RESUMEN
BACKGROUND: The tumor suppressor, protein phosphatase 2A (PP2A), is downregulated in hepatoblastoma. We aimed to examine the effects of two novel compounds of the tricyclic sulfonamide class, ATUX-3364 (3364) and ATUX-8385 (8385), designed to activate PP2A without causing immunosuppression, on human hepatoblastoma. METHODS: An established human hepatoblastoma cell line, HuH6, and a human hepatoblastoma patient-derived xenograft, COA67, were treated with increasing doses of 3364 or 8385, and viability, proliferation, cell cycle and motility were investigated. Cancer cell stemness was evaluated by real-time PCR and tumorsphere forming ability. Effects on tumor growth were examined using a murine model. RESULTS: Treatment with 3364 or 8385 significantly decreased viability, proliferation, cell cycle progression and motility in HuH6 and COA67 cells. Both compounds significantly decreased stemness as demonstrated by decreased abundance of OCT4, NANOG, and SOX2 mRNA. The ability of COA67 to form tumorspheres, another sign of cancer cell stemness, was significantly diminished by 3364 and 8385. Treatment with 3364 resulted in decreased tumor growth in vivo. CONCLUSION: Novel PP2A activators, 3364 and 8385, decreased hepatoblastoma proliferation, viability, and cancer cell stemness in vitro. Animals treated with 3364 had decreased tumor growth. These data provide evidence for further investigation of PP2A activating compounds as hepatoblastoma therapeutics.
Asunto(s)
Hepatoblastoma , Neoplasias Hepáticas , Humanos , Animales , Ratones , Hepatoblastoma/tratamiento farmacológico , Hepatoblastoma/genética , Hepatoblastoma/metabolismo , Neoplasias Hepáticas/genética , Proteína Fosfatasa 2/metabolismo , Proteína Fosfatasa 2/farmacología , Proteína Fosfatasa 2/uso terapéutico , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico , Línea Celular Tumoral , Proliferación CelularRESUMEN
Long-term use of low-toxic natural products holds the promise for eradicating cancer stem cells. In this study, we report that luteolin, a natural flavonoid, attenuates the stemness of ovarian cancer stem cells (OCSCs) by directly binding to KDM4C and epigenetic suppression of PPP2CA/YAP axis. Ovarian cancer stem like cells (OCSLCs) isolated by suspension culture and CD133 + ALDH+ cell sorting was employed as OCSCs model. The maximal non-toxic dose of luteolin suppressed stemness properties, including sphere-forming capacity, the expression of OCSCs markers, sphere-initiating and tumor-initiating capacities, as well as the percentage of CD133 + ALDH+ cells of OCSLCs. Mechanistic study showed that luteolin directly binds to KDM4C, blocks KDM4C-induced histone demethylation of PPP2CA promoter, inhibits PPP2CA transcription and PPP2CA-mediated YAP dephosphorylation, thereby attenuating YAP activity and the stemness of OCSLCs. Furthermore, luteolin sensitized OCSLCs to traditional chemotherapeutic drugs in vitro and in vivo. In summary, our work revealed the direct target of luteolin and the underlying mechanism of the inhibitory effect of luteolin on the stemness of OCSCs. This finding thus suggests a novel therapeutic strategy for eradicating human OCSCs driven by KDM4C.
Asunto(s)
Luteolina , Neoplasias Ováricas , Femenino , Humanos , Línea Celular Tumoral , Epigénesis Genética , Histona Demetilasas con Dominio de Jumonji/metabolismo , Luteolina/farmacología , Luteolina/uso terapéutico , Células Madre Neoplásicas/metabolismo , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Proteína Fosfatasa 2/metabolismo , Proteína Fosfatasa 2/farmacología , Proteína Fosfatasa 2/uso terapéutico , Proteínas Señalizadoras YAP/metabolismoRESUMEN
Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in adults. The disease is characterized by the accumulation of tumoral B cells resulting from a defect of apoptosis. We have in vitro and in vivo preclinically validated a tumor-penetrating peptide (named TT1) coupled to an interfering peptide (IP) that dissociates the interaction between the serine/threonine protein phosphatase 2A (PP2A) from its physiological inhibitor, the oncoprotein SET. This TT1-IP peptide has an antitumoral effect on CLL, as shown by the increased survival of mice bearing xenograft models of CLL, compared to control mice. The peptide did not show toxicity, as indicated by the mouse body weight and the biochemical parameters, such as renal and hepatic enzymes. In addition, the peptide-induced apoptosis in vitro of primary tumoral B cells isolated from CLL patients but not of those isolated from healthy patients. Finally, the peptide had approximately 5 h half-life in human serum and showed pharmacokinetic parameters compatible with clinical development as a therapeutic peptide against CLL.
Asunto(s)
Leucemia Linfocítica Crónica de Células B , Animales , Apoptosis , Linfocitos B/metabolismo , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/metabolismo , Ratones , Péptidos/farmacología , Péptidos/uso terapéutico , Proteína Fosfatasa 2/metabolismo , Proteína Fosfatasa 2/farmacología , Proteína Fosfatasa 2/uso terapéuticoRESUMEN
Protein phosphatase 2A (PP2A) is a well-known tumor suppressor frequently inhibited in human cancer. Alterations affecting PP2A subunits together with the deregulation of endogenous PP2A inhibitors such as CIP2A and SET have been described as contributing mechanisms to inactivate PP2A in prostate cancer. Moreover, recent findings highlight that functional inactivation of PP2A could represent a key event in the acquisition of castration-resistant phenotype and a novel molecular target with high impact at both clinical and therapeutic levels in prostate cancer.
