Vinblastine differs from Taxol as it inhibits the malignant phenotypes of NSCLC cells by increasing the phosphorylation of Op18/stathmin

Abstract

Taxol (paclitaxel) and vinblastine (VBL) are both efficacious chemotherapeutic agents that target the microtubules of tumor cells, but each functions in a mutual antagonistic manner. Op18/stathmin is a small molecular phosphoprotein which promotes depolymerization of microtubules. Non-small cell lung cancer (NSCLC) NCI-H1299 cells were employed to compare the curative effects of VBL and Taxol and explore the correlation between drug sensitivity and Op18/stathmin signaling. The present study found that VBL obviously promoted cellular apoptosis and initiated activation of caspase 3 and 9, and inhibited cell proliferation and colony formation, as well as cell migration in the NCI-H1299 cells in contrast with Taxol. VBL did not affect the expression of Op18/stathmin, but increased its phosphorylation at all 4 serine sites. Conversely, Taxol mainly decreased the expression of Op18/stathmin and the phosphorylation at Ser25 and Ser63 sites. Silencing of Op18/stathmin by RNA interference (RNAi) led to a great reduction in the differences in the cell proliferation inhibition between VBL and Taxol. VBL treatment notably weakened the expression of PP2A, Bcl-2, NF-κB and interleukin-10 (IL-10) and autocrine IL-10 compared with Taxol; whereas PP2A was substantially increased following Taxol induction. High expression of Op18/stathmin was found to be negatively correlated with the sensitivity of Taxol in the NSCLC cells, but had a minor impact on VBL cytotoxicity. These findings revealed that both VBL and Taxol induce cell apoptosis through Op18/stathmin, but the mechanisms are completely different. VBL is an attractive alternative to the treatment of Taxol-resistant tumors with high expression of Op18/stathmin.

Synergistic Effects of NOTCH/γ-Secretase Inhibition and Standard of Care Treatment Modalities in Non-small Cell Lung Cancer Cells

“…Additionally, H1299 was categorized as a paclitaxel-resistant cell line as compared to four other epithelial-derived carcinoma types (nasopharyngeal, gastric, breast and hepatocellular) in terms of cellular apoptosis, mitochondrial functionality and colony-forming capacity ( 38 ). In our 2D IncuCyte proliferation assay we showed that paclitaxel-induced proliferation reduction, at a 40 × lower dose, was similar to the reduction seen using an MTT assay 72 h post-treatment as reported by Shen et al ( 39 ).…”

Paclitaxel’s Mechanistic and Clinical Effects on Breast Cancer

“…Importantly, certain dominant-negative mutations of genes associated with the regulation of mitosis are responsible for the development of resistance of cancer cells, and thus the effectiveness of taxane therapy is decreased [55]. The second group of natural plant-derived chemo-drugs are alkaloids such as Vinblastine that acts as microtubule-disruptive agents inhibiting tubulin polymerization [56]. In summary, there are numerous chemotherapeutics against BC with different mechanisms of action.…”

Stathmin dynamics modulate the activity of eribulin in breast cancer cells

“…There were no significant changes in previous reports suggest that paclitaxel decreases stathmin expression in NSCLC and nasopharyngeal carcinoma cells. 27,29 Because overexpression of stathmin is associated with a poor prognosis and with chemoresistance in a variety of cancer cell types, 30 the inhibitory effects of eribulin on stathmin expression may increase sensitivity to other anticancer drugs. Notably, we showed that overexpression of stathmin, but not its knockdown, augments the antiproliferative effect of eribulin in breast cancer cells.…”

“…Vinblastine, a microtubule destabilizer, increases stathmin phosphorylation in a non-small cell lung cancer (NSCLC) cell line,27 and Machado-Neto et al28 showed that PTX, a microtubule stabilizer, induces stathmin phosphorylation in acute lymphoblastic leukemia cells. Vinblastine reduces PP2A expression, whereas PTX increases it markedly, in NSCLC cells 27. Because we found no significant effect of PTX on stathmin phosphorylation in breast cancer cell lines, the action of microtubuletargeting drugs on phosphorylation may vary according to cancer cell type.The molecular mechanisms by which eribulin activates PKA and CaMKII, and downregulates PP2A level, remain unknown; further studies should clarify the mechanism by which eribulin exerts posttranscriptional regulation of stathmin.In addition to eribulin-induced stathmin phosphorylation, we also found that continuous exposure to eribulin reduced stathmin expression by breast cancer cell lines.…”