Molecular mechanisms of synergistic action of Ramucirumab and Paclitaxel in Gastric Cancers cell lines

Abstract

Ramucirumab is approved both as monotherapy and in combination with paclitaxel for advanced gastric cancer in patients with disease progression after chemotherapy. in tumor cells, the VeGfA-VEGFR2 binding activates autocrine survival and migration signaling in angiogenesis independent manner. the present in vitro study investigated the effects of single and combined treatments with Ramucirumab and paclitaxel on cell growth and migration highlighting the mechanisms underlying the interaction between the two drugs in gastric cancer cells. cell growth and motility were investigated in human gastric cancer cell lines characterized by different tumorigenicity. The inhibitory effect on cell growth exerted by both drugs was potentiated by their combination and was synergistic. Ramucirumab was able to enhance the inhibitory effect exerted by Paclitaxel on cell cycle progression. A synergistic action was also observed in the expression of proteins crucial for cell motility, microtubule organization and epithelial-mesenchymal transition. Furthermore, synergistic inhibition of VEGFR2 expression was obtained by the drug combination. These findings highlighted the importance of the combined treatment to strongly inhibit all the main molecules of both PI3K/Akt/mTOR and MAPK pathways thus preventing possible reactivations due to cross-talk phenomena. The combined treatment with Ramucirumab seems to be a promising option to overcome the paclitaxel resistance.VEGFR2 plays a crucial role in gastric cancer pathogenesis and progression and Ramucirumab (Ram), a monoclonal antibody against VEGFR2, is the first antiangiogenic agent with demonstrated activity against advanced gastric cancer. Based on the results obtained by two different phase III studies, Ram is approved both as monotherapy and in combination with Paclitaxel (PTX) for this malignancy in patients with disease in progression after a preceding therapy based on platinum and fluoropyrimidin 1-5 .The proangiogenic actions of VEGFs in endothelial cells are mediated primarily through the binding and activation of VEGFR2 6 and retrospective studies considered VEGF and its receptors as possible biomarkers in gastric carcinoma 7-9 . Moreover, the recent discovery of the production of different VEGF ligands and of the expression of VEGFR1, VEGFR2 and VEGFR3 in epithelial cancer cells, suggests a direct role for these ligands and their receptors in the autocrine control of some biological processes. In epithelial tumor cells, the binding of VEGFA, the main ligand of VEGFR2, activates downstream survival and migration signaling pathways represented by PI3K/ Akt/mTOR and MAPK cascades in a cell autonomous and angiogenesis independent manner 10-13 .The combined treatment with Ram seems to be a promising option to prevent the resistance to PTX also in recurrent and metastatic gastric cancer patients receiving taxane-based first-line palliative chemotherapy 14 . PTX is known to interfere with microtubule architecture by binding to β-tubulin, thereby blocking cell cycle progression at th...

Reducing tumor invasiveness by ramucirumab and TGF‐β receptor kinase inhibitor in a diffuse‐type gastric cancer patient‐derived cell model

“…Western blot analyses revealed that combining the two agents also reduced mesenchymal (SNAIL, vimentin, and N‐cadherin) and induced epithelial (E‐cadherin) marker expression, suggesting reversal of the EMT in treated cell lines. These findings were consistent with those of a previous report evaluating the effects of a combination of ramucirumab and paclitaxel in GC cell lines, in which E‐cadherin was upregulated and N‐cadherin was downregulated 40 . Hence ramucirumab and TGF‐β receptor kinase inhibitor may profoundly reduce invasiveness of GC cells, especially those with high EMT features, such as malignant cells from diffuse‐type GC ascites.…”

Current Perspectives on Taxanes: Focus on Their Bioactivity, Delivery and Combination Therapy

“…Although none of these drugs separately were able to modulate the phosphorylation levels of the proteins involved in this pathway, when co-administered, strong inhibition of protein phosphorylation was detected. To sum up, the synergistic effect of ramucirumab and paclitaxel co-administration demonstrated in this study was confirmed by all measured parameters, i.e., cell growth inhibition, cell cycle progression inhibition, expression of proteins crucial for cell motility, microtubule organization, or VEGFR expression [ 147 ]. Thus, it seems, that this combination of drugs might be a successful treatment approach for gastric cancer, though we have to wait for some statistically more relevant data concerning possible long-term side effects caused by this drug co-administration since it has been used clinically only since 2014.…”

The Role and Expression of Angiogenesis-Related miRNAs in Gastric Cancer

“…Similarly, the biomarker analysis in the RAINBOW study was unsuccessful in identifying circulating predictive factors in plasma samples of GC patients [ 84 ]. Ramucirumab is frequently used in combination with paclitaxel because the combination of both drugs has a synergistic inhibitory effect on cell growth [ 85 ]. Ramucirumab acts by enhancing the growth inhibition of paclitaxel and the inhibitory effects of chemotherapy on cell migration and actin polymerization.…”

“…Ramucirumab acts by enhancing the growth inhibition of paclitaxel and the inhibitory effects of chemotherapy on cell migration and actin polymerization. Moreover, the two agents modulate the cell expression of VEGF-A and VEGFR-2 and the signaling of MAPK and the PI3K/AKT/mTOR pathways [ 85 ].…”