Abstract
Simple SummaryCancer therapy suffers from its high cost and high rate of adverse effects and relapse of the disease. Hence, the new (preferably natural), economic and safer therapeutic as well preventive measures have been on demand and have been subject of priority research. We have, earlier, demonstrated anticancer activity in the extracts of Ashwagandha leaves and propolis. A combination of Wi-A (an active anticancer ingredient in Ashwagandha extract) and CAPE (an active anticancer ingredient in propolis) was earlier shown to offer higher and cancer cell-selective cytotoxicity. In the present study, we report an anti-metastasis activity in the low dose combination of Wi-A and CAPE along with its mechanism of action and propose its use in cancer metastasis treatment.Withaferin A (Wi-A) and Caffeic Acid Phenethyl Ester (CAPE) are the bioactive ingredients of Ashwagandha (Withania somnifera) and propolis, respectively. Both of these natural compounds have been shown to possess anticancer activity. In the present study, we recruited a low dose of each of these compounds and developed a combination that exhibited remarkably potent anti-migratory and anti-angiogenic activities. Extensive molecular analyses including a cDNA array and expression analyses of the specific gene targets demonstrated that such activities are mediated through their effect on cell adhesion/tight junction proteins (Claudins, E-cadherin), inhibition of canonical Wnt/β-catenin signaling pathways and the consequent downregulation of EMT-signaling proteins (Vimentin, MMPs, VEGF and VEGFR) that play a critical role in cancer metastasis. The data supported that this novel combination of Wi-A and CAPE (Wi-ACAPE, containing 0.5 µM of Wi-A and 10 µM of CAPE) may be recruited for the treatment of metastatic and aggressive cancers and, hence, warrant further evaluation by recruiting a variety of experimental and clinical metastatic models.
Highlights
Cancer is a highly heterogenous disease involving multiple mechanisms which are responsible for its proliferation, migration and stem cell characteristics
Withaferin A (Wi-A) (0.5 μM), Caffeic Acid Phenethyl Ester (CAPE) (10 μM) or their combination-treated normal fibroblast did not show any change in the expression of MMP3 and vimentin proteins that are involved in the metastasis (Figure S2C)
Based on the cDNA array results, we investigated the effect of Wi-A, CAPE and their combination on the expression of several tight junctions (TJ) genes that play an important role in cell-to-cell adhesion, tissue integrity and metastasis [60,61]
Summary
Cancer is a highly heterogenous disease involving multiple mechanisms which are responsible for its proliferation, migration and stem cell characteristics. In spite of the tremendous progress that has been made in cancer research and therapy, it is coined as an uncurable disease due to its three main characteristics (i) metastasis, the phenomenon by which cancer cells move from the primary site to secondary sites in the body, (ii) drug resistance and (iii) cancer cell stemness [1,2,3] Each of these three involves the interplay of multiple proteins in numerous ways, as well as their functional networking that influences the cancer characteristics and, requires targeted treatment. VEGF, which plays a critical role in the formation of blood and lymph vessels as well as tumor angiogenesis, is found to be upregulated in most cancers and regulated by proteins involved in hypoxia signaling and the tumor microenvironment [31,32,33] Given these premises, Wnt/β-catenin, MMP and VEGF signaling have been suggested as cancer therapeutic targets [9,17,34]
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