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Dual targeting of retinoid X receptor and histone deacetylase with DW22 as a novel antitumor approach.

Wang L, Chen G, Chen K, Ren Y, Li H, Jiang X, Jia L, Fu S, Li Y, Liu X, Wang S, Yang J, Wu C - Oncotarget (2015)

Bottom Line: We found that the co-expression of RXR-α and HDAC1 was frequently appeared in lung cancer and breast cancer tissues and cell lines.Moreover, intravenous administration of DW22 significantly retarded tumor growth of A549 and MDA-MB-435 xenograft mice models, and induced no substantial weight loss and gross toxicity.In addition, DW22 also reduced cell proliferation, angiogenesis, and induced cell apoptosis in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, P.R. China.

ABSTRACT
Retinoid X receptor (RXR) and Histone deacetylase (HDAC) are considered important targets for cancer therapy due to their crucial roles in genetic or epigenetic regulations of cancer development and progression. Here, we evaluated the potential of dual targeting of RXR and HDAC using DW22 as a novel therapeutic approach to cancer treatment. We found that the co-expression of RXR-α and HDAC1 was frequently appeared in lung cancer and breast cancer tissues and cell lines. RXR was activated by DW22 in RXRα and HDAC1 overexpressed A549 and MDA-MB-435 cell lines. Meanwhile, DW22 inhibited the activity of HDAC by decreasing its expression in A549 and MDA-MB-435 cell lines, but not in RXRα and HDAC1 deficient cell lines. Moreover, DW22 suppressed cell growth, induced cell differentiation, prompted cell apoptosis and arrested cell cycle in A549, MDA-MB-435 or HL60 cell lines. Treatment human umbilical vascular endothelial cells (HUVECs) with DW22 suppressed migration, invasion and tube formation through decreasing VEGF expression. The up-regulation of Ac-H3 and p21, and down-regulation of VEGF caused by DW22 was markedly attenuated by silencing of HDAC1. Furthermore, knockdown of RXRα by siRNA completely blocked DW22-induced cell differentiation, but partially attenuated DW22-caused inhibition of cell proliferation, induction of cell apoptosis, and suppression of cell migration, invasion and tube formation. Moreover, intravenous administration of DW22 significantly retarded tumor growth of A549 and MDA-MB-435 xenograft mice models, and induced no substantial weight loss and gross toxicity. In addition, DW22 also reduced cell proliferation, angiogenesis, and induced cell apoptosis in vivo. Collectively, our data demonstrates that dual targeting of RXR and HDAC using DW22 possesses pleiotropic antitumor activities both in vitro and in vivo, providing a novel therapeutic approach for cancer treatment.

No MeSH data available.


Related in: MedlinePlus

The effects of DW22 on VEGF-induced migration, invasion, and tubular structure formation of endothelial cells(A) HUVECs invasion was measured by transwell assay after DW22 (1, 5, 20 μM) treated for 12 h. (B) HUVECs migration was measured by wound-healing migration assay after DW22 (1, 5, 20 μM) treated for 12 h. (C) In the biosensor system, migrating cells were indicated by the cell index. Data were analyzed using RTCA software 1.2 (supplied with the instrument). (D) HUVECs tube formation was measured after DW22 (1, 5, 20 μM) treated for 12 h. The experiments were performed as described in Materials and Methods. (E) The VEGF expression was assessed by western blot analyses in HUVEC, A549 and MDA-MB-435 cell lines after DW22 (1, 5, 20 μM) treated for 24 h. β-actin expression was used as a loading control. VEGF, MW 43 kD; β-actin, MW 43 kD. All error bars are s.e.m. *p < 0.05 compare with VEGF control group, **p < 0.01 compare with VEGF control group, ***p < 0.005 compare with VEGF control group.
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Figure 4: The effects of DW22 on VEGF-induced migration, invasion, and tubular structure formation of endothelial cells(A) HUVECs invasion was measured by transwell assay after DW22 (1, 5, 20 μM) treated for 12 h. (B) HUVECs migration was measured by wound-healing migration assay after DW22 (1, 5, 20 μM) treated for 12 h. (C) In the biosensor system, migrating cells were indicated by the cell index. Data were analyzed using RTCA software 1.2 (supplied with the instrument). (D) HUVECs tube formation was measured after DW22 (1, 5, 20 μM) treated for 12 h. The experiments were performed as described in Materials and Methods. (E) The VEGF expression was assessed by western blot analyses in HUVEC, A549 and MDA-MB-435 cell lines after DW22 (1, 5, 20 μM) treated for 24 h. β-actin expression was used as a loading control. VEGF, MW 43 kD; β-actin, MW 43 kD. All error bars are s.e.m. *p < 0.05 compare with VEGF control group, **p < 0.01 compare with VEGF control group, ***p < 0.005 compare with VEGF control group.

Mentions: The migration, invasion and angiogenesis of endothelial cell are necessary for tumor growth and metastasis [21]. Thus, we assessed the effects of DW22 on VEGF-induced migration, invasion, and tube formation of HUVECs in vitro. In order to exclude the cytotoxicity of DW22, the viability of HUVECs after treatment with DW22 was firstly examined. DW22 treatment for 12 h caused a slight decrease in the percentage of metabolically viable HUVECs at 20 μM (Supplementary Figure 5). In addition, treatment with DW22 for 36 h only resulted in a 15% inhibition of cell viability (Data not shown). Therefore, the maximal concentration of 20 μM was chosen in the following experiments. The effects of DW22 on the chemotactic motility of HUVECs were measured by wound-healing migration assay, RTCA and Transwell cell invasion assay. It was showed that DW22 dramatically reduced VEGF-induced HUVECs invasion and migration (Figure 4A, 4B, and 4C). Both effects of DW22 were concentration dependent, with significant inhibition first occurring at 1 μM. In the same concentration (5 μM), DW22 displayed a relatively weak ability to inhibit migration of HUVECs as compared with SAHA.


Dual targeting of retinoid X receptor and histone deacetylase with DW22 as a novel antitumor approach.

Wang L, Chen G, Chen K, Ren Y, Li H, Jiang X, Jia L, Fu S, Li Y, Liu X, Wang S, Yang J, Wu C - Oncotarget (2015)

The effects of DW22 on VEGF-induced migration, invasion, and tubular structure formation of endothelial cells(A) HUVECs invasion was measured by transwell assay after DW22 (1, 5, 20 μM) treated for 12 h. (B) HUVECs migration was measured by wound-healing migration assay after DW22 (1, 5, 20 μM) treated for 12 h. (C) In the biosensor system, migrating cells were indicated by the cell index. Data were analyzed using RTCA software 1.2 (supplied with the instrument). (D) HUVECs tube formation was measured after DW22 (1, 5, 20 μM) treated for 12 h. The experiments were performed as described in Materials and Methods. (E) The VEGF expression was assessed by western blot analyses in HUVEC, A549 and MDA-MB-435 cell lines after DW22 (1, 5, 20 μM) treated for 24 h. β-actin expression was used as a loading control. VEGF, MW 43 kD; β-actin, MW 43 kD. All error bars are s.e.m. *p < 0.05 compare with VEGF control group, **p < 0.01 compare with VEGF control group, ***p < 0.005 compare with VEGF control group.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4496394&req=5

Figure 4: The effects of DW22 on VEGF-induced migration, invasion, and tubular structure formation of endothelial cells(A) HUVECs invasion was measured by transwell assay after DW22 (1, 5, 20 μM) treated for 12 h. (B) HUVECs migration was measured by wound-healing migration assay after DW22 (1, 5, 20 μM) treated for 12 h. (C) In the biosensor system, migrating cells were indicated by the cell index. Data were analyzed using RTCA software 1.2 (supplied with the instrument). (D) HUVECs tube formation was measured after DW22 (1, 5, 20 μM) treated for 12 h. The experiments were performed as described in Materials and Methods. (E) The VEGF expression was assessed by western blot analyses in HUVEC, A549 and MDA-MB-435 cell lines after DW22 (1, 5, 20 μM) treated for 24 h. β-actin expression was used as a loading control. VEGF, MW 43 kD; β-actin, MW 43 kD. All error bars are s.e.m. *p < 0.05 compare with VEGF control group, **p < 0.01 compare with VEGF control group, ***p < 0.005 compare with VEGF control group.
Mentions: The migration, invasion and angiogenesis of endothelial cell are necessary for tumor growth and metastasis [21]. Thus, we assessed the effects of DW22 on VEGF-induced migration, invasion, and tube formation of HUVECs in vitro. In order to exclude the cytotoxicity of DW22, the viability of HUVECs after treatment with DW22 was firstly examined. DW22 treatment for 12 h caused a slight decrease in the percentage of metabolically viable HUVECs at 20 μM (Supplementary Figure 5). In addition, treatment with DW22 for 36 h only resulted in a 15% inhibition of cell viability (Data not shown). Therefore, the maximal concentration of 20 μM was chosen in the following experiments. The effects of DW22 on the chemotactic motility of HUVECs were measured by wound-healing migration assay, RTCA and Transwell cell invasion assay. It was showed that DW22 dramatically reduced VEGF-induced HUVECs invasion and migration (Figure 4A, 4B, and 4C). Both effects of DW22 were concentration dependent, with significant inhibition first occurring at 1 μM. In the same concentration (5 μM), DW22 displayed a relatively weak ability to inhibit migration of HUVECs as compared with SAHA.

Bottom Line: We found that the co-expression of RXR-α and HDAC1 was frequently appeared in lung cancer and breast cancer tissues and cell lines.Moreover, intravenous administration of DW22 significantly retarded tumor growth of A549 and MDA-MB-435 xenograft mice models, and induced no substantial weight loss and gross toxicity.In addition, DW22 also reduced cell proliferation, angiogenesis, and induced cell apoptosis in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, P.R. China.

ABSTRACT
Retinoid X receptor (RXR) and Histone deacetylase (HDAC) are considered important targets for cancer therapy due to their crucial roles in genetic or epigenetic regulations of cancer development and progression. Here, we evaluated the potential of dual targeting of RXR and HDAC using DW22 as a novel therapeutic approach to cancer treatment. We found that the co-expression of RXR-α and HDAC1 was frequently appeared in lung cancer and breast cancer tissues and cell lines. RXR was activated by DW22 in RXRα and HDAC1 overexpressed A549 and MDA-MB-435 cell lines. Meanwhile, DW22 inhibited the activity of HDAC by decreasing its expression in A549 and MDA-MB-435 cell lines, but not in RXRα and HDAC1 deficient cell lines. Moreover, DW22 suppressed cell growth, induced cell differentiation, prompted cell apoptosis and arrested cell cycle in A549, MDA-MB-435 or HL60 cell lines. Treatment human umbilical vascular endothelial cells (HUVECs) with DW22 suppressed migration, invasion and tube formation through decreasing VEGF expression. The up-regulation of Ac-H3 and p21, and down-regulation of VEGF caused by DW22 was markedly attenuated by silencing of HDAC1. Furthermore, knockdown of RXRα by siRNA completely blocked DW22-induced cell differentiation, but partially attenuated DW22-caused inhibition of cell proliferation, induction of cell apoptosis, and suppression of cell migration, invasion and tube formation. Moreover, intravenous administration of DW22 significantly retarded tumor growth of A549 and MDA-MB-435 xenograft mice models, and induced no substantial weight loss and gross toxicity. In addition, DW22 also reduced cell proliferation, angiogenesis, and induced cell apoptosis in vivo. Collectively, our data demonstrates that dual targeting of RXR and HDAC using DW22 possesses pleiotropic antitumor activities both in vitro and in vivo, providing a novel therapeutic approach for cancer treatment.

No MeSH data available.


Related in: MedlinePlus