RESUMEN
BACKGROUND/AIM: Intraperitoneal chemotherapy with taxanes provides high locoregional drug concentrations. Regarding their synergy with hyperthermia, results have been inconclusive. In this in vitro study, the thermal enhancement of the effect of paclitaxel and docetaxel on ovarian cancer cells under conditions mimicking those during hyperthermic intraperitoneal chemotherapy (HIPEC) is evaluated. MATERIALS AND METHODS: Cisplatin-resistant SKOV-3 and OVCAR-3 ovarian cancer cells were exposed for 2 h to 0.1, 1 and 3 µΜ of paclitaxel and docetaxel at 37°C (normothermia) and 41.5°C (hyperthermia). Cell proliferation and cell-cycle distribution were evaluated after 24 h, 3 days and 7 days. RESULTS: A concentration-dependent cytotoxic effect on cell proliferation was observed. Concurrent hyperthermia caused an increased arrest of cells in the G2/M phase. At 7 days, thermal enhancement of drug effect was shown only for treatment of OVCAR-3 cells with 1 µM paclitaxel. CONCLUSION: The concentration-dependent cytotoxic effect of paclitaxel and docetaxel supports their intraperitoneal use. Due to the lack of or only minimal thermal enhancement, normothermic may be as effective as hyperthermic intraoperative intraperitoneal chemotherapy with taxanes, avoiding, however, potential oncological and treatment-related adverse effects of concurrent hyperthermia.
Asunto(s)
Docetaxel/administración & dosificación , Docetaxel/uso terapéutico , Hipertermia Inducida , Neoplasias Ováricas/terapia , Paclitaxel/administración & dosificación , Paclitaxel/uso terapéutico , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Terapia Combinada , Femenino , Fase G2/efectos de los fármacos , Humanos , Inyecciones Intraperitoneales , Mitosis/efectos de los fármacos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patologíaRESUMEN
Kindlin-1 is an integrin tail binding protein that controls integrin activation. Mutations in the FERMT-1 gene, which encodes for Kindlin-1, lead to Kindler syndrome in man, which is characterized by skin blistering, premature skin aging and skin cancer of unknown etiology. Here we show that loss of Kindlin-1 in mouse keratinocytes recapitulates Kindler syndrome and also produces enlarged and hyperactive stem cell compartments, which lead to hyperthickened epidermis, ectopic hair follicle development and increased skin tumor susceptibility. Mechanistically, Kindlin-1 controls keratinocyte adhesion through ß1-class integrins and proliferation and differentiation of cutaneous epithelial stem cells by promoting α(v)ß(6) integrin-mediated transforming growth factor-ß (TGF-ß) activation and inhibiting Wnt-ß-catenin signaling through integrin-independent regulation of Wnt ligand expression. Our findings assign Kindlin-1 the previously unknown and essential task of controlling cutaneous epithelial stem cell homeostasis by balancing TGF-ß-mediated growth-inhibitory signals and Wnt-ß-catenin-mediated growth-promoting signals.