ABSTRACT
Human epidermal growth factor receptor 2 (HER2) is frequently overexpressed in human ovarian cancers and its overexpression is associated with increased angiogenesis, increased metastasis and reduced survival. Inhibition of HER2 in HER2-overexpressing cancers can lead to reduced angiogenesis and improved survival. Previously, we reported that SV40 T/t-common polypeptide has transcriptional repression activity and can inhibit HER2 expression. In this study, we investigated the effect of T/t-common on the angiogenesis-inducing activity of HER2-overexpressing human SK-OV-3 ovarian cancer cells. We found that compared to conditioned medium from control SK-OV-3 cancer cells, conditioned medium from T/t-common-expressing SK-OV-3 cells had a reduced ability to induce endothelial cell migration and tube formation in vitro and microvessel formation in vivo. These data indicate that T/t-common can inhibit the ability of SK-OV-3 cancer cells to induce angiogenesis. T/t-common was found to be able to downregulate the expression of several proangiogenic factors, including vascular endothelial growth factor-A, interleukin-8, basic fibroblast growth factor, matrix metalloproteinase-2 and urokinase-type plasminogen activator, and upregulate antiangiogenic factors, including thrombospondin-1 and tissue inhibitor of metalloproteinases-1 in SK-OV-3 cancer cells. Finally, we demonstrated that T/t-common could inhibit the angiogenesis and growth of HER2-overexpressing human ovarian tumor in NOD/SCID mice. Taken together, the data suggest that T/t-common had the potential to be developed as a new antiangiogenic agent specific for treating HER2-overexpressing ovarian cancers.
Subject(s)
Antigens, Polyomavirus Transforming/therapeutic use , Neovascularization, Pathologic/therapy , Ovarian Neoplasms/blood supply , Ovarian Neoplasms/therapy , Peptides/therapeutic use , Receptor, ErbB-2/antagonists & inhibitors , Animals , Cell Line , Cell Line, Tumor , Cell Movement , Cell Proliferation/drug effects , Culture Media, Conditioned , Female , Gene Expression Regulation, Neoplastic , Humans , Mice , Mice, Inbred NOD , Ovarian Neoplasms/genetics , Receptor, ErbB-2/geneticsABSTRACT
Photodynamic therapy (PDT) is a relatively new cytotoxic treatment, predominantly used in anti-cancer approaches, that depends on the retention of photosensitizers in tumor and their activation after light exposure. Photosensitizers are photoactive compounds such as porphyrins and chlorins that upon photoactivation, effect strongly localized oxidative damage within the target cells. The ability to confine activation of the photosensitizer by restricting illumination to the tumor allows for a certain degree of selectivity. Nevertheless, the targeted delivery of photosensitizers to defined cells is a major problem in PDT of cancer, and one area of importance is photosensitizer targeting. Alterations or increased levels in receptor expression of specific cellular type occur in the diseased tissues. Therefore, photosensitizers can be covalently attached to molecules such as peptides, leading to a receptor-mediated targeting strategy. These active-targeting approaches may be particularly useful for anti-vascular PDT. Moreover, it has been shown that the photocytotoxicity of photodynamic drugs could be enhanced by delivering high amounts of a photosensitizer into subcellular organelles such as the nucleus where nucleic acids represent target molecules sensitive to photodamage. The recent progresses in the use of active-targeting strategy with synthetic peptides and the interest of using an active-targeting strategy in PDT, which could allow efficient cellular internalization of photosensitizers, are described in this review.
