Abstract
Gastric cancer is the second common cause of cancer related death worldwide and lacks highly effective treatment for advanced disease. Nab-paclitaxel is a novel microtubule-inhibitory cytotoxic agent that has not been tested in gastric cancer as of yet. In this study, human gastric cancer cell lines AGS, NCI-N87 and SNU16 were studied. Nab-paclitaxel inhibited cell proliferation with an IC50 of 5 nM in SNU16, 23 nM in AGS and 49 nM in NCI-N87 cells after 72-hour treatment, which was lower than that of oxaliplatin (1.05 μM to 1.51 μM) and epirubicin (0.12 μM to 0.25 μM). Nab-paclitaxel treatment increased expression of the mitotic-spindle associated phospho-stathmin irrespective of the baseline total or phosphorylated stathmin level, and induced mitotic cell death as confirmed through increased expression of cleaved-PARP and caspase-3. After a two-week nab-paclitaxel, oxaliplatin or epirubicin treatment, the average in vivo local tumor growth inhibition rate was 77, 17.2 and 21.4 percent, respectively (p = 0.002). Effects of therapy on tumoral proliferative and apoptotic indices corresponded with tumor growth inhibition data, while expression of phospho-stathmin also increased in tissues. There was an increase in median animal survival after nab-paclitaxel treatment (93 days) compared to controls (31 days, p = 0.0007), oxaliplatin (40 days, p = 0.0007) or to docetaxel therapy (81 days, p = 0.0416). The strong antitumor activity of nab-paclitaxel in experimental gastric cancer supports such microtubule-inhibitory strategy for clinical application. Nab-paclitaxel benefits were observed independent from phosphorylated stathmin expression at baseline, putting into question the consideration of nab-paclitaxel use in gastric cancer based on this putative biomarker.
Highlights
Gastric cancer (GC) is the fourth most prevalent cancer and the second most common cause of cancer-related deaths throughout the world [1,2,3]
Nab-paclitaxel inhibits gastric cancer cell proliferation Nab-paclitaxel inhibited gastric cancer cell proliferation in a dose-dependent fashion, and inhibition in cell proliferation appeared to follow the same order as expression of phosphostathmin (Figure 1B)
The present study clearly demonstrates that nab-paclitaxel has significantly stronger antitumor effects on gastric cancer cell lines than currently used cytotoxic agents oxaliplatin and epirubicin in vitro and in vivo, measured by antiproliferative effects, apoptosis, mitotic cell death, localized antitumor response and survival related to tumor burden
Summary
Gastric cancer (GC) is the fourth most prevalent cancer and the second most common cause of cancer-related deaths throughout the world [1,2,3]. The combination of oxaliplatin and 5-fluorouracil, with and without epirubicin, has become the most widely used regimen in first-line chemotherapy for advanced gastric cancer [6,7] This combination treatment has the potential for considerable side effects and still carries limited efficacy, while patients’ prognosis remains dismal with a median survival of around 10 months [8,9,10,11]. Compared to the response rate of 38,45% yielded by a combination of oxaliplatin with 5-fluorouracil and folinic acid, paclitaxel did not result in superior survival but caused more side effects, especially in elderly patients [9,20,21,22]. The potential role of nab-paclitaxel in gastric cancer cells is not tested as of yet
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