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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

IGF-1R knockdown could inhibit the proliferation of SKOV3-T. (A) IGF-1R expression was knocked down in SKOV3-T cells using lentivirus system and cells were analyzed by flow cytometry (up panel) and western blot (down panel) analysis; Cell proliferation (B) and clone formation (C) analysis both indicated that in SKOV3 KD cells, the cell growth was inhibited, while according to cell cycle analysis (D), SKOV3-T KD cells owned less S-phase cells in order to slower cell multiplification; In in vivo carcinogenic model, SKOV3-T KD exhibited slower tumor growth rate contrasting to SKOV3-T (E), indicating that IGF-1R was important to SKVO3-T cells when HER2-related cascade was blocked. To be clear, in this figure, “SKOV3-T” sample means control virus treated SKOV3-T cells.
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Fig3: IGF-1R knockdown could inhibit the proliferation of SKOV3-T. (A) IGF-1R expression was knocked down in SKOV3-T cells using lentivirus system and cells were analyzed by flow cytometry (up panel) and western blot (down panel) analysis; Cell proliferation (B) and clone formation (C) analysis both indicated that in SKOV3 KD cells, the cell growth was inhibited, while according to cell cycle analysis (D), SKOV3-T KD cells owned less S-phase cells in order to slower cell multiplification; In in vivo carcinogenic model, SKOV3-T KD exhibited slower tumor growth rate contrasting to SKOV3-T (E), indicating that IGF-1R was important to SKVO3-T cells when HER2-related cascade was blocked. To be clear, in this figure, “SKOV3-T” sample means control virus treated SKOV3-T cells.

Mentions: As shown above, IGF-1R could fasten the cell growth of SKOV3, which was similar to the quick growth of SKOV3-T. In order to further analyze the biofunction(s) of IGF-1R in SKOV3-T cells, a lentivirus vector to knock down IGF-1R was packed and transduced into SKOV3-T cells, while cells transduced with virus CON054 were set as negative control. As shown in Figure 3A, IGF-1R expression was inhibited according to flow cytometry and western blot analysis. Furtherly, cell proliferation assay showed that SKOV3-T KD cells grow more slowly than SKOV3-T (Figure 3B); similarly, the agar clone formation capacity of SKOV3-T KD cells was weaker (Figure 3C); meanwhile, in the cell cycling assay shown in Figure 3D, SKOV3-T KD exhibited less S-phase cells (28.84%) than SKOV3-T (31.23%), indicating thatIGF-1R could affect the cell cycle, thus influence the cell proliferation of SKOV3-T. Further in vivo experiment also displayed the importance of IGF-1R in SKOV3-T, for the mean tumor volume of SKOV3-T was ~1257 mm3, while SKOV3 KD was ~1115 mm3 (Figure 3E).Figure 3


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)

IGF-1R knockdown could inhibit the proliferation of SKOV3-T. (A) IGF-1R expression was knocked down in SKOV3-T cells using lentivirus system and cells were analyzed by flow cytometry (up panel) and western blot (down panel) analysis; Cell proliferation (B) and clone formation (C) analysis both indicated that in SKOV3 KD cells, the cell growth was inhibited, while according to cell cycle analysis (D), SKOV3-T KD cells owned less S-phase cells in order to slower cell multiplification; In in vivo carcinogenic model, SKOV3-T KD exhibited slower tumor growth rate contrasting to SKOV3-T (E), indicating that IGF-1R was important to SKVO3-T cells when HER2-related cascade was blocked. To be clear, in this figure, “SKOV3-T” sample means control virus treated SKOV3-T cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig3: IGF-1R knockdown could inhibit the proliferation of SKOV3-T. (A) IGF-1R expression was knocked down in SKOV3-T cells using lentivirus system and cells were analyzed by flow cytometry (up panel) and western blot (down panel) analysis; Cell proliferation (B) and clone formation (C) analysis both indicated that in SKOV3 KD cells, the cell growth was inhibited, while according to cell cycle analysis (D), SKOV3-T KD cells owned less S-phase cells in order to slower cell multiplification; In in vivo carcinogenic model, SKOV3-T KD exhibited slower tumor growth rate contrasting to SKOV3-T (E), indicating that IGF-1R was important to SKVO3-T cells when HER2-related cascade was blocked. To be clear, in this figure, “SKOV3-T” sample means control virus treated SKOV3-T cells.
Mentions: As shown above, IGF-1R could fasten the cell growth of SKOV3, which was similar to the quick growth of SKOV3-T. In order to further analyze the biofunction(s) of IGF-1R in SKOV3-T cells, a lentivirus vector to knock down IGF-1R was packed and transduced into SKOV3-T cells, while cells transduced with virus CON054 were set as negative control. As shown in Figure 3A, IGF-1R expression was inhibited according to flow cytometry and western blot analysis. Furtherly, cell proliferation assay showed that SKOV3-T KD cells grow more slowly than SKOV3-T (Figure 3B); similarly, the agar clone formation capacity of SKOV3-T KD cells was weaker (Figure 3C); meanwhile, in the cell cycling assay shown in Figure 3D, SKOV3-T KD exhibited less S-phase cells (28.84%) than SKOV3-T (31.23%), indicating thatIGF-1R could affect the cell cycle, thus influence the cell proliferation of SKOV3-T. Further in vivo experiment also displayed the importance of IGF-1R in SKOV3-T, for the mean tumor volume of SKOV3-T was ~1257 mm3, while SKOV3 KD was ~1115 mm3 (Figure 3E).Figure 3

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