ABSTRACT
A 38-year-old man with a diagnosis of BRAF-mutated metastatic melanoma was referred to our clinic. He had been under treatment with 60-mg oral cobimetinib daily for 21 days/7 day off in combination with 960 mg vemurafenib twice daily. The patient had symptoms of blurred vision and photophobia in his right eye. A slit-lamp examination revealed bilateral central corneal stromal opacity and epithelial microcystic edema Involvement was more severe in the right eye compared with the left eye. Fourteen days after the first visit, the patient's symptoms and slit-lamp findings were largely resolved. We suggest that endothelium pump failure was involved in this acute corneal decompensation case similar to the mechanism in retinal pigment epithelium.
ABSTRACT
Objective To examine the effects of the MEK inhibitor on human pancreatic cancer cells, and to explore the molecular mechanisms. Methods Human pancreatic cancer cell lines CFPANC1, PANC1 and MiaPaCa2 were treated with MEK inhibitor PD98059 or DMSO, the sensitivity was analyzed by an MTT assay, and cell cycle distribution was evaluated by flow cytometry( FCM), The transcriptional level and protein expression of tumor suppressor genes were detected by real-time RT-PCR and western blot respectively. DNA methyltransferase (Dnmt)1, 3a and 3b were also assayed by western blot, The methylation status of the promoter of the p16INK4A gene was assayed by methylation-specific PCR (MSP). Results PD98059 inhibited to various degrees the growth of three pancreatic cancer cell lines, accompanied by G0-G1 cell cycle arrest. PD98059 up-regulated the expression of p16INK4a, p21WAF1, p27KIP1 mRNA, demethylated the hypermethylation status of p16INK4a gene promoter, and decreased Dnmtl and Dnmt3b in CFPANC1 and PANC1 cell lines. PD98059 only increased the expression of p27KIP1, while the changes of p16INK4a, p21WAF1 and Dnmt were less marked in MiaPaCa2 cell line. Conclusions MEK inhibitor PD98059 down-regulate the activation of Dnmt and up-regulate tumor supress genes, along with the inhibition of cell proliferation and cell cycle progression.
ABSTRACT
OBJECTIVE: The objectives of this study were to determine the efficacy of AZD6244, a potent, selective MEK inhibitor, in epithelial ovarian cancer (EOC) cells and to determine the enhanced cell death by combined treatment of paclitaxel and AZD6244. METHODS: EOC cells were treated with tenfold dilutions of AZD6244 (0.1 to 10 micrometer) for 24, 48 and 72 hours. Cell viability was determined by the CellTiter 96 AQueous One Solution Cell Proliferation Assay. The apoptotic cascade was assessed by Caspase-Glo assays. ERK activation was evaluated by Western blot analyses. Cytokine profiling was performed from culture supernatants using the Luminex 200 system. RESULTS: In vitro cell viability showed that ovarian cancer cells with high p-ERK activities (A2780, R454, 01-28) exhibited significant growth inhibition. Cells with low p-ERK activities (R182, CP70), however, were resistant to AZD6244. Caspase-3 was not activated during AZD6244-induced growth inhibition. AZD6244 significantly inhibited p-ERK1/2 in both cell types regardless of constitutive levels of p-ERK. Proinflammatory cytokines including IL-6, IL-8, MCP-1 and GM-CSF were significantly decreased. Paclitaxel activated the p-ERK levels in paclitaxel-resistant R182 cells with low basal p-ERK level. MEK inhibition by AZD6244 enhanced paclitaxel-induced apoptosis significantly in R182 cells. CONCLUSION: These results demonstrate that AZD6244 has a potent growth inhibitory effect in ovarian cancer cells with high p-ERK activities. In addition, targeted inhibition of the extracellular signal-regulated kinase pathway with AZD6244 can enhance the anti-tumor efficacy of the cytotoxic paclitaxel.