RESUMEN
Cisplatin is a commonly used chemotherapeutic drug for treatment of oral carcinoma, and combinatorial effects are expected to exert greater therapeutic efficacy compared with monotherapy. Poly(ADP-ribosyl)ation is reported to be involved in a variety of cellular processes, such as DNA repair, cell death, telomere regulation, and genomic stability. Based on these properties, poly(ADP-ribose) polymerase (PARP) inhibitors are used for treatment of cancers, such as BRCA1/2 mutated breast and ovarian cancers, or certain solid cancers in combination with anti-cancer drugs. However, the effects on oral cancer have not been fully evaluated. In this study, we examined the effects of PARP inhibitor on the survival of human oral cancer cells in vitro and xenografted tumors derived from human oral cancer cells in vivo. In vitro effects were assessed by microculture tetrazolium and survival assays. The PARP inhibitor AZD2281 (olaparib) showed synergetic effects with cisplatin in a dose-dependent manner. Combinatorial treatment with cisplatin and AZD2281 significantly inhibited xenografted tumor growth compared with single treatment of cisplatin or AZD2281. Histopathological analysis revealed that cisplatin and AZD2281 increased TUNEL-positive cells and decreased Ki67- and CD31-positive cells. These results suggest that PARP inhibitors have the potential to improve therapeutic strategies for oral cancer.
Asunto(s)
Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Cisplatino/uso terapéutico , Sinergismo Farmacológico , Neoplasias de la Boca/tratamiento farmacológico , Ftalazinas/uso terapéutico , Piperazinas/uso terapéutico , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Línea Celular Tumoral , Cisplatino/administración & dosificación , Cisplatino/farmacología , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Ftalazinas/administración & dosificación , Ftalazinas/farmacología , Piperazinas/administración & dosificación , Piperazinas/farmacologíaRESUMEN
Poly(ADP-ribosyl)ation is known to be involved in a variety of cellular processes, such as DNA repair, cell death, telomere regulation, genomic stability and cell differentiation by poly(ADP-ribose) polymerase (PARP). While PARP inhibitors are presently under clinical investigation for cancer therapy, little is known about their side effects. However, PARP involvement in mesenchymal stem cell (MSC) differentiation potentiates MSC-related side effects arising from PARP inhibition. In this study, effects of PARP inhibitors on MSCs were examined. MSCs demonstrated suppressed osteogenic differentiation after 1 µM PJ34 treatment without cytotoxicity, while differentiation of MSCs into chondrocytes or adipocytes was unaffected. PJ34 suppressed mRNA induction of osteogenic markers, such as Runx2, Osterix, Bone Morphogenetic Protein-2, Osteocalcin, bone sialoprotein, and Osteopontin, and protein levels of Bone Morphogenetic Protein-2, Osterix and Osteocalcin. PJ34 treatment also inhibited transcription factor regulators such as Smad1, Smad4, Smad5 and Smad8. Extracellular mineralized matrix formation was also diminished. These results strongly suggest that PARP inhibitors are capable of suppressing osteogenic differentiation and poly(ADP-ribosyl)ation may play a physiological role in this process through regulation of BMP-2 signaling. Therefore, PARP inhibition may potentially attenuate osteogenic metabolism, implicating cautious use of PARP inhibitors for cancer treatments and monitoring of patient bone metabolism levels.
Asunto(s)
Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/efectos de los fármacos , Fenantrenos/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Adipogénesis/efectos de los fármacos , Animales , Proteína Morfogenética Ósea 2/genética , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Condrogénesis/efectos de los fármacos , Masculino , Células Madre Mesenquimatosas/metabolismo , Ratones , Ratones Endogámicos C57BL , Osteocalcina/genética , Osteogénesis/efectos de los fármacos , Osteopontina/genética , Poli Adenosina Difosfato Ribosa/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Rutile TiO2 nanorods with lengths greater than 600 nm and aspect ratios greater than ca. 16 were synthesized through a one-pot hydrothermal method using lactic acid (LA) as a structure-directing agent. Under the hydrothermal treatment at 200 °C, the LA concentration higher than 1.6 mol dm-3 and the hydrothermal time of 72 h were needed to obtain 100% rutile nanorods. The length and the width of the nanorods increased with the increasing LA concentration. The photocatalytic activity of the synthesized nanorods was evaluated for the oxygen evolution in aqueous AgNO3 solutions under ultraviolet irradiation. Calcination of the synthesized nanorods at 400 °C was required to decompose residual organic compounds on the surface and improve the oxygen evolution. The highest oxygen evolution rate was obtained with the nanorods after being calcined at 800 °C. It is worth noting that the nanorods retained their shape (aspect ratio of 8.8) at 800 °C. Selected area electron diffraction patterns indicated that the side or the end surface of the nanorods was attributable to the {110} or {111} facet, respectively. Deposition of Pt or PbO2 on the nanorods revealed that the {110} or {111} facet acted as reductive or oxidative sites. For comparison, near-spherical TiO2 nanoparticles were synthesized by a sol-gel method. Furthermore, using glycolic acid as the structure-directing agent, we synthesized small rutile TiO2 nanorods (aspect ratio of 9) and changed the shape to near-spherical (aspect ratio of 1.3) by calcining at 800 °C. Time-resolved diffuse reflectance spectra were measured to determine the lifetime of the photogenerated electrons. The photocatalytic activity of the nanorods was much lower than that of the near-spherical TiO2 nanoparticles. However, the nanorods synthesized with LA are useful as catalyst support or platforms for various applications because of their unique morphology and high heat resistance.
RESUMEN
The autofluorescence visualization method (AVM) uses blue excitation light to assist in the diagnosis of epithelial dysplasia. It detects epithelial dysplasia as a black area, which is known as fluorescence visualization loss (FVL). In this study, we evaluated the detection accuracy for epithelial dysplasia of the tongue using the objective AVM and assessed its possible clinical utility. Seventy-nine tongue specimens clinically suspected to have leukoplakia or squamous cell carcinoma (SCC) were analyzed. First, the AVM was subjectively performed using the Visually Enhanced Lesion scope (VELscope), and the iodine-staining method was then performed. After biopsy, the histopathological results and the luminance ratio between the lesion and healthy tissue were compared, and a receiver operating characteristic curve was created. The cutoff value for the objective AVM was determined; the lesion was considered FVL-positive or -negative when the luminance ratio was higher or lower than the cutoff value, respectively. The histopathological diagnoses among the 79 specimens were SCC (n=30), leukoplakia with dysplasia (n=34), and leukoplakia without dysplasia (n=15). The cutoff value of the luminance ratio was 1.62, resulting in 66 FVL-positive and 13 FVL-negative specimens. The luminance ratio was significantly higher in the epithelial dysplasia-positive than -negative group (P<0.000 1). The objective AVM showed much higher consistency between histopathological results than did the two methods (kappa statistic=0.656). In conclusion, objective autofluorescence visualization has a potential as an auxiliary method for diagnosis of epithelial dysplasia.