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Anti-IGF-1R monoclonal antibody inhibits the carcinogenicity activity of acquired trastuzumab-resistant SKOV3.

Wang W, Zhang Y, Lv M, Feng J, Peng H, Geng J, Lin Z, Zhou T, Li X, Shen B, Ma Y, Qiao C - J Ovarian Res (2014)

Bottom Line: Reversing the resistance often results in better clinical therapeutic effect.It was also confirmed preliminarily that the mechanism of antibody might be to inhibit the activation of IGF-1R and downstream MAPK, AKT pathway transduction.In similar cases, not only acquired but also de novo, good curative effect might be achieved using combined antibody therapy strategies.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Cellular and Molecular Immunology, Institute of Immunology, Henan University, Kaifeng, 475001, China. 1790735517@qq.com.

ABSTRACT

Background: Antibody resistance, not only de novo but also acquired cases, usually exists and is related with lower survival rate and high risk of recurrence. Reversing the resistance often results in better clinical therapeutic effect. Previously, we established a trastuzumab-resistant ovarian cancer cell line, named as SKOV3-T, with lower HER2 and induced higher IGF-1R expression level to keep cell survival.

Methods: IGF-1R was identified important for SKOV3-T growth. Then, a novel anti-IGF-1R monoclonal antibody, named as LMAb1, was used to inhibit SKOV3-T in cell growth/proliferation, migration, clone formation and in vivo carcinogenicity.

Results: In both in vitro and in vivo assays, LMAb1 showed effective anti-tumor function, especially when being used in combination with trastuzumab, which was beneficial to longer survival time of mice as well as smaller tumor. It was also confirmed preliminarily that the mechanism of antibody might be to inhibit the activation of IGF-1R and downstream MAPK, AKT pathway transduction.

Conclusion: We achieved satisfactory anti-tumor activity using trastuzumab plus LMAb1 in trastuzumab-resistant ovarian cancer model. In similar cases, not only acquired but also de novo, good curative effect might be achieved using combined antibody therapy strategies.

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Related in: MedlinePlus

Acquired trastuzumab-resistant cell line SKOV3-T cells grow faster than SKOV3. SKOV3 cells were cultivated for 8 months in the presence of 20 μg/ml trastuzumab continuously to obtain SKOV3-T cells. The comparison of SKOV3-T and parental SKOV3 cells by (A) cell proliferation, (B) cell counting, (C) agar clone formation, (D) transwell, and (E)in vivo carcinogenic assays. In cell counting assays, cells were cultured in day 0 at the start concentration of 1 × 104 per 24-well, and in day 1 to day 6, the cells were digested everyday and the whole cell number was counted. The trastuzumab-resistant SKOV3-T seemed to have significantly enhanced cell growth/proliferation, clone formation, stronger invasion and migration character both in vitro and in vivo versus non-resistant SKOV3 cells.
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Fig1: Acquired trastuzumab-resistant cell line SKOV3-T cells grow faster than SKOV3. SKOV3 cells were cultivated for 8 months in the presence of 20 μg/ml trastuzumab continuously to obtain SKOV3-T cells. The comparison of SKOV3-T and parental SKOV3 cells by (A) cell proliferation, (B) cell counting, (C) agar clone formation, (D) transwell, and (E)in vivo carcinogenic assays. In cell counting assays, cells were cultured in day 0 at the start concentration of 1 × 104 per 24-well, and in day 1 to day 6, the cells were digested everyday and the whole cell number was counted. The trastuzumab-resistant SKOV3-T seemed to have significantly enhanced cell growth/proliferation, clone formation, stronger invasion and migration character both in vitro and in vivo versus non-resistant SKOV3 cells.

Mentions: Human ovarian cancer SKOV3 cells, which over express HER2, werecultured continuously for 8 months in the presence of 10 μg/ml trastuzumab, resulting in the acquisition of trastuzumab resistance in the surviving cell population. Compared with the parental cells, the resistant SKOV3 cells had a significant higher viability or proliferative capacity in cell proliferation assay (Figure 1A) in 96-well plate and cell counting assay (Figure 1B); meanwhile, SKOV3-Tdisplayeddramatically increased colony formation on the agar cloning assay, for the clones were obviously bigger and much more than SKOV3 (Figure 1C); furthermore, in transwell assays, SKOV3-T exhibited stronger migration capacity, for after 24 hours, about 626 SKOV3-T cells moved while only less than 100 SKOV3 cells moved across the well (Figure 1D); furthermore, in in vivo carcinogenic assay, the mean volume of SKOV3-T transplanted tumor was significantly larger than SKOV3 (Figure 1E). These results suggest that trastuzumab-resistant ovarian cancer cells SKOV3-T growth much faster and migrate better than SKOV3, suggesting stronger malignancy and metastasis character of SKOV3-Tin vivo than non-resistant cells.Figure 1


Anti-IGF-1R monoclonal antibody inhibits the carcinogenicity activity of acquired trastuzumab-resistant SKOV3.

Wang W, Zhang Y, Lv M, Feng J, Peng H, Geng J, Lin Z, Zhou T, Li X, Shen B, Ma Y, Qiao C - J Ovarian Res (2014)

Acquired trastuzumab-resistant cell line SKOV3-T cells grow faster than SKOV3. SKOV3 cells were cultivated for 8 months in the presence of 20 μg/ml trastuzumab continuously to obtain SKOV3-T cells. The comparison of SKOV3-T and parental SKOV3 cells by (A) cell proliferation, (B) cell counting, (C) agar clone formation, (D) transwell, and (E)in vivo carcinogenic assays. In cell counting assays, cells were cultured in day 0 at the start concentration of 1 × 104 per 24-well, and in day 1 to day 6, the cells were digested everyday and the whole cell number was counted. The trastuzumab-resistant SKOV3-T seemed to have significantly enhanced cell growth/proliferation, clone formation, stronger invasion and migration character both in vitro and in vivo versus non-resistant SKOV3 cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4260252&req=5

Fig1: Acquired trastuzumab-resistant cell line SKOV3-T cells grow faster than SKOV3. SKOV3 cells were cultivated for 8 months in the presence of 20 μg/ml trastuzumab continuously to obtain SKOV3-T cells. The comparison of SKOV3-T and parental SKOV3 cells by (A) cell proliferation, (B) cell counting, (C) agar clone formation, (D) transwell, and (E)in vivo carcinogenic assays. In cell counting assays, cells were cultured in day 0 at the start concentration of 1 × 104 per 24-well, and in day 1 to day 6, the cells were digested everyday and the whole cell number was counted. The trastuzumab-resistant SKOV3-T seemed to have significantly enhanced cell growth/proliferation, clone formation, stronger invasion and migration character both in vitro and in vivo versus non-resistant SKOV3 cells.
Mentions: Human ovarian cancer SKOV3 cells, which over express HER2, werecultured continuously for 8 months in the presence of 10 μg/ml trastuzumab, resulting in the acquisition of trastuzumab resistance in the surviving cell population. Compared with the parental cells, the resistant SKOV3 cells had a significant higher viability or proliferative capacity in cell proliferation assay (Figure 1A) in 96-well plate and cell counting assay (Figure 1B); meanwhile, SKOV3-Tdisplayeddramatically increased colony formation on the agar cloning assay, for the clones were obviously bigger and much more than SKOV3 (Figure 1C); furthermore, in transwell assays, SKOV3-T exhibited stronger migration capacity, for after 24 hours, about 626 SKOV3-T cells moved while only less than 100 SKOV3 cells moved across the well (Figure 1D); furthermore, in in vivo carcinogenic assay, the mean volume of SKOV3-T transplanted tumor was significantly larger than SKOV3 (Figure 1E). These results suggest that trastuzumab-resistant ovarian cancer cells SKOV3-T growth much faster and migrate better than SKOV3, suggesting stronger malignancy and metastasis character of SKOV3-Tin vivo than non-resistant cells.Figure 1

Bottom Line: Reversing the resistance often results in better clinical therapeutic effect.It was also confirmed preliminarily that the mechanism of antibody might be to inhibit the activation of IGF-1R and downstream MAPK, AKT pathway transduction.In similar cases, not only acquired but also de novo, good curative effect might be achieved using combined antibody therapy strategies.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Cellular and Molecular Immunology, Institute of Immunology, Henan University, Kaifeng, 475001, China. 1790735517@qq.com.

ABSTRACT

Background: Antibody resistance, not only de novo but also acquired cases, usually exists and is related with lower survival rate and high risk of recurrence. Reversing the resistance often results in better clinical therapeutic effect. Previously, we established a trastuzumab-resistant ovarian cancer cell line, named as SKOV3-T, with lower HER2 and induced higher IGF-1R expression level to keep cell survival.

Methods: IGF-1R was identified important for SKOV3-T growth. Then, a novel anti-IGF-1R monoclonal antibody, named as LMAb1, was used to inhibit SKOV3-T in cell growth/proliferation, migration, clone formation and in vivo carcinogenicity.

Results: In both in vitro and in vivo assays, LMAb1 showed effective anti-tumor function, especially when being used in combination with trastuzumab, which was beneficial to longer survival time of mice as well as smaller tumor. It was also confirmed preliminarily that the mechanism of antibody might be to inhibit the activation of IGF-1R and downstream MAPK, AKT pathway transduction.

Conclusion: We achieved satisfactory anti-tumor activity using trastuzumab plus LMAb1 in trastuzumab-resistant ovarian cancer model. In similar cases, not only acquired but also de novo, good curative effect might be achieved using combined antibody therapy strategies.

Show MeSH
Related in: MedlinePlus