Paclitaxel in combination with cetuximab exerts antitumor effect by suppressing NF-κB activity in human oral squamous cell carcinoma cell lines

Abstract

Abstract. In the present study, we examined the antitumor effect of paclitaxel (PTX) in combination with cetuximab in oral squamous cell carcinoma (OSCC) and the mechanism of its enhanced antitumor activity. Treatment of OSCC (HSC2, HSC3 and HSC4) cells with PTX (0.02 µg/ml) and cetuximab (1 µg/ml) combination resulted in a significant inhibition of cell growth in vitro compared to either agent alone. Moreover, it was found by Hoechst 33258 staining that DNA fragmentation markedly occurred in OSCC cells treated with PTX and cetuximab combination treatment. Furthermore, PTX and cetuximab combination treatment reduced the expression of p65 (NF-κB) protein in OSCC cells. In our in vivo experiment, HSC2 tumor-bearing nude mice were treated with PTX (20 mg/kg/day, twice/week, 3 weeks) and/or cetuximab (20 mg/kg/day, twice/week, 3 weeks). Tumor growth was significantly suppressed by PTX and cetuximab combined treatment when compared to PTX or cetuximab alone, or the untreated control. TUNEL-positive cells were upregulated in HSC2 tumors treated with PTX and cetuximab. In addition, immunohistochemical staining revealed that expression of p65 was downregulated in HSC2 tumors treated with PTX and cetuximab. Our results indicate that cetuximab may enhance the effect of PTX in OSCC through the downregulation of PTX induced p65 expression. Therefore, the combination of PTX and cetuximab might be a promising option for OSCC treatment. IntroductionOral squamous cell carcinoma (OSCC) is the 8th most common cancer in humans, which accounts for ~2% of all carcinomas in women and 4% in men worldwide (1,2). Over 300,000 new cases of OSCC are diagnosed annually with ~11,000 new cases in Japan (3). Surgery, chemotherapy and radiotherapy are the standards for the treatment of head and neck squamous cell carcinomas (HNSCCs) including OSCC. However, despite recent advances in cancer diagnosis, surgery, chemotherapy, radiotherapy and other treatment methods, the overall survival rate of OSCC is ~50% in the advanced stage of the disease (4,5). Almost 60% of HNSCC patients are diagnosed with locally advanced disease at presentation (6). Therefore, it is important to establish more promising therapeutic strategies.Cetuximab (Erbitux ® ; formerly IMC-C225) is a chimeric (mouse/human) IgG1 monoclonal antibody that targets the extracellular ligand-binding domain of EGFR with high affinity and inhibits tumor growth, invasion, angiogenesis and metastasis (7,8). Cetuximab causes G1 phase cell cycle arrest by decreasing cyclin-dependent kinase 2 (CDK2) and increasing p27Kip1 levels in tumor cell lines (9). Paclitaxel (PTX) is a diterpenoid isolated from the bark of the Pacific yew, Taxus brevifolia (10). PTX induces mitotic arrest and cell death by binding to microtubules, promoting microtubule assembly, and stabilizing tubulin polymers against depolymerization affecting cells in the G2/M-phase (11,12).Most of the available reports on HNSCC demonstrated the effect of cetuximab in combination with cisplatin/platinumbased drugs or radiotherapy (7,1...

A novel intraperitoneal metastatic xenograft mouse model for survival outcome assessment of esophageal adenocarcinoma

“…All mice had measurable tumor two weeks after OE19 cell injection. The mice were then randomly grouped (n = 5 per group) and treated intraperitoneally as described earlier with vehicle, paclitaxel (20 mg/kg, 2 times a week for 2 weeks) [ 25 ] or carboplatin (50 mg/kg, 2 times a week for 2 weeks) [ 26 ]. Subcutaneous tumor size was measured twice a week for two weeks and TV with RTV was calculated as described earlier.…”

Paclitaxel Plus Cetuximab as 1st Line Chemotherapy in Platinum-Based Chemoradiotherapy-Refractory Patients With Squamous Cell Carcinoma of the Head and Neck

“…As preclinical studies have shown that the combination of cetuximab (Cmab) and taxanes seems to be synergistic (10, 11), paclitaxel (PTX) plus Cmab is a palliative option after failure of platinum-based therapy, offering overall response rates (ORRs) of 38–55% and median OS of 7.6–10 months (12–14). Among others, Hitt et al prospectively showed that PTX and Cmab was active (ORR54%, median PFS 4.2months, median OS 8.1 months) as 1st line treatment in R/M HNSCC patients, for whom platinum is contraindicated (15).…”

Superior Therapeutic Efficacy of Nanoparticle Albumin Bound Paclitaxel Over Cremophor-Bound Paclitaxel in Experimental Esophageal Adenocarcinoma

“…All mice had measurable tumor two weeks after OE19 cell injection. The mice were then randomly grouped (n = 5 per group) and treated intraperitoneally as described earlier with vehicle, nab-paclitaxel (10 mg/kg in 100 μl of PBS, 2 times a week) [34] , paclitaxel (20 mg/kg, 2 times a week for 2 weeks) [35] or carboplatin (50 mg/kg, 2 times a week for 2 weeks) [36] alone and in combinations. The tumor size was measured twice a week for four weeks with slide calipers and tumor volume (TV) was calculated as (W 2 XL)/2, where W is width and L is length of the tumor [37] .…”

“…Two weeks after tumor cell injection mice were randomly grouped (n = 5 per group). For mice survival studies mice were treated intraperitoneally as described earlier with vehicle, nab-paclitaxel (10 mg/kg in 100 μl of PBS, 2 times a week) [34] , paclitaxel (20 mg/kg, 2 times a week for 2 weeks) [35] or carboplatin (50 mg/kg, 2 times a week for 2 weeks) [36] alone and in combinations. Animals were examined daily for signs of distress or development of jaundice, and body weight was measured once a week.…”