Novel Drugs with High Efficacy against Tumor Angiogenesis

Abstract

Angiogenesis is involved in physiological and pathological processes in the body. Tumor angiogenesis is a key factor associated with tumor growth, progression, and metastasis. Therefore, there is great interest in developing antiangiogenic strategies. Hypoxia is the basic initiating factor of tumor angiogenesis, which leads to the increase of vascular endothelial growth factor (VEGF), angiopoietin (Ang), hypoxia-inducible factor (HIF-1), etc. in hypoxic cells. The pathways of VEGF and Ang are considered to be critical steps in tumor angiogenesis. A number of antiangiogenic drugs targeting VEGF/VEGFR (VEGF receptor) or ANG/Tie2, or both, are currently being used for cancer treatment, or are still in various stages of clinical development or preclinical evaluation. This article aims to review the mechanisms of angiogenesis and tumor angiogenesis and to focus on new drugs and strategies for the treatment of antiangiogenesis. However, antitumor angiogenic drugs alone may not be sufficient to eradicate tumors. The molecular chaperone heat shock protein 90 (HSP90) is considered a promising molecular target. The VEGFR system and its downstream signaling molecules depend on the function of HSP90. This article also briefly introduces the role of HSP90 in angiogenesis and some HSP90 inhibitors.

Keywords: HSP inhibitors; Tie/Ang; VEGF/VEGFR; anti-tumor angiogenesis; novel drugs.

Figure 1

VEGF signaling pathway. After the VEGF level reaches the maximal concentration level at the leading edge of the vascular sprout, it binds to VEGFR and induces the migration of endothelial tip cells. Once VEGFR is activated, it leads to a series of downstream pathways. The transduction of downstream Raf-MEK-MAPK, P13K/AKT, (ERK)1/2/FAK, and other signals affects endothelial cell proliferation and survival. PI3K/Akt signaling is responsible for the expression of other molecules required for tumor cell invasion and metastasis, including Cdc42, Rho, and Rac proteins. VEGFA can activate c-Src and Yes proteins through VEGFR and phosphorylated adhesion factors, such as VE-cadherin and β-catenin, in the presence of TSAd to increase the vascular permeability. Furthermore, activated endothelial nitric oxide synthase (eNOS) affects vascular permeability by releasing nitric oxide in blood vessels. VEGFR can activate the P38/MAPK signaling pathway through Nck and Fyn binding, induce changes in the cytoskeleton, and promote tube formation in endothelial cells. VEGF, vascular endothelial growth factor; and VEGFR, vascular endothelial growth factor receptor.

Figure 2

Angiopoietin signaling pathway. When Ang1 binds to Tie2, Tie2 auto-phosphorylates. Tie2 receptors regulate downstream signaling pathways, such as PI3K/AKT, MAPK)/ERK (also known as Ras/Raf/MEK/ERK), Survivin, and eNOS, and inhibits Caspase-9 and Bad, among others. These pathways are involved in reducing angiogenesis and vascular permeability, favoring vascular stability. Following Tie2 activation, FOXO-1 is phosphorylated and inactivated, thereby, promoting endothelial cell quiescence, survival, and vascular stability. In addition, the phosphorylation of Tie2 also prevents NF-κB signaling activation. In activated endothelial cells, Ang2 is released from endothelial Weibel–Palade bodies. It will antagonize Ang1–Tie2 signaling and inhibit Tie-2 phosphorylation, leading to vascular instability, vascular leakage, inflammation, etc., thereby promoting angiogenesis. Under these conditions, the FOXO-1 transcription factor is activated and promotes the transcription of Ang2 mRNA, further promoting vascular destabilization. Ang, Angiopoietin; and WPB, Weibel–Palade bodies.