Repurposing vitamin D for treatment of human malignancies via targeting tumor microenvironment

Wu, Xu; Hu, Wei; Lü, Lei; Zhao, Yueshui; Zhou, Yong; Xiao, Zhangang; Zhang, Lin; Zhang, Hanyu; Li, Xiaobing; Li, Wanping; Wang, Shengpeng; Cho, Chi Hin; Shen, Jing; Li, Mingxing

doi:10.1016/j.apsb.2018.09.002

Cited by 95 publications

(57 citation statements)

References 186 publications

(252 reference statements)

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“…These results show that 1,25(OH) 2 D 3 action extends to tumor stromal fibroblasts and that 1,25(OH) 2 D 3 is an important regulator of CAF differentiation. Together with other findings suggesting anti-inflammatory and anti-angiogenic effects of 1,25(OH) 2 D 3 at the level of immune and endothelial cells [ 122 ], they widen the prodifferentiation action of 1,25(OH) 2 D 3 to cells of the tumor microenvironment, which may have important consequences on cancer development.…”

Section: Effects Of 125(oh) 2 Dsupporting

confidence: 68%

Vitamin D Effects on Cell Differentiation and Stemness in Cancer

Fernández‐Barral

Bustamante-Madrid

Ferrer-Mayorga

et al. 2020

Cancers

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Vitamin D3 is the precursor of 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3), a pleiotropic hormone that is a major regulator of the human genome. 1,25(OH)2D3 modulates the phenotype and physiology of many cell types by controlling the expression of hundreds of genes in a tissue- and cell-specific fashion. Vitamin D deficiency is common among cancer patients and numerous studies have reported that 1,25(OH)2D3 promotes the differentiation of a wide panel of cultured carcinoma cells, frequently associated with a reduction in cell proliferation and survival. A major mechanism of this action is inhibition of the epithelial–mesenchymal transition, which in turn is largely based on antagonism of the Wnt/β-catenin, TGF-β and EGF signaling pathways. In addition, 1,25(OH)2D3 controls the gene expression profile and phenotype of cancer-associated fibroblasts (CAFs), which are important players in the tumorigenic process. Moreover, recent data suggest a regulatory role of 1,25(OH)2D3 in the biology of normal and cancer stem cells (CSCs). Here, we revise the current knowledge of the molecular and genetic basis of the regulation by 1,25(OH)2D3 of the differentiation and stemness of human carcinoma cells, CAFs and CSCs. These effects support a homeostatic non-cytotoxic anticancer action of 1,25(OH)2D3 based on reprogramming of the phenotype of several cell types.

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Section: Effects Of 125(oh) 2 Dsupporting

confidence: 68%

Vitamin D Effects on Cell Differentiation and Stemness in Cancer

Fernández‐Barral

Bustamante-Madrid

Ferrer-Mayorga

et al. 2020

Cancers

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“…The TME, which consists of resident fibroblasts, endothelial cells, pericytes, leukocytes, extracellular matrix, immune cells 17 , 18 , and the immune cells infiltrated in the solid tumor such as macrophages or neutrophils play a significant role in the metastasis of malignancy 19 , 20 , 21 , 22 . Therefore, we hypothesized that targeting a molecule that can regulate the tumor immune microenvironment along with anti-VEGFR2 may solve the problem of invasiveness and metastasis that is induced by VEGF/VEGFR2 inhibitor.…”

Section: Introductionmentioning

confidence: 99%

VEGFR2-targeted antibody fused with IFN mut regulates the tumor microenvironment of colorectal cancer and exhibits potent anti-tumor and anti-metastasis activity

Shang

Gao

Zhu

et al. 2021

Acta Pharmaceutica Sinica B

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Although interferon α (IFN α ) and anti-angiogenesis antibodies have shown appropriate clinical benefit in the treatment of malignant cancer, they are deficient in clinical applications. Previously, we described an anti-vascular endothelial growth factor receptor 2 (VEGFR2)-IFN α fusion protein named JZA01, which showed increased in vivo half-life and reduced side effects compared with IFN α , and it was more effective than the anti-VEGFR2 antibody against tumors. However, the affinity of the IFN α component of the fusion protein for its receptor-IFNAR1 was decreased. To address this problem, an IFN α -mutant fused with anti-VEGFR2 was designed to produce anti-VEGFR2-IFN α mut, which was used to target VEGFR2 with enhanced anti-tumor and anti-metastasis efficacy. Anti-VEGFR2-IFN α mut specifically inhibited proliferation of tumor cells and promoted apoptosis. In addition, anti-VEGFR2-IFN α mut inhibited migration of colorectal cancer cells and invasion by regulating the PI3K–AKT–GSK3 β –snail signal pathway. Anti-VEGFR2-IFN α mut showed superior anti-tumor efficacy with improved tumor microenvironment (TME) by enhancing dendritic cell maturation, dendritic cell activity, and increasing tumor-infiltrating CD8 + T cells. Thus, this study provides a novel approach for the treatment of metastatic colorectal cancer, and this design may become a new approach to cancer immunotherapy.

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“…Many studies have shown that anti-angiogenic drugs can normalize tumor blood vessels within a certain time window, which can improve tumor blood flow perfusion and enhance chemotherapeutic drug delivery into tumors 27 , 41 . This may alter the microenvironment and metabolic state of cancer cells 42 , which makes them more sensitive to chemotherapy, radiotherapy or immunotherapy. In this study, we demonstrated that SMI can prune the microvessels and promote vascular maturation, which lead to improved vascular structure.…”

Section: Discussionmentioning

confidence: 99%

Identification of bioactive anti-angiogenic components targeting tumor endothelial cells in Shenmai injection using multidimensional pharmacokinetics

Zhong

Jiang

et al. 2020

Acta Pharmaceutica Sinica B

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Shenmai injection (SMI) is a well-defined herbal preparation that is widely and clinically used as an adjuvant therapy for cancer. Previously, we found that SMI synergistically enhanced the activity of chemotherapy on colorectal cancer by promoting the distribution of drugs in xenograft tumors. However, the underlying mechanisms and bioactive constituents remained unknown. In the present work, the regulatory effects of SMI on tumor vasculature were determined, and the potential anti-angiogenic components targeting tumor endothelial cells (TECs) were identified. Multidimensional pharmacokinetic profiles of ginsenosides in plasma, subcutaneous tumors, and TECs were investigated. The results showed that the concentrations of protopanaxadiol-type (PPD) ginsenosides (Rb1, Rb2/Rb3, Rc, and Rd) in both plasma and tumors, were higher than those of protopanaxatriol-type (Rg1 and Re) and oleanane-type (Ro) ginsenosides. Among PPD-type ginsenosides, Rd exhibited the greatest concentrations in tumors and TECs after repeated injection. In vivo bioactivity results showed that Rd suppressed neovascularization in tumors, normalized the structure of tumor vessels, and improved the anti-tumor effect of 5-fluorouracil (5FU) in xenograft mice. Furthermore, Rd inhibited the migration and tube formation capacity of endothelial cells in vitro . In conclusion, Rd may be an important active form to exert the anti-angiogenic effect on tumor after SMI treatment.

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Repurposing vitamin D for treatment of human malignancies via targeting tumor microenvironment

Cited by 95 publications

References 186 publications

Vitamin D Effects on Cell Differentiation and Stemness in Cancer

Vitamin D Effects on Cell Differentiation and Stemness in Cancer

VEGFR2-targeted antibody fused with IFN mut regulates the tumor microenvironment of colorectal cancer and exhibits potent anti-tumor and anti-metastasis activity

Identification of bioactive anti-angiogenic components targeting tumor endothelial cells in Shenmai injection using multidimensional pharmacokinetics

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