The multiple combination of Paclitaxel, Ramucirumab and Elacridar reverses the paclitaxel-mediated resistance in gastric cancer cell lines

Abstract

IntroductionPaclitaxel (PTX) interferes with microtubule architecture by binding to β-tubulin, thereby blocking progression at the G2/M phase and inducing apoptosis. This study aimed to investigate molecular processes underlying PTX-mediated resistance in gastric cancer (GC) cells. MethodsPTX-mediated resistance involves many processes, and in this work some of the factors involved in the resistance mechanism were identified by comparing two GC lines with PTX induced resistance to their sensitive counterparts. ResultsThus, the key feature of PTX-resistant cells was the overexpression of pro-angiogenic factors such as VEGFA, VEGFC, and Ang2, known to support tumor cell growth. A second relevant change detected in PTX-resistant lines was the elevated level of TUBβIII, a tubulin isoform that opposes microtubule stabilization. A third identified factor contributing to PTX-resistance was P-glycoprotein (P-gp), a transporter responsible for chemotherapy efflux from the cells, highly expressed in PTX-resistant lines.Discussion These findings were in line with a greater sensitivity of resistant cells to treatment with both Ramucirumab and Elacridar. Ramucirumab significantly reduced the expression of angiogenic molecules and TUBβIII, while Elacridar restored the access of chemotherapy, recovering its anti-mitotic and pro-apoptotic effects. Finally, this study highlighted the role played by exosomes in spreading factors responsible for resistance in the tumor microenvironment.

Unveiling the Potential of Extracellular Vesicles as Biomarkers and Therapeutic Nanotools for Gastrointestinal Diseases

“…They not only have the capability to alter gene expression in target cells through their mRNA or miR cargo [ 39 ] but also crucially contribute to modulating the microenvironment of GIDs. For example, they are involved in modifying the tumor microenvironment, triggering processes such as angiogenesis [ 40 ] and metastasis, and establishing hypoxia [ 31 , 41 ].…”

Extracellular Vesicles and Cancer Multidrug Resistance: Undesirable Intercellular Messengers?

“…In the gastric cancer cell lines HGC27 and KATOIII, paclitaxel-resistant clones with P-gp upregulation released EVs with higher P-gp content than sensitive clones. Furthermore, the addition of EVs from the resistant cells to the sensitive counterparts stimulated the resistance to paclitaxel, most likely due to enhanced drug efflux [ 121 ]. Also, EVs from drug-resistant HepG2 (i.e., hepatocellular carcinoma) cells increased the resistance of parental HepG2 cells to cisplatin.…”