Combination of 131I-trastuzumab and lanatoside C enhanced therapeutic efficacy in HER2 positive tumor model

Abstract

Lanatoside C has a promising anti-tumor activity and is a potential candidate for radiosensitizers. In this study, we have investigated the therapeutic efficacy of the combination of ¹³¹I-trastuzumab and lanatoside C for inhibition of human epidermal growth factor receptor 2 (HER2) positive tumor progression in NCI-N87 xenograft model. The combination treatment (¹³¹I-trastuzumab and lanatoside C) showed highest cytotoxicity when compared to non-treated control or trastuzumab alone or ¹³¹I alone or ¹³¹I-trastuzumab alone in vitro. Biodistribution studies using ¹³¹I-trastuzumab or combination of ¹³¹I-trastuzumab and lanatoside C showed tumor uptake in BALB/c nude mice bearing HER2 positive NCI-N87 tumor xenograft model. The higher tumor uptake was observed in ¹³¹I-trastuzumab (19.40 ± 0.04% ID/g) than in the combination of ¹³¹I-trastuzumab and lanatoside C (14.02 ± 0.02% ID/g) at 24 h post-injection. Most importantly, an antitumor effect was observed in mice that received the combination of ¹³¹I-trastuzumab and lanatoside C (p = 0.009) when compared to control. In addition, mice received lanatoside C alone (p = 0.085) or ¹³¹I-trastuzumab alone (p = 0.160) did not significantly inhibit tumor progression compared with control. Taken together, our data suggest that combination of ¹³¹I-trastuzumab and lanatoside C might be a potential synergistic treatment for radioimmunotherapy to control the HER2 positive tumor.

Figure 1

Lanatoside C suppressed growth of cancel cell lines. Inhibitory effect of lanatoside C on cell viability of NCI-N87 (A) and MDA-MB231 (B) cells. Data are presented as percentage of cell viability in which the 0.01% DMSO treated control sample is set 100%. The average of experimental triplicates ± standard deviation is shown. ***p < 0.001.

Figure 2

Lanatoside C enhanced ¹³¹I-trastuzumab RIT in vitro. NCI-N87 cells were treated with various activity of ¹³¹I-trastuzumab RIT (A), ¹³¹I-trastuzumab RIT combined with lanatoside C (B), ¹³¹I alone (C) and trastuzumab alone (D), and cell viability was determined by Ez-Cytox assay. Data are presented as percentage of cell viability in which the 0.01% DMSO treated control sample is set 100%. The average of experimental triplicates ± standard deviation is shown. ***p < 0.001, **p < 0.01, and *p < 0.05.

Figure 3

Lanatoside C enhanced ¹³¹I-trastuzumab RIT in xenograft model. When the NCI-N87 tumor volume reached approximately 150 mm³, the BALB/c nude mice were treated with non-treated control group (untreated control), vehicle control group (0.01% DMSO in saline, 100 μl, the first 3 days), lanatoside C (6 mg/kg body weight, the first 3 days intraperitoneal injection), ¹³¹I-trastuzumab group (400 μCi, once tail vein injection), and combination of ¹³¹I-trastuzumab and lanatoside C (lanatoside C, 6 mg/kg body weight, the first 3 days intraperitoneal injection, and ¹³¹I-trastuzumab, 400 μCi, once tail vein injection). **p < 0.01, and *p < 0.05.

Figure 4

Biodistribution pattern (% ID/g) of ¹³¹I-trastuzumab or combination of ¹³¹I-trastuzumab and lanatoside C in tumor (tumor xenograft NCI-N87) bearing BALB/c nude mice at 4 h (A), 24 h (B), and 48 h (C).