Abstract
To evaluate the effects of curcumin (CUR) on tumor progression and angiogenesis in cervical cancer- (CaSki-) implanted nude mice and on the angiogenic biomarkers: vascular endothelial growth factor (VEGF), cyclooxygenase-2 (COX-2), and epidermal growth factor receptor (EGFR). CaSki cells were subcutaneously injected in nude mice to establish subcutaneous tumors. One month after injection, mice were orally administered vehicle or 500, 1,000, and 1,500 mg/kg of CUR daily × 30 consecutive days. Tumor volume was measured every 3-4 days. At the end of the study, tumor microvasculature was observed under confocal microscope, and immunohistochemical analyses were performed to detect CD31, VEGF, COX-2, and EGFR. CUR at the doses of 1,000 and 1,500 mg/kg showed significant tumor growth retardation (21.03% and 35.57%) versus CaSki + vehicle group. The microvascular density (MVD) in CaSki + vehicle group was significantly increased versus Control + vehicle group and significantly reduced by CUR (1,000 and 1,500 mg/kg). VEGF, COX-2, and EGFR expressions were upregulated in CaSki + vehicle group and attenuated significantly by CUR (1,000 and 1,500 mg/kg). In conclusion, high dose CUR inhibited tumor growth and angiogenesis in CaSki-implanted mice probably mediated by the downregulation of VEGF, COX-2 and EGFR. CUR may have a role in treating human cervical cancer and should be explored further.
Highlights
Cervical cancer is the second most common cancer in women worldwide and is the most frequent cancer in many developing countries [1]
In the original hypothesis formulated by Folkman in the early 1970s of angiogenic control of tumor growth [17], it was proposed that tumor growth was limited by diffusion to a size of 1-2 mm unless additional blood vessels were recruited to the tumor site
We demonstrated that a strong correlation was found between vascular endothelial growth factor (VEGF) expression and increased tumor microvasculature in CaSki + vehicle group. These results suggest strongly that VEGF and angiogenesis promoted by VEGF play important roles in tumor growth
Summary
Cervical cancer is the second most common cancer in women worldwide and is the most frequent cancer in many developing countries [1]. Antiangiogenic treatment strategies offer a number of compelling advantages over conventional cytotoxic cancer therapies because endothelial cells are not transformed and drug resistance is not induced. In this regard, discovery of nontoxic antiangiogenic phytochemicals could have greater practical significance compared to nonselective cytotoxic therapies to control the tumor growth and metastasis by targeting angiogenesis. Activation of EGFR results in activation of MEKextracellular signal-regulated kinase1/2 (ERK1/2) and phosphatidylinositol 3-kinase (PI3K-) Akt pathways [3] These two pathways regulate VEGF expression through changes in VEGF transcriptional activity which is a major mediator of tumor angiogenesis. EGFR seems to have an important role in tumor angiogenesis and the prognostic of advanced cervical cancer
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