Background: Hepatocellular carcinoma (HCC) is the fourth most common malignant tumor in China.Temozolomide (TMZ) is a common chemotherapy drug which can effectively kill HCC cells in vitro.However, it is possible that HCC cells possess intrinsic resistance to TMZ. A key mechanism of TMZ resistance is the overexpression of O6-methylguanine-DNA methyltransferase (MGMT). Studies have shown that MAPK may be related to MGMT expression, U0126 is a highly selective inhibitor of MEK1 and MEK2, which were crucial molecule in cascade of mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/ERK) pathway. Sorafenib was another widely applicated target drug in HCC which could inhibit multiple kinases including MAPK/ERK. This research was aimed to investigate the efficacy of MAPK/ERK inhibitor U0126 and sorafenib combine with TMZ in the treatment of HCC.Methods: In HCC cells, MAPK/ERK signaling pathway was blocked by U0126 and sorafenib. The effect of blocking MAPK/ERK signaling pathway on TMZ-induced cytotoxicity was evaluated by MTT assay, flow cytometry and TUNEL assay. DNA damage protein and the expression of MGMT were detected by Western-blot. After the downregulation of MAPK/ERK signaling pathway, MGMT mRNA expression and the protein expression of MGMT were quantified by quantitative real-time polymerase chain reaction (RT-qPCR) and immunofluorescence assay, respectively. HepG2 cells were transfected with an MGMT over expression plasmid. After transfection, the effect of U0126 on TMZ-induced cytotoxicity was evaluated by MTT and Western-Blot in MGMT OE cells. The influence of Sorafenib on TMZ-induced cytotoxicity to HCC cells was also detected by MTT assay.Results: U0126 can enhance the chemosensitivity of HCC cells to TMZ. At the same time, we also found that U0126 increases the damage to DNA caused by TMZ in HepG2 cells. Moreover, the results from RT-qPCR and Western blot showed that U0126 downregulated MGMT mRNA and MGMT protein expression via blocking MAPK/ERK pathway. Furthermore, after transfection with an MGMT expression plasmid, overexpression of MGMT restored U0126-induced chemosensitivity to TMZ in HCC cells. Sorafenib can also increase the chemosensitivity of HCC cells to TMZ.Conclusions: Our studies suggest great clinical potential for the utilization of combined U0126 and TMZ in patients with advanced HCC.
Background: Microwave ablation (MWA) is widely used to treat unresectable primary and secondary malignancies of the liver, and a limited number of studies indicate that ablation can cause not only necrosis at the in situ site but also an immunoreaction of the whole body. This study aimed to investigate the effects of MWA on cytokines in patients who underwent MWA for a hepatic malignancy. Methods: Patients admitted to the Oncology Department in the First Affiliated Hospital of Soochow University between June 2015 and February 2019 were selected. Peripheral blood was collected from patients with a hepatic malignancy treated with MWA. The levels of cytokines (IL-2, IFN-γ, TNF-α, IL-12 p40, IL-12 p70, IL-4, IL-6, IL-8, IL-10, and vascular endothelial growth factor (VEGF)) were detected with a Milliplex® MAP Kit. The comparison times were as follows: before ablation, 24 h after ablation, 15 days after ablation, and 30 days after ablation. Data were analyzed using a paired sample t-tests and Spearman's correlation analysis. Results: A total of 43 patients with hepatic malignancies were assessed. There were significant differences in IL-2, IL-12 p40, IL-12 p70, IL-1β, IL-8, and TNF-α at 24 h after MWA. Significant increases (> 2-fold vs. before ablation) were observed in IL-2, IL-1β, IL-6, IL-8, IL-10, and TNF-α after MWA. Elevated IL-2 and IL-6 levels after ablation were positively correlated with energy output during the MWA procedure. Conclusions: WA treatment for hepatic malignancies can alter the serum levels of several cytokines such as IL-2 and IL-6.
Background: Bone is among the most common metastasis sites in patients with advanced cancer.Approximately two-thirds of bone metastasis results in pain, the majority of which is moderate to unbearable pain, which seriously affects the quality of life of patients. With the development of ablation techniques, microwave ablation (MWA) has great potential to eliminate the pain caused by bone metastasis. This study aimed to evaluate the efficacy and safety of image-guided (computed tomography-guided) percutaneous MWA for metastatic osseous pain.Methods: This is a retrospective study involving 18 patients with cancer-related pain caused by osseous or soft tissue metastasis in the First Affiliated Hospital of Soochow University from June 2015 to October 2020.All patients (14 men and 4 women; mean age 60.2 years) underwent image-guided percutaneous palliative MWA. A paired-sample t-test was used to compare the changes in Numeric Rating Scale (NRS) score and dosage of morphine preoperatively and postoperatively (at 24 h, 3 days, and 14 days after MWA). In addition, we assessed the level of pain relief according to the patients' subjective feelings. Results:The paired-samples t-test showed that the NRS score (6.83±0.92 vs. 1.67±0.97, P<0.05) and dosage of morphine (85.56±17.23 vs. 32.78±4.61, P<0.05) were significantly decreased at 3 days after MWA. At 14 days after MWA, the NRS score (6.83±0.92 vs. 0.94±0.87, P<0.05) and dosage of morphine (85.56±17.23 vs. 10.56±8.73, P<0.05) were also markedly decreased. Moreover, according to the patients' subjective feeling, 88.89% patients had pain relief postoperatively, while the remaining patients had no progress.Conclusions: Image-guided (Computed Tomography-guided) percutaneous MWA can effectively relieve pain, thus improving the quality of life in patients with osseous metastasis. MWA is a feasible, safe, and effective treatment for pain caused by bone metastasis.
BackgroundThe alkylating agent temozolomide (TMZ) is widely used to treat melanoma in clinical practice. However, cells expressing the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) are highly resistant to this drug. Vemurafenib (vMF), a targeted BRAF kinase inhibitor, is applied to treat BRAF-V600 mutant metastatic melanoma. Studies have suggested that blocking this pathway prevents MGMT from affecting TMZ sensitization. However, reports of the use of the combination of vMF and TMZ in the treatment of melanoma are lacking.MethodsCell viability was detected by MTT assay, cell apoptosis was assayed by flow cytometry, and the mRNA level of the MGMT gene was measured by RT-qPCR. Western blotting, immunofluorescence staining were utilized to determine the expression of the protein. The pcDNA3.1-MGMT vector was transiently transfected to generate MGMT-overexpressing cells for experiments. A nude mouse malignant melanoma xenograft model was established for in vivo drug experiments.ResultsvMF increased TMZ-induced cytotoxicity by increasing DNA damage. vMF inhibited the MAPK/ERK signaling pathway and the mRNA and protein expression of the MGMT gene. vMF did not inhibit MGMT protein expression in A375-MGMT OE cells, and the vMF-induced sensitization effect was attenuated. Moreover, TMZ exposure activated ERK activity in malignant melanoma. The expression of MGMT and p-ERK1/2 was positively correlated in melanoma tissues.ConclusionvMF sensitized melanoma to TMZ by inhibiting the MAPK/ERK-MGMT pathway, and the combination of vMF and TMZ is expected to improve the clinical treatment effect on malignant melanoma.
BackgroundMicrowave ablation (MWA) is widely used to treat unresectable primary and secondary malignancies of the liver, and a limited number of studies indicate that ablation can cause not only necrosis at the in situ site but also an immunoreaction of the whole body. This study aimed to investigate the effects of MWA on cytokines in patients who underwent MWA against a hepatic malignancy.MethodsPatients admitted to the Oncology Department in the First Affiliated Hospital of Soochow University between June 2015 and February 2019 were selected. Peripheral blood was collected from patients with a hepatic malignancy treated with MWA. The levels of cytokines (IL-2, IFN-γ, TNF-α, IL-12 p40, IL-12 p70, IL-4, IL-6, IL-8, IL-10, and vascular endothelial growth factor (VEGF)) were detected with a MILLIPLEX® MAP Kit. The comparison times were as follows: before ablation, 24 hours after ablation, 15 days after ablation, and 30 days after ablation. Data were analyzed using a paired sample t-test and Spearman’s correlation analysis.ResultsA total of 43 patients with hepatic malignancies were recorded. There were significant differences in IL-2, IL-12 p40, IL-12 p70, IL-1β, IL-8, and TNF-α at 24 hours after MWA. Significant increases (>2-fold vs. before ablation) were observed in IL-2, IL-1β, IL-6, IL-8, IL-10, and TNF-α after MWA. Elevated IL-2 and IL-6 levels after ablation were positively correlated with energy output during the MWA procedure.ConclusionsMWA treatment for hepatic malignancies can alter the serum levels of several cytokines and affect the tumor status.
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