Novel Nonsecosteroidal Vitamin D Receptor Modulator Combined with Gemcitabine Enhances Pancreatic Cancer Therapy through Remodeling of the Tumor Microenvironment

Kang, Zisheng; Yu, Tong; Li, Yanyi; Gao, Yi; Hou, Siyuan; Hao, Meixi; Han, Xiangxin; Wang, Bin; Wang, Qianqian; Zhang, Can

doi:10.1021/acs.jmedchem.0c01197

Cited by 16 publications

(8 citation statements)

References 37 publications

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“…There is convincing evidence in the literature that vitamin D is able to affect cancer progression at several levels by affecting tumor microenvironment composition consequently reducing cancer cell growth, inhibiting angiogenesis, and interfering with metastatic processes ( 30 , 31 ).…”

Section: Discussionmentioning

confidence: 99%

Vitamin D Reduces Thyroid Cancer Cells Migration Independently From the Modulation of CCL2 and CXCL8 Chemokines Secretion

et al. 2022

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BackgroundVitamin D3 is largely involved in the regulation of calcium homeostasis. More recently, it was demonstrated that vitamin D exerts several beneficial effects against cancer progression through several mechanisms, including the reduction of cancer cells proliferation and migration. CXCL8 and CCL2 are two chemokines secreted by thyroid tumor cells. In the thyroid tumor microenvironment, these chemokines exert several pro-tumorigenic effects including the one to increase the metastatic potential. The aim of the present study was to investigate if vitamin D could modulate both thyroid cancer cell migration and their ability to secrete CCL2 and CXCL8.MethodsTPC-1 (RET/PTC rearranged) and 8505C (BRAFV600e mutated) thyroid cancer cell lines were treated with increasing concentrations of 1,25-OH-vitamin D3 (0–1,000 nM). Cell viability was assessed by WST-1 assay, cell migration was evaluated by transwell–migration chamber system, and CCL2 and CXCL8 levels were measured in the cell culture supernatants by ELISA.ResultsVitamin D did not affect cell viability but reduced, in a dose-dependent and significant manner, thyroid cancer cell migration (ANOVAs p < 0.05 for both TPC-1 and 8505C). Vitamin D differently modulated the secretion of CCL2 and CXCL8, by significantly inhibiting the secretion of CCL2 in both thyroid cancer cell lines and inhibiting the secretion of CXCL8 only in TPC-1 (ANOVAs p < 0.05).ConclusionsVitamin D treatment of thyroid cancer cell lines reduces cell migration independently from the inhibition of the secretion of pro-tumorigenic chemokines. Future studies specifically designed at clarifying the pathways involved in the different inhibitory effects of vitamin D on CCL2 and CXCL8 in thyroid cancer cells appear worthwhile.

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Section: Discussionmentioning

confidence: 99%

Vitamin D Reduces Thyroid Cancer Cells Migration Independently From the Modulation of CCL2 and CXCL8 Chemokines Secretion

et al. 2022

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“…Three of these compounds inhibited activation of PSCs, and in combination with gemcitabine, one of these (compound I5) demonstrated anti-tumor activity. In animal studies I5 activity displayed similar activity to calcipotriol with minor calcemic effects (44).…”

Section: Pancreatic Ductal Adenocarcinomamentioning

confidence: 85%

New Roles for Vitamin D Superagonists: From COVID to Cancer

2021

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Vitamin D is a potent steroid hormone that induces widespread changes in gene expression and controls key biological pathways. Here we review pathophysiology of vitamin D with particular reference to COVID-19 and pancreatic cancer. Utility as a therapeutic agent is limited by hypercalcemic effects and attempts to circumvent this problem have used vitamin D superagonists, with increased efficacy and reduced calcemic effect. A further caveat is that vitamin D mediates multiple diverse effects. Some of these (anti-fibrosis) are likely beneficial in patients with COVID-19 and pancreatic cancer, whereas others (reduced immunity), may be beneficial through attenuation of the cytokine storm in patients with advanced COVID-19, but detrimental in pancreatic cancer. Vitamin D superagonists represent an untapped resource for development of effective therapeutic agents. However, to be successful this approach will require agonists with high cell-tissue specificity.

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“…Collectively, the results from these observational and clinical studies, together with recent laboratory-based evidence [ 19 , 20 , 82 , 83 ], provide a rationale for using vitamin D or its analogues as an economical agent in combination with chemo- or immunotherapy for PC treatment. Several clinical trials of vitamin D (or its analogue paricalcitol) alone or in combination with other treatments for PC are ongoing ( Table 2 ).…”

Section: Vitamin D and Pancreatic Cancer Survival And Mortalitymentioning

confidence: 99%

Vitamin D: Promises on the Horizon and Challenges Ahead for Fighting Pancreatic Cancer

Wei

Wang

Zuo

et al. 2021

Cancers

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Pancreatic cancer has a dismal prognosis, while its incidence is increasing. This is attributed, in part, to a profound desmoplastic and immunosuppressive tumor microenvironment associated with this cancer and resistance to current available therapies. Novel and effective intervention strategies are urgently needed to improve the outcomes of patients with pancreatic cancer. Vitamin D has pleiotropic functions beyond calcium–phosphate homeostasis and has been extensively studied both in the laboratory and clinic as a potential preventive agent or adjunct to standard therapies. Accumulating evidence from ecological, observational, and randomized controlled trials suggests that vitamin D has beneficial effects on risk, survival, and mortality in pancreatic cancer, although controversies still exist. Recent advances in demonstrating the important functions of vitamin D/vitamin D receptor (VDR) signaling in the regulation of stromal reprogramming, the microbiome, and immune response and the emergence of checkpoint immunotherapy provide opportunities for using vitamin D or its analogues as an adjunct for pancreatic cancer intervention. Many challenges lie ahead before the benefits of vitamin D can be fully realized in pancreatic cancer. These challenges include the need for randomized controlled trials of vitamin D to assess its impact on the risk and survival of pancreatic cancer, optimizing the timing and dosage of vitamin D or its analogues as an adjunct for pancreatic cancer intervention and elucidating the specific role of vitamin D/VDR signaling in the different stages of pancreatic cancer. Nevertheless, vitamin D holds great promise for reducing risk and improving outcomes of this disease.

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Novel Nonsecosteroidal Vitamin D Receptor Modulator Combined with Gemcitabine Enhances Pancreatic Cancer Therapy through Remodeling of the Tumor Microenvironment

Cited by 16 publications

References 37 publications

Vitamin D Reduces Thyroid Cancer Cells Migration Independently From the Modulation of CCL2 and CXCL8 Chemokines Secretion

Vitamin D Reduces Thyroid Cancer Cells Migration Independently From the Modulation of CCL2 and CXCL8 Chemokines Secretion

New Roles for Vitamin D Superagonists: From COVID to Cancer

Vitamin D: Promises on the Horizon and Challenges Ahead for Fighting Pancreatic Cancer

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