Low-dose chemotherapy drugs can suppress tumours by restraining tumour vessel growth and preventing the repair of damaged vascular endothelial cells. Cisplatin is a broad-spectrum, cell cycle-non-specific drug, but has serious side effects if used at high doses. There have been few reports on the anti-angiogenic effects of low-dose cisplatin and hence the effect of low-dose metronomic (LDM) chemotherapy on the proliferation and neovascularization of H22 hepatocarcinoma cells is discussed in this research. The influence of LDM chemotherapy with cisplatin on human umbilical vascular endothelial cells (HUVECs) and proliferation of the HepG(2) human hepatocarcinoma cell line were measured using MTT assays. The LDM group was treated with cisplatin 0.6 mg/kg/day; the control group with saline 0.2 ml; the maximum tolerated dose (MTD) group with cisplatin 9 mg/kg/day. Vascular endothelial growth factor (VEGF) and matrix metallopeptidase 2 (MMP-2) were detected using immunohistochemical staining. A chicken chorio-allantoic membrane (CAM) model was used to check the inhibitory effect of LDM chemotherapy with cisplatin on neovascularization in vivo. Low-dose cisplatin inhibited HUVEC proliferation in a dose- and time-dependent manner, but was ineffective in inhibiting HepG(2) cell proliferation. Tumour growth was delayed in mice receiving LDM cisplatin, without apparent body weight loss, compared with mice that received MTD cisplatin. Microvessel density and expression of VEGF and MMP-2 were much lower in mice receiving LDM cisplatin than in the control and MTD groups. Continuous low-dose cisplatin suppressed CAM angiogenesis in vivo. LDM chemotherapy with cisplatin can inhibit the growth of blood vessel endothelial cells in vitro and shows anti-angiogenic ability in vivo.
Lung cancer, including small-cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC), are the most common tumor types, which represent 13% of newly diagnosed cancer cases worldwide. SCLC represents 15% of all lung cancer cases. Although an increasing number of novel targeted drugs are employed for the treatment of NSCLC, including Iressa, Tarceva and Conmana, there have been almost no major breakthroughs in SCLC over the last 30 years. Therefore, new drug targets are required to treat or prevent SCLC. Aberrant Wnt signaling is associated with numerous types of tumors, and it plays a key role in cell proliferation and survival. Recent preclinical studies suggested that XAV939 is a small-molecule inhibitor of the Wnt signaling pathway. In the present study, whether XAV939 is able to inhibit the proliferation of SCLC cells and the underlying mechanism were investigated. The inhibition of cell proliferation was detected by Cell Counting Kit-8 (CCK-8) assay. The mRNA expression of β-catenin and cyclin D1 were detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and the protein expression of β-catenin and cyclin D1 was determined by western blotting. The results from the CCK-8 cell viability assay confirmed that XAV939 is able to inhibit the proliferation of SCLC cells in a dose-dependent manner. However, the effects of XAV939 were not time-dependent. By contrast, the effect of DDP treatment was time- and dose-dependent. Furthermore, the effect of combination treatment with XAV939 and DDP was antagonistic at low doses and synergistic at high doses. It was also observed that the mRNA and protein expression of β-catenin and cyclin D1 was significantly in SCLC cells following XAV939 treatment compared with the control group. These findings suggested that XAV939 is able to inhibit the proliferation of H446 cells, at least partially, through downregulating the Wnt/β-catenin signaling pathway. All of these results may provide potential therapeutic approaches for the treatment of SCLC.
Small cell lung cancer (SCLC) is the most aggressive type of lung cancer due to a fast tumor doubling time and early hematogenous spread. Advances in the treatment of non-small cell lung cancer using targeted therapies having been made, but no targeted drugs for SCLC have been approved. The Wnt signaling pathway is associated with tumor progression and metastasis; therefore, the inhibition of Wnt/β-catenin signaling is a strategy for anticancer drugs. Tankyrase 1 (TNKS1) is overexpressed in a number of types of cancer and XAV939 is a small molecule inhibitor of TNKS1 which may inhibit tumor growth. The present study aimed to investigate the potential molecular mechanisms underlying XAV939-induced suppression of the viability of SCLC cells. MTT assays were used to determine the viability-inhibition rate of cells and to identify the drug concentration which optimally inhibited cell viability. Flow cytometry was used to determine whether XAV939 induced apoptosis of SCLC cells, and to analyze the effect of the drug on the cell cycle. The results of the present study identified that XAV939 inhibited the viability of NCI-H446 cells in a dose-dependent manner, but cisplatin inhibited NCI-H446 cell viability in a time- and dose-dependent manner. The combination of XAV939 and cisplatin exhibited a slightly more pronounced inhibition of cell viability at an increased dose of XAV939. In addition, XAV939 markedly induced cell apoptosis of the SCLC cell line H446 by increasing the proportion of cells in the G0/G1 phase, leading to inhibition of the cell cycle. The results of the present study indicated that XAV939 inhibited the viability of the NCI-H446 SCLC cell line by inducing cell apoptosis through the Wnt signaling pathway. Therefore, XAV939 may be useful for the treatment of SCLC.
We examined whether low dose radiation (LDR) exposure (75 mGy) could increase the therapeutic efficacy of cyclophosphamide (CTX) by comparing the effects of tumor suppression, tumor cell apoptosis, cell cycle and proliferation of bone marrow in vivo. Kunming mice implanted with S(180) sarcoma cells were given 75 mGy whole body gamma-ray radiation exposure and CTX (300 mg/kg) by intraperitoneal injection 36 hours after LDR. Proliferation of bone marrow and tumor cells was analyzed by flow cytometry. Cytochrome c leakage from the tumor was measured by Western-blot. We discovered that tumor growth was significantly reduced in the group exposed to CTX add to LDR. The apoptosis of tumor cells increased significantly after LDR. The tumor cells were arrested in G(1) phase in the groups treated with CTX and CTX + LDR, but cell cycle was more significantly arrested in mice exposed to LDR followed by CTX than in mice exposed only to LDR or CTX chemotherapy. Concentration of bone marrow cells and proliferation index in CTX + LDR mice were higher than those in the untreated mice. LDR or CTX + LDR could induce greater cytochrome c levels and caspase-3 activity in tumors. These results suggest that low dose radiation can enhance the anti-tumor effect of the chemotherapy agent CTX markedly. Furthermore, LDR significantly protects hematopoetic function of the bone marrow, which is of practical significance on adjuvant chemotherapy.
Abstract. Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. The aim of the present study was to reveal the prognostic significance of CD147 and to preliminarily explore the molecular mechanisms involved. Blood and tumor tissue specimens were obtained from 133 HCC patients. All patients were followed up for 4 years. The serum and tissue levels of CD147 were analyzed using ELISA and immunohistochemistry, respectively. The SMMC-7721 hepatoma carcinoma cell line was transfected with CD147 overexpression vector and cell migration was evaluated using a wound healing assay. Extracellular signal-regulated kinase (ERK) inhibitor UO126 was applied to study the role of the ERK pathway in cell migration. CD147 expression in HCC tissue was associated with poor prognosis of patients [odds ratio (OR): 3.13, 95% confidence interval (CI): 1.52-6.43], and patients with no CD147 expression had a significantly survival advantage (P=0.016). However, serum CD147 levels had no such prognostic significance (OR: 1.94, 95% CI: 0.96-3.91; P=0.097). In the wound healing assay, the wound distance in the non-transfected cell group was wider than that in the transfected cell group without UO126 treatment (178.0±31.1 vs. 106.0±20.7 µm; P=0.003), but similar to that in the transfected cell group with 10 µM UO126 treatment (170.4±13.2 µm; P=0.629). The present study revealed that the expression of CD147 in HCC tissue is an independent prognostic indicator. In addition CD147 overexpression may be associated with tumor cell migration and ERK signaling pathway activation.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.