Limits...
α-santalol inhibits the angiogenesis and growth of human prostate tumor growth by targeting vascular endothelial growth factor receptor 2-mediated AKT/mTOR/P70S6K signaling pathway.

Saraswati S, Kumar S, Alhaider AA - Mol. Cancer (2013)

Bottom Line: However, recently, most of these anticancer drugs have some adverse effects.Discovery of novel VEGFR2 inhibitors as anticancer drug candidates is still needed.Furthermore, α-santalol reduced the cell viability and induced apoptosis in PC-3 cells, which were correlated with the downregulation of AKT, mTOR and P70S6K expressions.

View Article: PubMed Central - HTML - PubMed

Affiliation: Camel Biomedical Research Unit, College of Pharmacy and Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia. saritasaraswati@gmail.com.

ABSTRACT

Background: VEGF receptor 2 (VEGFR2) inhibitors, as efficient antiangiogenesis agents, have been applied in the cancer treatment. However, recently, most of these anticancer drugs have some adverse effects. Discovery of novel VEGFR2 inhibitors as anticancer drug candidates is still needed.

Methods: We used α-santalol and analyzed its inhibitory effects on human umbilical vein endothelial cells (HUVECs) and Prostate tumor cells (PC-3 or LNCaP) in vitro. Tumor xenografts in nude mice were used to examine the in vivo activity of α-santalol.

Results: α-santalol significantly inhibits HUVEC proliferation, migration, invasion, and tube formation. Western blot analysis indicated that α-santalol inhibited VEGF-induced phosphorylation of VEGFR2 kinase and the downstream protein kinases including AKT, ERK, FAK, Src, mTOR, and pS6K in HUVEC, PC-3 and LNCaP cells. α-santalol treatment inhibited ex vivo and in vivo angiogenesis as evident by rat aortic and sponge implant angiogenesis assay. α-santalol significantly reduced the volume and the weight of solid tumors in prostate xenograft mouse model. The antiangiogenic effect by CD31 immunohistochemical staining indicated that α-santalol inhibited tumorigenesis by targeting angiogenesis. Furthermore, α-santalol reduced the cell viability and induced apoptosis in PC-3 cells, which were correlated with the downregulation of AKT, mTOR and P70S6K expressions. Molecular docking simulation indicated that α-santalol form hydrogen bonds and aromatic interactions within the ATP-binding region of the VEGFR2 kinase unit.

Conclusion: α-santalol inhibits angiogenesis by targeting VEGFR2 regulated AKT/mTOR/P70S6K signaling pathway, and could be used as a potential drug candidate for cancer therapy.

Show MeSH

Related in: MedlinePlus

α-santalol and positive control inhibited migration, invasion, and tube formation of HUVECs. (A) α-santalol inhibited HUVEC migration in wound healing assay. Cells were wounded with pipette and treated with vehicle or indicated concentrations of compounds. After 24 hours, the migrated cells were quantified by manual counting. (B) α-santalol inhibited HUVEC invasion in Transwell assay. A total of at 5 × 104 HUVECs were seeded in the top chamber and treated with vehicle or different concentrations of compounds. After 24 hours, the HUVECs that invaded through the membrane were stained and quantified. (C) α-santalol inhibited tube formation of HUVECs. After treated with vehicle or indicated concentrations of compounds for 10 hours, tubular structure in each group was quantified by manual counting. The percentage of inhibition was expressed using vehicle treated cells at 100%. Values are mean ± SEM (n = 6) of three independent experiments. *p < 0.05; **p < 0.01; ***p < 0.001 versus vehicle control.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4221991&req=5

Figure 3: α-santalol and positive control inhibited migration, invasion, and tube formation of HUVECs. (A) α-santalol inhibited HUVEC migration in wound healing assay. Cells were wounded with pipette and treated with vehicle or indicated concentrations of compounds. After 24 hours, the migrated cells were quantified by manual counting. (B) α-santalol inhibited HUVEC invasion in Transwell assay. A total of at 5 × 104 HUVECs were seeded in the top chamber and treated with vehicle or different concentrations of compounds. After 24 hours, the HUVECs that invaded through the membrane were stained and quantified. (C) α-santalol inhibited tube formation of HUVECs. After treated with vehicle or indicated concentrations of compounds for 10 hours, tubular structure in each group was quantified by manual counting. The percentage of inhibition was expressed using vehicle treated cells at 100%. Values are mean ± SEM (n = 6) of three independent experiments. *p < 0.05; **p < 0.01; ***p < 0.001 versus vehicle control.

Mentions: Effect of α-santalol on the chemotactic motility of HUVECs is shown in Figure 3A. HUVECs migrated into the clear area. α-santalol significantly inhibited the migration of endothelial cells in a dose dependent manner (Figure 3A) and maximum inhibition of endothelial cell migration was observed at 20 μM and was almost similar to that of zero hour incubation. We next performed transwell assay to measure the effect of α-santalol on cell invasion. As shown in Figure 3B, α-santalol significantly inhibited the invasion of HUVEC as compared to control (p < 0.001). Maturation of migrated endothelial cells into a capillary tube is a critical early step [3]. Therefore, we investigated the effect of α- santalol on HUVEC tube formation. When HUVECs were seeded on the growth factor–reduced matrigel, robust tubular-like structures were formed (Figure 3C). α-santalol effectively reduced the width and length of endothelial tubes at 10 and 20 μM (Figure 3C).


α-santalol inhibits the angiogenesis and growth of human prostate tumor growth by targeting vascular endothelial growth factor receptor 2-mediated AKT/mTOR/P70S6K signaling pathway.

Saraswati S, Kumar S, Alhaider AA - Mol. Cancer (2013)

α-santalol and positive control inhibited migration, invasion, and tube formation of HUVECs. (A) α-santalol inhibited HUVEC migration in wound healing assay. Cells were wounded with pipette and treated with vehicle or indicated concentrations of compounds. After 24 hours, the migrated cells were quantified by manual counting. (B) α-santalol inhibited HUVEC invasion in Transwell assay. A total of at 5 × 104 HUVECs were seeded in the top chamber and treated with vehicle or different concentrations of compounds. After 24 hours, the HUVECs that invaded through the membrane were stained and quantified. (C) α-santalol inhibited tube formation of HUVECs. After treated with vehicle or indicated concentrations of compounds for 10 hours, tubular structure in each group was quantified by manual counting. The percentage of inhibition was expressed using vehicle treated cells at 100%. Values are mean ± SEM (n = 6) of three independent experiments. *p < 0.05; **p < 0.01; ***p < 0.001 versus vehicle control.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4221991&req=5

Figure 3: α-santalol and positive control inhibited migration, invasion, and tube formation of HUVECs. (A) α-santalol inhibited HUVEC migration in wound healing assay. Cells were wounded with pipette and treated with vehicle or indicated concentrations of compounds. After 24 hours, the migrated cells were quantified by manual counting. (B) α-santalol inhibited HUVEC invasion in Transwell assay. A total of at 5 × 104 HUVECs were seeded in the top chamber and treated with vehicle or different concentrations of compounds. After 24 hours, the HUVECs that invaded through the membrane were stained and quantified. (C) α-santalol inhibited tube formation of HUVECs. After treated with vehicle or indicated concentrations of compounds for 10 hours, tubular structure in each group was quantified by manual counting. The percentage of inhibition was expressed using vehicle treated cells at 100%. Values are mean ± SEM (n = 6) of three independent experiments. *p < 0.05; **p < 0.01; ***p < 0.001 versus vehicle control.
Mentions: Effect of α-santalol on the chemotactic motility of HUVECs is shown in Figure 3A. HUVECs migrated into the clear area. α-santalol significantly inhibited the migration of endothelial cells in a dose dependent manner (Figure 3A) and maximum inhibition of endothelial cell migration was observed at 20 μM and was almost similar to that of zero hour incubation. We next performed transwell assay to measure the effect of α-santalol on cell invasion. As shown in Figure 3B, α-santalol significantly inhibited the invasion of HUVEC as compared to control (p < 0.001). Maturation of migrated endothelial cells into a capillary tube is a critical early step [3]. Therefore, we investigated the effect of α- santalol on HUVEC tube formation. When HUVECs were seeded on the growth factor–reduced matrigel, robust tubular-like structures were formed (Figure 3C). α-santalol effectively reduced the width and length of endothelial tubes at 10 and 20 μM (Figure 3C).

Bottom Line: However, recently, most of these anticancer drugs have some adverse effects.Discovery of novel VEGFR2 inhibitors as anticancer drug candidates is still needed.Furthermore, α-santalol reduced the cell viability and induced apoptosis in PC-3 cells, which were correlated with the downregulation of AKT, mTOR and P70S6K expressions.

View Article: PubMed Central - HTML - PubMed

Affiliation: Camel Biomedical Research Unit, College of Pharmacy and Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia. saritasaraswati@gmail.com.

ABSTRACT

Background: VEGF receptor 2 (VEGFR2) inhibitors, as efficient antiangiogenesis agents, have been applied in the cancer treatment. However, recently, most of these anticancer drugs have some adverse effects. Discovery of novel VEGFR2 inhibitors as anticancer drug candidates is still needed.

Methods: We used α-santalol and analyzed its inhibitory effects on human umbilical vein endothelial cells (HUVECs) and Prostate tumor cells (PC-3 or LNCaP) in vitro. Tumor xenografts in nude mice were used to examine the in vivo activity of α-santalol.

Results: α-santalol significantly inhibits HUVEC proliferation, migration, invasion, and tube formation. Western blot analysis indicated that α-santalol inhibited VEGF-induced phosphorylation of VEGFR2 kinase and the downstream protein kinases including AKT, ERK, FAK, Src, mTOR, and pS6K in HUVEC, PC-3 and LNCaP cells. α-santalol treatment inhibited ex vivo and in vivo angiogenesis as evident by rat aortic and sponge implant angiogenesis assay. α-santalol significantly reduced the volume and the weight of solid tumors in prostate xenograft mouse model. The antiangiogenic effect by CD31 immunohistochemical staining indicated that α-santalol inhibited tumorigenesis by targeting angiogenesis. Furthermore, α-santalol reduced the cell viability and induced apoptosis in PC-3 cells, which were correlated with the downregulation of AKT, mTOR and P70S6K expressions. Molecular docking simulation indicated that α-santalol form hydrogen bonds and aromatic interactions within the ATP-binding region of the VEGFR2 kinase unit.

Conclusion: α-santalol inhibits angiogenesis by targeting VEGFR2 regulated AKT/mTOR/P70S6K signaling pathway, and could be used as a potential drug candidate for cancer therapy.

Show MeSH
Related in: MedlinePlus