons against breast cancer.
RESUMEN
Aurora A kinase (Aurora A) is a serine/threonine kinase regulating control of multiple events during cell-cycle progression. Playing roles in promoting proliferation and inhibiting cell death in cancer cells leads Aurora A to become a target for cancer therapy. It is overexpressed and associated with a poor prognosis in ovarian cancer. Improving cisplatin therapy outcomes remains an important issue for advanced-stage ovarian cancer treatment, and Aurora A inhibitors may improve it. In the present study, we identified natural compounds with higher docking scores than the known Aurora A ligand through structure-based virtual screening, including the natural compound fangchinoline, which has been associated with anticancer activities but not yet investigated in ovarian cancer. The binding and inhibition of Aurora A by fangchinoline were verified using cellular thermal shift and enzyme activity assays. Fangchinoline reduced viability and proliferation in ovarian cancer cell lines. Combination fangchinoline and cisplatin treatment enhanced cisplatin-DNA adduct levels, and the combination index revealed synergistic effects on cell viability. An in vivo study showed that fangchinoline significantly enhanced cisplatin therapeutic effects in OVCAR-3 ovarian cancer-bearing mice. Fangchinoline may inhibit tumor growth and enhance cisplatin therapy in ovarian cancer. This study reveals a novel Aurora A inhibitor, fangchinoline, as a potentially viable adjuvant for ovarian cancer therapy.
Asunto(s)
Aurora Quinasa A/metabolismo , Bencilisoquinolinas/administración & dosificación , Cisplatino/administración & dosificación , Aductos de ADN/efectos de los fármacos , Neoplasias Ováricas/tratamiento farmacológico , Animales , Aurora Quinasa A/química , Bencilisoquinolinas/química , Bencilisoquinolinas/farmacología , Línea Celular Tumoral , Cisplatino/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Sinergismo Farmacológico , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Ratones , Modelos Moleculares , Simulación del Acoplamiento Molecular , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Conformación Proteica , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Traditional Chinese medicine (TCM) has been proposed to prevent urolithiasis. In China, Flos carthami (FC, also known as Carthamus tinctorius) (Safflower; Chinese name: Hong Hua/) has been used to treat urological diseases for centuries. We previously performed a screening and confirmed the in vivo antilithic effect of FC extract. Here, ex vivo organ bath experiment was further performed to study the effect of FC extract on the inhibition of phenylepinephrine (PE) (10(-4) and 10(-3) M) ureteral peristalsis of porcine ureters with several α 1-adrenergic antagonists (doxazosin, tamsulosin, and terazosin) as experimental controls. The results showed that doxazosin, tamsulosin, and terazosin dose (approximately 4.5 × 10(-6) - 4.5 × 10(-1) µg/mL) dependently inhibited both 10(-4) and 10(-3) M PE-induced ureteral peristalsis. FC extract achieved 6.2% ± 10.1%, 21.8% ± 6.8%, and 24.0% ± 5.6% inhibitions of 10(-4) M PE-induced peristalsis at doses of 5 × 10(3), 1 × 10(4), and 2 × 10(4) µg/mL, respectively, since FC extract was unable to completely inhibit PE-induced ureteral peristalsis, suggesting the antilithic effect of FC extract is related to mechanisms other than modulation of ureteral peristalsis.
RESUMEN
Glioblastoma multiforme is one of the most serious malignant brain tumors and is characterized by resistance to chemotherapy and radiation therapy. Recent studies suggest that autophagy may play an important role not only in the regulation of cancer development and progression but also in determining the response of cancer cells to anticancer therapy. The purpose of the present study was to assess the relationship between protein expressions of two autophagy markers, LC3B and Beclin-1, with clinical parameters in astrocytoma patients. Furthermore, the expression of CD133, a marker of the cancer stem-like cells, in astrocytoma patients was also investigated. A total of 106 thin-section slides were retrospectively collected from astrocytoma patients. LC3B, but not Beclin-1, protein expression was found to significantly correlate with resistance to radiation- or chemotherapy. In addition, high intensity of LC3B staining was predictive of poor prognosis. Furthermore, survival time of patients with high-level expression in both CD133 and LC3B was significantly shorter than those with weak expression in both CD133 and LC3B. These results suggest that astrocytoma cancer stem-like cells together with enhanced autophagy may cause resistance to radiation therapy/chemotherapy and that targeting the cancer stem-like cell in astrocytoma may offer a viable therapeutic approach.
Asunto(s)
Astrocitoma/metabolismo , Astrocitoma/patología , Autofagia/fisiología , Biomarcadores de Tumor/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Antígeno AC133 , Anciano , Antígenos CD/metabolismo , Proteínas Reguladoras de la Apoptosis/metabolismo , Beclina-1 , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Femenino , Glicoproteínas/metabolismo , Humanos , Masculino , Proteínas de la Membrana/metabolismo , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Péptidos/metabolismo , Pronóstico , Estudios RetrospectivosRESUMEN
Endothelin-1, a potent vasoconstrictive peptide, has been implicated in the pathogenesis of cerebral vasospasm following subarachnoid hemorrhage (SAH). The goal of this study was to evaluate the effect of continuous intravenous infusion of a highly selective endothelin-converting enzyme-1 inhibitor, CGS 35066, on the prevention and reversal of cerebral vasospasm following SAH. New Zealand white rabbits were subjected to SAH by injecting autologous arterial blood into the cisterna magna. Infusion of CGS 35066 at dosages of 1, 3, or 10 mg/kg/ day was initiated either 1 hr and 24 hrs later in the prevention and reversal protocols, respectively. Animals were sacrificed by perfusion-fixation 48 hrs after SAH induction. The cross-sectional areas of basilar arteries were measured using computer-assisted videomicroscopy. Ultrastructural changes in basilar arteries were determined using electron microscopy. CGS 35066 significantly prevented and reversed the arterial narrowing after SAH in all three groups. The mean cross-sectional areas of arteries from animals in both the prevention and reversal protocol groups that received 10 mg/kg/day of CGS 35066 did not differ significantly from those of the healthy controls. Histological studies of the basilar artery in the 10 mg/kg/day treatment group did not show pathomorphological changes, such as corrugation of the endothelium seen at 2 days after SAH induction or vacuole formation in the endothelial cells noted in the vehicle-treated SAH group. These findings suggest that CGS 35066 is a promising therapeutic agent for the prevention and reversal of cerebral vasospasm after SAH. It also prevents the pathological changes in vascular walls due to SAH.
Asunto(s)
Arteria Basilar/ultraestructura , Benzofuranos/uso terapéutico , Organofosfonatos/uso terapéutico , Inhibidores de Proteasas/uso terapéutico , Hemorragia Subaracnoidea/etiología , Vasoespasmo Intracraneal/tratamiento farmacológico , Vasoespasmo Intracraneal/prevención & control , Animales , Arteria Basilar/efectos de los fármacos , Arteria Basilar/patología , Infusiones Intravenosas , Masculino , Conejos , Hemorragia Subaracnoidea/complicaciones , Vasoespasmo Intracraneal/etiologíaRESUMEN
BACKGROUND: Endothelin-1 (ET-1) is a potent and long-acting vasoconstrictive peptide that has been implicated in the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage (SAH). ET-1 has been shown to be present in the cerebrospinal fluid of patients after SAH, and substances produced during hemolysis of subarachnoid blood clots are believed to be responsible for stimulating the production of ET-1. The biosynthesis of ET-1 is a multi-step process, involving the conversion of the relatively inactive precursor big ET-1 to the mature peptide by endothelin converting enzyme (ECE), a metalloprotease. Consequently, ECE inhibitors are expected to suppress the biosynthesis of ET-1 and reduce the pathologic impact resulting from overproduction of this peptide. The purpose of the present study was to investigate the effects of an ECE inhibitor, CGS 26303, on hemolysate-induced injury of cerebral vessel endothelial cells as well as the production of ET-1 from these cells. METHODS: Different doses of CGS 26303 and hemolysate were added to the culture medium for 48 hours. Cell injury was assessed by cell morphology and density, while the productions of ET-1 and big ET-1 were determined by radioimmunoassays. RESULTS: Hemolysate alone increased the levels of ET-1 and big ET-1 in culture medium and caused substantial cell loss. Treatment with CGS 26303 inhibited the hemolysate-induced increases in the levels of ET-1 and big ET-1 and reduced endothelial cell injury. The protective effects of CGS 26303 were modest when this inhibitor was added simultaneously with hemolysate, but were prominent and dose-dependent when the inhibitor was given 30 minutes before the addition of hemolysate. CONCLUSION: These results suggest that overproduction of ET-1 contributes significantly to hemolysate-induced damage to cerebrovascular endothelial cells.
Asunto(s)
Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Endotelina-1/metabolismo , Endotelinas/metabolismo , Endotelio Vascular/efectos de los fármacos , Organofosfonatos/farmacología , Precursores de Proteínas/metabolismo , Hemorragia Subaracnoidea/fisiopatología , Tetrazoles/farmacología , Vasoespasmo Intracraneal/fisiopatología , Animales , Ácido Aspártico Endopeptidasas/fisiología , Bovinos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Enzimas Convertidoras de Endotelina , Endotelio Vascular/fisiopatología , Humanos , Metaloendopeptidasas , ConejosRESUMEN
Increasing evidence has implicated endothelin-1 (ET-1), a potent vasoconstrictive peptide, in the pathophysiology of cerebral vasospasm after subarachnoid haemorrhage (SAH). Endothelin-converting enzyme-1 (ECE-1), the protease involved in the final step of post-translational processing of ET-1, cleaves the inactive precursor big ET-1 at the Trp(21)-Val (22) peptide bond. In our previous study, we found that an inhibitor of ECE-1, CGS 26303, could prevent and reverse the arterial narrowing after SAH in rabbits. CGS 26393, a prodrug of CGS 26303, is an orally active, long-acting inhibitor of ECE-1. The present study examined the effects of CGS 26393 on the prevention and reversal of cerebral vasospasm after SAH. New Zealand white rabbits were subjected to experimental SAH by injecting autologous blood into the cisterna magna. In the prevention study, the drug was given orally 1 h before the induction of SAH. All drug treatments in the reversal study were initiated at 23 h after induction of SAH. One of three dosages (3, 10 or 30 mg/kg) of CGS 26393 or vehicle was administrated orally twice daily, and all animals were sacrificed by perfusion and fixation 48 h after SAH. Basilar arteries were removed and sectioned, and cross-sectional areas were measured. Cerebrospinal fluid (CSF) was collected prior to perfusion. Oral administration of CGS 26393 attenuated SAH-induced cerebral vasospasm in a dose-dependent manner in both the prevention and reversal groups. These effects achieved statistical significance at all dosages when compared with the SAH-only or SAH plus vehicle groups. Moreover, the attenuation of vasospasm following oral administration of CGS 26393 was more efficacious than that obtained with bolus injections of CGS 26303. The levels of free CGS 26303 in the CSF were increased in a dose-dependent manner in all three CGS 26393-treated groups. This study provides the first evidence that oral administration of an inhibitor of ECE-1, CGS 26393, is capable of preventing and reversing cerebral vasospasm following SAH. These findings also reinforce evidence demonstrating that treatment with an ECE-1 inhibitor is a potentially viable therapeutic approach for reducing cerebral vasospasm after SAH.