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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

Schematic form of the proposed mechanisms of the effect of DW22 on cancer cellsDW22 exerts its anticancer activity on cancer cells by activating RXR and inhibiting HDAC, and synergistically results in the activation of their target gene, subsequently leads to the induction of cell differentiation and apoptosis, the inhibition of cell growth, and the suppression of cell invasion and angiogenesis. HAT(histone acetyltransferase); CoA(Acetyl-CoA); RARE(RAR/RXR binding element).
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Figure 7: Schematic form of the proposed mechanisms of the effect of DW22 on cancer cellsDW22 exerts its anticancer activity on cancer cells by activating RXR and inhibiting HDAC, and synergistically results in the activation of their target gene, subsequently leads to the induction of cell differentiation and apoptosis, the inhibition of cell growth, and the suppression of cell invasion and angiogenesis. HAT(histone acetyltransferase); CoA(Acetyl-CoA); RARE(RAR/RXR binding element).

Mentions: In summary, this study firstly demonstrates that dual targeting of RXR and HDAC using DW22 possesses pleiotropic antitumor activities in vitro and in vivo (Figure 7), providing a sound scientific base for developing this novel approach for treatment cancer.


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)

Schematic form of the proposed mechanisms of the effect of DW22 on cancer cellsDW22 exerts its anticancer activity on cancer cells by activating RXR and inhibiting HDAC, and synergistically results in the activation of their target gene, subsequently leads to the induction of cell differentiation and apoptosis, the inhibition of cell growth, and the suppression of cell invasion and angiogenesis. HAT(histone acetyltransferase); CoA(Acetyl-CoA); RARE(RAR/RXR binding element).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 7: Schematic form of the proposed mechanisms of the effect of DW22 on cancer cellsDW22 exerts its anticancer activity on cancer cells by activating RXR and inhibiting HDAC, and synergistically results in the activation of their target gene, subsequently leads to the induction of cell differentiation and apoptosis, the inhibition of cell growth, and the suppression of cell invasion and angiogenesis. HAT(histone acetyltransferase); CoA(Acetyl-CoA); RARE(RAR/RXR binding element).
Mentions: In summary, this study firstly demonstrates that dual targeting of RXR and HDAC using DW22 possesses pleiotropic antitumor activities in vitro and in vivo (Figure 7), providing a sound scientific base for developing this novel approach for treatment cancer.

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