Abstract
Lack of effective anti-metastatic drugs creates a major hurdle for metastatic lung cancer therapy. For successful lung cancer treatment, there is a strong need of newer therapeutics with metastasis-inhibitory potential. In the present study, we determined the anti-metastatic and anti-angiogenic potential of a natural plant triterpenoid, Cucurbitacin B (CuB) against non-small cell lung cancer (NSCLC) both in vitro and in vivo. CuB demonstrated a strong anti-migratory and anti-invasive ability against metastatic NSCLC at nanomolar concentrations. CuB also showed significant tumor angiogenesis-inhibitory effects as evidenced by the inhibition of migratory, invasive and tube-forming capacities of human umbilical vein endothelial cells. CuB-mediated inhibition of angiogenesis was validated by the inhibition of pre-existing vasculature in chick embryo chorio-allantoic membrane and matrigel plugs. Similarly, CuB inhibited the migratory behavior of TGF-β1-induced experimental EMT model. The CuB-mediated inhibition of metastasis and angiogenesis was attributable to the downregulation of Wnt/β-catenin signaling axis, validated by siRNA-knockdown of Wnt3 and Wnt3a. The CuB-mediated downregulation of Wnt/β-catenin signaling was also validated using 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis model in vivo. Collectively, our findings suggest that CuB inhibited the metastatic abilities of NSCLC through the inhibition of Wnt/β-catenin signaling axis.
Highlights
Lack of effective anti-metastatic drugs creates a major hurdle for metastatic lung cancer therapy
We found that Cucurbitacin B (CuB) induced a significant dose- and time-dependent inhibition of cellular migration in A549 cells, starting with the concentrations of 25 nM at 12 and 24 h, and 10 nM at 48 h, respectively
Malignant progression is characterized by the alterations in normal cellular behavior leading to deregulated proliferation, migration, invasion and angiogenic capabilities, thereby facilitating cancer metastasis
Summary
Lack of effective anti-metastatic drugs creates a major hurdle for metastatic lung cancer therapy. We determined the anti-metastatic and anti-angiogenic potential of a natural plant triterpenoid, Cucurbitacin B (CuB) against non-small cell lung cancer (NSCLC) both in vitro and in vivo. Canonical Wnt/β -catenin signaling pathway is well known to be functionally important in the regulation of cellular proliferation, differentiation, motility as well as polarity Aberrations in this pathway are implicated in the pathogenesis of multiple tumor types, including lung cancer[9,10,11]. We sought to determine the anti-migratory and anti-invasive potential of CuB on metastatic human NSCLC cells and in the 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis mice model. Our findings suggest that CuB inhibits migratory and invasive abilities of both moderately as well as highly metastatic NSCLC cells through the downregulation of Wnt/β -catenin signaling axis. CuB exhibits potent anti-angiogenic activity in vitro, ex vivo as well as in vivo
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