DHPAC, a novel microtubule depolymerizing agent, suppresses angiogenesis and vasculogenic mimicry formation of human non‐small cell lung cancer

Abstract

Angiogenesis and vasculogenic mimicry (VM) are the main causes of tumor metastasis and recurrence. In this study, we investigated the antiangiogenesis and anti-VM formation of a novel microtubule depolymerizing agent, DHPAC, as well as combretastatin A4 (CA4, a combretastatin derivate) in non-small-cell lung cancer (NSCLC), subsequently elucidating the underlying mechanisms. In human umbilical vein endothelial cells (HUVECs), DHPAC could enter cells and inhibit proliferation, migration, and angiogenesis in the presence and absence of conditioned medium from H1299 cells. Interestingly, the inhibition was enhanced under the stimulation of the conditioned medium. Under hypoxia or normoxia, DHPAC suppressed signal transducer and activator of transcription 3 phosphorylation and reduced vascular endothelial growth factor (VEGF) expression and secretion from HUVECs, thus impeding the activation of the downstream signal transduction pathway of VEGF/VEGFR2. However, JNK inhibitors reversed the inhibitory effect of DHPAC on the angiogenesis, suggesting that DHPAC regulated angiogenesis through activating JNK. In H1299 cells, DHPAC could inhibit proliferation, migration, invasion, and the formation of VM. In addition, DHPAC inhibited the phosphorylation of FAK and AKT and decreased the expressions of VEGF, matrix metalloproteinase 2 (MMP2), MMP9 and Laminin 5, suggesting that DHPAC inhibited VM formation via the FAK/AKT signaling pathway. In addition, CA4 showed a similar effect as DHPAC against angiogenesis and VM formation. These new findings support the use of microtubule destabilizing agents as a promising strategy for cancer therapy.

Clinical and Prognostic Role of Vasohibin-1 Expression in Solid Tumors

“…Interestingly, considering that the indispensable effect of VASH1 on maintaining vascular health and inhibiting angiogenesis, this unexpected result is worth a thorough discussion. Firstly, as we know, VASH1 is induced by angiogenic factors, to illustrate, VEGF and FGF-2 [4]. There is a positive relevance between the intensity of VASH1 and VEGFA in tumor cells [31,44].…”

Alternative Vascularization Mechanisms in Tumor Resistance to Therapy

“…Nanoparticle-based approaches have been proposed to target established VM, including cyclic RGD-functionalized nanoparticles [ 124 ], and liposomes incorporating chemotherapy and VM-targeting drugs [ 125 , 126 ]. The microtubule depolymerizing, vascular disrupting agents combretastatin A4 and DHPAC are another example of compounds that target already formed VM, rather than preventing it [ 127 ].…”

SUMOylation of PUM2 promotes the vasculogenic mimicry of glioma cells via regulating CEBPD

“…Vasculogenic mimicry (VM) phenomenon is a model of tumor microcirculation that does not depend on endothelial cells, 6,7 which refers to the tube structure formed by tumor cells with “endothelial cell function” through self‐deformation and matrix remodeling. Such tumor cells exhibit multiple phenotypes, such as dedifferentiation and embryogenesis, and have the dual characteristics of “endothelial cells” and “tumor cells.” Many studies have shown that VM exists in many fast‐growing solid tumors, like hepatocellular carcinoma, non‐small cell lung cancer, lung adenocarcinoma, and breast cancer 8‐11 . The existence of VM greatly decreases the efficacy of antiangiogenesis in chemotherapy drugs 12 .…”