Abstract
Angiogenesis is required for tumor growth and metastasis, and targeting angiogenesis is a novel anticancer strategy. However, cancer development is a complex multistep process, and single antiangiogenic agents have limited therapeutic efficacy. Here, we report a triple fusion protein, namely CTT peptide-endostatin mimic-kringle 5 (AARP), consisting of MMP-2/9-selective inhibitory peptide (CTT peptide) and well-known endogenous antiangiogenic agents (endostatin mimic and kringle 5), which can simultaneously target matrix metalloproteinases (MMP) and endothelial cells, blocking their actions. AARP was bacterially expressed, and biologic activity of purified AARP was assessed. AARP could significantly inhibit the enzymatic activity of MMP-2/9, proliferation, migration, and tube formation of endothelial cells in vitro. The antitumor activity of AARP was shown in a concentration-dependent manner when injected i.p. into immunodeficient mice bearing multidrug-resistant human epidermoid carcinomas (KB), and AARP is superior to clinical grade endostatin in inhibiting KB xenograft growth. In mouse models of Lewis lung carcinoma (LLC) and hepatoma H22, when given as a single dose, AARP is highly effective for reducing tumor growth, angiogenesis, and metastasis, and increasing survival time. AARP possessed significantly greater antiangiogenic activity than endostatin mimic, CTT peptide-kringle 5 (RK5) both in vitro and in vivo. Compared with conventional chemotherapeutic agents (cyclophosphamide and paclitaxel), AARP is also effective. More importantly, AARP is cytocompatible and no tissue toxicity could be observed after large dose administration. Taken together, our findings suggest AARP is a highly effective, safe, and more potent antiangiogenic agent for blocking tumor angiogenesis and metastasis, and warrants further testing for clinical applications.
Highlights
Angiogenesis is a program of deliberately orchestrated cellular events that includes endothelial cell proliferation, migration and differentiation, and remodeling of the extracellular matrix (ECM; refs. 1, 2)
One is named AARPa, another AARPb according to the position of 25aa fused with RK5
RK5 showed an apparent molecular weight of 12 kDa, AARPa and AARPb showed an apparent molecular weight of 15 kDa, matching the calculated molecular weight based on the sequence (Fig. 1B)
Summary
Angiogenesis is a program of deliberately orchestrated cellular events that includes endothelial cell proliferation, migration and differentiation, and remodeling of the extracellular matrix (ECM; refs. 1, 2). Angiogenesis is tightly regulated by a balance between angiogenic activators and inhibitors [1]. Angiogenesis is a rate-limiting step in the development and progression of tumors because tumor growth is generally limited to. 1 to 2 mm in the absence of a blood supply [3]. In the tumor microenvironment, when angiogenic stimulators outbalance angiogenic inhibitors, generating a proangiogenic response and an increased blood vessel density to allow the tumor to progress [3, 4]. Interfering with angiogenesis is a promising strategy in cancer therapy to delay tumor growth by preventing a tumor from developing its own blood supply system [3, 5]
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