RESUMEN
Ovarian cancer persists to be the most lethal gynecological malignancy, demanding rigorous treatments involving radio-chemotherapy that trigger toxicity and consequently mortality among patients. An improved understanding of the disease progression may pioneer curative therapies. Mouse epithelial ovarian cancer cell lines, ID8 and ID8-VEGF (overexpressing VEGF) were intraperitoneally injected in C57BL/6 female mice to develop a Syngeneic Ovarian cancer mouse model. It was observed that ID8-VEGF cells were able to induce aggressive tumor growth in mice compared to ID8 cells. Furthermore, results of the current in vitro study comparing ID8 and ID8-VEGF demonstrated that highly tumorigenic ID8-VEGF had reduced gap junctional intercellular communication (GJIC) due to intracellular Connexin 43 (Cx43) expression. Additionally, ID8 cells with reduced tumorigenic capability expressed significant GJIC. Furthermore, loss of GJIC in ID8-VEGF cells induced shorter tunneling nanotube formations, while ID8 cells develops longer tunneling nanotube to maintain cellular crosstalk. The administration of a pharmacological drug 4-phenylbutyrate (4PBA) ensured the restoration of GJIC in both the ovarian cancer cell lines. Additionally, 4PBA treatment significantly inhibited the migration of ovarian cancer cell lines and tumor formation in ovarian cancer mice models. In summary, the 4PBA-mediated restoration of GJIC suppressed migration (in vitro) and tumorigenesis (in vivo) of ovarian cancer cells. The present study suggests that Cx43 assembled GJIC and its supportive signaling pathways are a prospective target for restricting ovarian cancer progression.
Asunto(s)
Conexina 43 , Neoplasias Ováricas , Humanos , Femenino , Ratones , Animales , Conexina 43/metabolismo , Factor A de Crecimiento Endotelial Vascular , Ratones Endogámicos C57BL , Comunicación Celular/fisiología , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/metabolismo , Movimiento Celular/fisiología , CarcinogénesisRESUMEN
In epithelial ovarian cancers, the presence of tumor-associated macrophages (TAMs) is well correlated with the poor disease outcomes. TAMs are know to suppress the immune system, induce pro-tumoral functions and inhibit anti-tumor responses associated with chemotherapy. In this study, we have evaluated the synergistic efficacy of TAM repolarization and intraperitoneal paclitaxel in epithelial ovarian cancers. We demonstrate that hyaluronic acid-based nanoparticles encapsulating miR-125b (HA-PEI-miR-125b) can specifically target TAMs in the peritoneal cavity of a syngeneic ID8-VEGF ovarian cancer mouse model and can repolarize macrophages to an immune-activating phenotype. These HA-PEI-miR-125b nanoparticles in combination with intraperitoneal paclitaxel can enhance the anti-tumor efficacy of paclitaxel during the later stages of disease progression as seen by the significant reduction in the ascitic fluid and peritoneal VEGF levels. Furthermore, these HA-PEI-miR-125b nanoparticles do not induce systemic toxicity and thus warrant a further evaluation in the clinical setting.
Asunto(s)
Carcinoma Epitelial de Ovario/terapia , Macrófagos Peritoneales/efectos de los fármacos , MicroARNs/genética , Nanopartículas/administración & dosificación , Paclitaxel/farmacología , Animales , Antineoplásicos Fitogénicos/farmacología , Apoptosis , Biomarcadores de Tumor/genética , Carcinoma Epitelial de Ovario/genética , Carcinoma Epitelial de Ovario/patología , Proliferación Celular , Terapia Combinada , Sistemas de Liberación de Medicamentos , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Ácido Hialurónico/química , Macrófagos Peritoneales/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Nanopartículas/química , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The objective of this study was to evaluate intraperitoneal (IP) metronomic chemotherapy using sustained release paclitaxel (PTX) delivery from electrospun biodegradable polymeric yarns woven into suturable nanotextiles. Following confirmation of in vitro PTX efficacy in ID8-VEGF epithelial ovarian cancer cells, in vivo studies were performed upon surgical peritoneal implantation of nanotextile implants in orthotopic, syngeneic ID8-VEGF tumor-bearing C57BL/6 mice. In comparison to the clinical PTX-solution, there was a significant enhancement of anti-tumor efficacy and safety with PTX-nanotextiles. After 35-days, the peritoneum of tumor-bearing mice with PTX-nanotextiles was completely devoid of tumor nodules and ascitic fluid. Additionally, VEGF levels measured in peritoneal lavage fluid were 300-fold lower compared to PTX-solution and 600-fold lower as compared to untreated tumor-bearing animals. PTX-solution treated group also developed severe metastatic lesions and progressive ascitic fluid buildup. More importantly, no signs of systemic/ organ toxicity were observed in PTX-nanotextile implanted mice, unlike the systemic toxic effects induced by PTX-solution. Collectively, our results show the therapeutic and safety advantages offered by combining clinically translatable metronomic low-dose chemotherapy and IP pharmacokinetics using biodegradable nanotextile implants in addressing the challenges of late-stage ovarian cancer.