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Cancer Sci
2018 Oct 01;10910:3285-3293. doi: 10.1111/cas.13741.
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Curcumin analog, GO-Y078, overcomes resistance to tumor angiogenesis inhibitors.
Shimazu K
,
Inoue M
,
Sugiyama S
,
Fukuda K
,
Yoshida T
,
Taguchi D
,
Uehara Y
,
Kuriyama S
,
Tanaka M
,
Miura M
,
Nanjyo H
,
Iwabuchi Y
,
Shibata H
.
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Tumor angiogenesis inhibition is one of the most potent strategies in cancer chemotherapy. From past clinical studies, inhibition of the vascular endothelial growth factor pathway successfully treats malignant tumors. However, vascular endothelial growth factor inhibitors alone cannot cure tumors. Moreover, resistance to small molecule inhibitors has also been reported. Herein, we show the antiangiogenic potential of a newly synthesized curcumin analog, GO-Y078, that possibly functions through inhibition of actin stress fiber formation, resulting in mobility inhibition; this mechanism is different from that of vascular endothelial growth factor inhibition. In addition, we examined the detailed mechanism of action of the antiangiogenesis potential of GO-Y078 using human umbilical venous epithelial cells resistant to angiogenesis inhibitors (HUVEC-R). GO-Y078 inhibited the growth and mobility of HUVEC-R at 0.75 μmol/L concentration. Expression analyses by microarray and RT-PCR showed that expressions of genes including that of fibronectin 1 were significantly suppressed. Among these genes, fibronectin 1 is abundantly expressed and, therefore, seems to be a good target for GO-Y078. In a knockdown experiment using Si-oligo of fibronectin 1 (FN1), FN1 expression was decreased to half of that in mock experiments as well as GO-Y078. Knockdown of FN1 resulted in the suppression of HUVEC-R growth at 24 hours after treatment. Fibronectin is a key molecule contributing to angiogenesis that could be inhibited by GO-Y078. Thus, resistance to vascular endothelial growth factor inhibition can be overcome using GO-Y078.
Figure 1. Chemical structures of diarylpentanoid curcumin analogs. A, GOâY078; B, GOâY030; C, GOâY022; D, GOâY136; E, Appearance of 30Â mg GOâY030 (left) and GOâY136 (right) in PBS
Figure 2. Effect of GOâY078 on HUVEC resistant to angiogenesis inhibitors. A, Growth inhibition of HUVECKi2 with GOâ078 (open rectangle), sorafenib (closed rectangle), sunitinib (closed circle), and Ki8751 (open circle). B, Growth property of HUVECKi2 without (closed circle) and with 1.0 μmol/L GOâY078 (open circle). *P < .001. C, Wound healing assay of HUVECKi2 with GOâY078. D, Graphical view of the inhibition of the mobility of HUVECKi2. Open, shaded, and closed bars indicate treatments with mock, 0.5 μmol/L, and 1.0 μmol/L, respectively. *P < .001, **no significance
Figure 3. Summary of the microarray analysis of HUVEC treated by GOâY078
Figure 4.
RTâ€PCR of the candidate transcripts in HUVECKi2 affected by GOâ€Y078. Relative expression values of the basal levels (closed bars) and those of the treated levels with 0.5 μmol/L GOâ€Y078 (shaded bars) are indicated. A, fibronectin 1 (FN1); B, other candidates
Figure 5. Doseâ€dependent inhibition of fibronectin 1 (FN1) by GOâ€Y078. Relative expression values of the Mock (indicated by closed bars) and those of the treated levels with 0.5 μmol/L (shaded bars) and 1.0 μmol/L GOâ€Y078 (open bars) are indicated. *P < .001, **P < .05. ***no significance
Figure 6. Kinetic inhibition of fibronectin 1 (FN1) in HUVECKi2. Relative amount of fibronectin is indicated at each time (h) after treatment. HUVECKi2 was treated with 0.5 μmol/L GOâ€Y078 (closed rectangle), 1.0 μmol/L GOâ€Y078 (closed triangle), 1.0 μmol/L sorafenib (closed circle), and 1.0 μmol/L sunitinib (open rectangle). Mock is indicated by open circle. *P < .05, **P < .001
Figure 7. Knockdown effect of fibronectin 1 (FN1) on the growth of HUVECKi2. A, Efficacies of Siâ€oligos to FN1
mRNA in the attached HUVECKi2. B, Effects on the growth of the attached HUVECKi2 treated with FN1â€Siâ€oligo (open circle), controlâ€Siâ€oligo (closed rectangle), and without Siâ€oligo (closed circle). C, Efficacies of Siâ€oligos to FN1
mRNA in the suspended HUVECKi2. D, Effects of the growth of the suspended HUVECKi2 treated with the FN1â€Siâ€oligo (open circle), controlâ€Siâ€oligo (closed rectangle), and without Siâ€oligo (closed circle)
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