Curcumin, a natural polyphenol compound from the perennial herb Curcuma longa, has been proved to be beneficial for tumor-bearing animals through inhibiting tumor neovasculature formation, but the underlying mechanisms are unclear. Here, we aim to test whether curcumin affects VEGF-VEGFR2 signaling pathway and attenuates defective hematopoiesis induced by VEGF in tumor model. We demonstrated that curcumin inhibited proliferation, migration of HUVEC under VEGF stimulation and caused HUVEC apoptosis, and blocked VEGFR2 activation and its downstream signaling pathways in vitro. Furthermore, in VEGF over-expressing tumor model, curcumin significantly inhibited the tumor growth accelerated by VEGF in a dose-dependent manner and improved anemia and extramedullary hematopoiesis in livers and spleens of tumor-bearing mice induced by tumor-derived VEGF. Immunohistochemical analysis showed that curcumin normalized vasculature structures of livers and reduced tumor microvessel density. ELISA revealed that curcumin suppressed VEGF secretion from tumor cells both in vitro and in vivo. Survival analysis showed that curcumin significantly improved survival ability of VEGF tumor-bearing mice. Taken together, these findings establish curcumin as a modulator of VEGF and VEGF-VEGFR2 signaling pathway, with potential implication for improving the quality of life of cancer patients.

No abstract

Combinatorial therapies that target multiple signaling pathways may provide improved therapeutic responses over monotherapies. Celecoxib and curcumol are two highly hydrophobic drugs which show bioavailability problems due to their poor aqueous solubility. In the present study, we evaluated the effects of celecoxib and curcumol alone and in combination on cell proliferation, invasion, migration, cell cycle and apoptosis induction in non-small cell lung cancer (NSCLC) cells using in vitro and in vivo experiments. Our data showed that the sensitivity of a combined therapy using low concentration of celecoxib and curcumol was higher than that of celecoxib or curcumol alone. Suppression of NF-κB transcriptional activity, activation of caspase-9/caspase-3, cell cycle G1 arrest, and inhibition of survival MAPK and PI3K/AKT signaling pathway contributed to the synergistic effects of this combination therapy for induction of apoptosis. Additionally, either celecoxib alone or in combination with curcumol inhibited NSCLC cell migration and invasion by suppressing FAK and matrix metalloproteinase-9 activities. Furthermore, the combined treatment reduced tumor volume and weight in xenograft mouse model, and significantly decreased tumor metastasis nodules in lung tissues by tail vein injection. Our results confirm and provide mechanistic insights into the prominent anti-proliferative activities of celecoxib and/or curcumol on NSCLC cells, which provide a rationale for further detailed preclinical and potentially clinical studies of this combination for the therapy of lung cancer.