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MFTZ-1 reduces constitutive and inducible HIF-1α accumulation and VEGF secretion independent of its topoisomerase II inhibition.

Dai M, Miao ZH, Ren X, Tong LJ, Yang N, Li T, Lin LP, Shen YM, Ding J - J. Cell. Mol. Med. (2010)

Bottom Line: In this study, we further examined the effects of MFTZ-1 on hypoxia-inducible factor-1α (HIF-1α) accumulation, vascular endothelial growth factor (VEGF) secretion and angiogenesis.Mechanistic studies revealed that MFTZ-1 did not affect the degradation of HIF-1α protein or the level of HIF-1α mRNA.The results reveal an important feature that MFTZ-1 can reduce constitutive, HIF-1α-independent VEGF secretion and concurrently antagonize inducible, HIF-1α-dependent VEGF secretion.

View Article: PubMed Central - PubMed

Affiliation: Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, PR China.

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MFTZ-1 inhibits angiogenesis. (A) MFTZ-1 inhibited hypoxia-induced HUVECs tube formation. HUVEC cells (1.2 × 104) were incubated in M199 medium supplemented with 0.5% FBS at hypoxia for 10 hrs to form complete tubes. Treatment with MFTZ-1 abrogated hypoxia-induced tube formation. (a) Control; (b) 0.2 μM MFTZ-1; (c) inhibition rates of tube formation were calculated as in the section of Materials and Methods. Values were expressed as means; bars, ±S.D., n= 3. (B) MFTZ-1 inhibited serum-induced HUVECs tube formation. HUVEC cells (1 × 104) were cultured in M199 medium supplemented with 20% FBS at normoxia with or without MFTZ-1. After incubation for 6 hrs at 37°C, capillary networks were photographed and quantified. (a) Control; b. 0.2 μM MFTZ-1; (c) inhibition rates were calculated and expressed as in (A). (C) HUVEC (5 × 104) cells were cultured in a Transwell Boyden Chamber using a polycarbonate filter with a pore size of 8.0 μm coated with a 1% gelatin in serum-free M199 medium with or without MFTZ-1. For migration detection, 20% FBS were added into the lower chamber. After incubation for 6 hrs at 37°C, the migrated cells were photographed and quantified as described in Materials and Methods. (a) Control; (b) 0.2 μM MFTZ-1; (c) inhibition rates of HUVEC migration by MFTZ-1. Values are expressed as means; bars, ±S.D., n= 3. (D) MFTZ-1 inhibited new microvessel outgrowth arising from rat aortic ring. Data shown were representative of three independent experiments. Student’s t-tests were conducted to compare drug treatment with each control, respectively, significance was indicated as * for P < 0.05 and ** for P < 0.01.
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fig05: MFTZ-1 inhibits angiogenesis. (A) MFTZ-1 inhibited hypoxia-induced HUVECs tube formation. HUVEC cells (1.2 × 104) were incubated in M199 medium supplemented with 0.5% FBS at hypoxia for 10 hrs to form complete tubes. Treatment with MFTZ-1 abrogated hypoxia-induced tube formation. (a) Control; (b) 0.2 μM MFTZ-1; (c) inhibition rates of tube formation were calculated as in the section of Materials and Methods. Values were expressed as means; bars, ±S.D., n= 3. (B) MFTZ-1 inhibited serum-induced HUVECs tube formation. HUVEC cells (1 × 104) were cultured in M199 medium supplemented with 20% FBS at normoxia with or without MFTZ-1. After incubation for 6 hrs at 37°C, capillary networks were photographed and quantified. (a) Control; b. 0.2 μM MFTZ-1; (c) inhibition rates were calculated and expressed as in (A). (C) HUVEC (5 × 104) cells were cultured in a Transwell Boyden Chamber using a polycarbonate filter with a pore size of 8.0 μm coated with a 1% gelatin in serum-free M199 medium with or without MFTZ-1. For migration detection, 20% FBS were added into the lower chamber. After incubation for 6 hrs at 37°C, the migrated cells were photographed and quantified as described in Materials and Methods. (a) Control; (b) 0.2 μM MFTZ-1; (c) inhibition rates of HUVEC migration by MFTZ-1. Values are expressed as means; bars, ±S.D., n= 3. (D) MFTZ-1 inhibited new microvessel outgrowth arising from rat aortic ring. Data shown were representative of three independent experiments. Student’s t-tests were conducted to compare drug treatment with each control, respectively, significance was indicated as * for P < 0.05 and ** for P < 0.01.

Mentions: Previous reports show that compounds capable of reducing HIF-1α accumulation and VEGF secretion simultaneously inhibit angiogenesis directly [15, 32]. Also hypoxia-induced HIF-1α is essential for hypoxia-induced angiogenesis, especially tube formation [33]. To further investigate whether MFTZ-1 has anti-angiogenic effects, we employed a series of standard angiogenesis models. In the HUVEC tube formation assay, MFTZ-1 potently suppressed the cord formation of HUVEC stimulated by hypoxia (Fig. 5A) or serum at normoxia (Fig. 5B) at a concentration as low as 0.04 μM (Fig. 1). In term of endothelial migration, HUVEC chemotactically (20% FBS) moved from the upper side to the lower side of the membrane in the Boyden chamber [15]. MFTZ-1 repressed this process in a concentration-dependent manner (Fig. 5C). An ex vivo model further demonstrated that MFTZ-1 prominently prevented new microvessel outgrowth arising from rat aortic ring (Fig. 5D). All the experiments were manipulated with MFTZ-1 at its sub-cytotoxic concentration regimens (0.008 μM to 1 μM), the concentration of which is 10-fold lower than required for its targeting Top2 [13].


MFTZ-1 reduces constitutive and inducible HIF-1α accumulation and VEGF secretion independent of its topoisomerase II inhibition.

Dai M, Miao ZH, Ren X, Tong LJ, Yang N, Li T, Lin LP, Shen YM, Ding J - J. Cell. Mol. Med. (2010)

MFTZ-1 inhibits angiogenesis. (A) MFTZ-1 inhibited hypoxia-induced HUVECs tube formation. HUVEC cells (1.2 × 104) were incubated in M199 medium supplemented with 0.5% FBS at hypoxia for 10 hrs to form complete tubes. Treatment with MFTZ-1 abrogated hypoxia-induced tube formation. (a) Control; (b) 0.2 μM MFTZ-1; (c) inhibition rates of tube formation were calculated as in the section of Materials and Methods. Values were expressed as means; bars, ±S.D., n= 3. (B) MFTZ-1 inhibited serum-induced HUVECs tube formation. HUVEC cells (1 × 104) were cultured in M199 medium supplemented with 20% FBS at normoxia with or without MFTZ-1. After incubation for 6 hrs at 37°C, capillary networks were photographed and quantified. (a) Control; b. 0.2 μM MFTZ-1; (c) inhibition rates were calculated and expressed as in (A). (C) HUVEC (5 × 104) cells were cultured in a Transwell Boyden Chamber using a polycarbonate filter with a pore size of 8.0 μm coated with a 1% gelatin in serum-free M199 medium with or without MFTZ-1. For migration detection, 20% FBS were added into the lower chamber. After incubation for 6 hrs at 37°C, the migrated cells were photographed and quantified as described in Materials and Methods. (a) Control; (b) 0.2 μM MFTZ-1; (c) inhibition rates of HUVEC migration by MFTZ-1. Values are expressed as means; bars, ±S.D., n= 3. (D) MFTZ-1 inhibited new microvessel outgrowth arising from rat aortic ring. Data shown were representative of three independent experiments. Student’s t-tests were conducted to compare drug treatment with each control, respectively, significance was indicated as * for P < 0.05 and ** for P < 0.01.
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Related In: Results  -  Collection

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fig05: MFTZ-1 inhibits angiogenesis. (A) MFTZ-1 inhibited hypoxia-induced HUVECs tube formation. HUVEC cells (1.2 × 104) were incubated in M199 medium supplemented with 0.5% FBS at hypoxia for 10 hrs to form complete tubes. Treatment with MFTZ-1 abrogated hypoxia-induced tube formation. (a) Control; (b) 0.2 μM MFTZ-1; (c) inhibition rates of tube formation were calculated as in the section of Materials and Methods. Values were expressed as means; bars, ±S.D., n= 3. (B) MFTZ-1 inhibited serum-induced HUVECs tube formation. HUVEC cells (1 × 104) were cultured in M199 medium supplemented with 20% FBS at normoxia with or without MFTZ-1. After incubation for 6 hrs at 37°C, capillary networks were photographed and quantified. (a) Control; b. 0.2 μM MFTZ-1; (c) inhibition rates were calculated and expressed as in (A). (C) HUVEC (5 × 104) cells were cultured in a Transwell Boyden Chamber using a polycarbonate filter with a pore size of 8.0 μm coated with a 1% gelatin in serum-free M199 medium with or without MFTZ-1. For migration detection, 20% FBS were added into the lower chamber. After incubation for 6 hrs at 37°C, the migrated cells were photographed and quantified as described in Materials and Methods. (a) Control; (b) 0.2 μM MFTZ-1; (c) inhibition rates of HUVEC migration by MFTZ-1. Values are expressed as means; bars, ±S.D., n= 3. (D) MFTZ-1 inhibited new microvessel outgrowth arising from rat aortic ring. Data shown were representative of three independent experiments. Student’s t-tests were conducted to compare drug treatment with each control, respectively, significance was indicated as * for P < 0.05 and ** for P < 0.01.
Mentions: Previous reports show that compounds capable of reducing HIF-1α accumulation and VEGF secretion simultaneously inhibit angiogenesis directly [15, 32]. Also hypoxia-induced HIF-1α is essential for hypoxia-induced angiogenesis, especially tube formation [33]. To further investigate whether MFTZ-1 has anti-angiogenic effects, we employed a series of standard angiogenesis models. In the HUVEC tube formation assay, MFTZ-1 potently suppressed the cord formation of HUVEC stimulated by hypoxia (Fig. 5A) or serum at normoxia (Fig. 5B) at a concentration as low as 0.04 μM (Fig. 1). In term of endothelial migration, HUVEC chemotactically (20% FBS) moved from the upper side to the lower side of the membrane in the Boyden chamber [15]. MFTZ-1 repressed this process in a concentration-dependent manner (Fig. 5C). An ex vivo model further demonstrated that MFTZ-1 prominently prevented new microvessel outgrowth arising from rat aortic ring (Fig. 5D). All the experiments were manipulated with MFTZ-1 at its sub-cytotoxic concentration regimens (0.008 μM to 1 μM), the concentration of which is 10-fold lower than required for its targeting Top2 [13].

Bottom Line: In this study, we further examined the effects of MFTZ-1 on hypoxia-inducible factor-1α (HIF-1α) accumulation, vascular endothelial growth factor (VEGF) secretion and angiogenesis.Mechanistic studies revealed that MFTZ-1 did not affect the degradation of HIF-1α protein or the level of HIF-1α mRNA.The results reveal an important feature that MFTZ-1 can reduce constitutive, HIF-1α-independent VEGF secretion and concurrently antagonize inducible, HIF-1α-dependent VEGF secretion.

View Article: PubMed Central - PubMed

Affiliation: Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, PR China.

Show MeSH
Related in: MedlinePlus