A New Role for Vitamin D: The Enhancement of Oncolytic Viral Therapy in Pancreatic Cancer

LaRocca, Christopher J.; Warner, Susanne G.

doi:10.3390/biomedicines6040104

Cited by 15 publications

(11 citation statements)

References 81 publications

(102 reference statements)

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“…Epidemiological studies show that vitamin D3 supplementation is effective in the improvement of vascular function [21,22] and has a beneficial effect on the function of the left ventricle in patients with heart failure [23,24,25]. In addition, vitamin D has been shown to inhibit the migration and growth of cancer cells [26,27,28,29]. However, it is unknown if calcitriol is also able to attenuate the progression of cancer cells apart from its beneficial effect in the inhibition of DoIC.…”

Section: Introductionmentioning

confidence: 99%

Calcitriol Attenuates Doxorubicin-Induced Cardiac Dysfunction and Inhibits Endothelial-to-Mesenchymal Transition in Mice

Tsai

Lin

Hang

et al. 2019

Cells

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Doxorubicin (Dox) is an effective anti-neoplasm drug, but its cardiac toxicity limits its clinical use. Endothelial-to-mesenchymal transition (EndMT) has been found to be involved in the process of heart failure. It is unclear whether EndMT contributes to Dox-induced cardiomyopathy (DoIC). Calcitriol, an active form Vitamin D3, blocks the growth of cancer cells by inhibiting the Smad pathway. To investigate the effect of calcitriol via inhibiting EndMT in DoIC, C57BL/6 mice and endothelial-specific labeled mice were intraperitoneally administered Dox twice weekly for 4 weeks (32 mg/kg cumulative dose) and were subsequently treated with or without calcitriol for 12 weeks. Echocardiography revealed diastolic dysfunction at 13 weeks following the first Dox treatment, accompanied by increased myocardial fibrosis and up-regulated pro-fibrotic proteins. Calcitriol attenuated Dox-induced myocardial fibrosis, down-regulated pro-fibrotic proteins and improved diastolic function. Endothelial fate tracing revealed that EndMT-derived cells contributed to Dox-induced cardiac fibrosis. In vitro, human umbilical vein endothelial cells and mouse cardiac fibroblasts were treated with Transforming growth factor (TGF)-β with or without calcitriol. Morphological, immunofluorescence staining, and Western blot analyses revealed that TGF-β-induced EndMT and fibroblast-to-myofibroblast transition (FMT) were attenuated by calcitriol by the inhibition of the Smad2 pathway. Collectively, calcitriol attenuated DoIC through the inhibition of the EndMT and FMT processes.

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Section: Introductionmentioning

confidence: 99%

Calcitriol Attenuates Doxorubicin-Induced Cardiac Dysfunction and Inhibits Endothelial-to-Mesenchymal Transition in Mice

Tsai

Lin

Hang

et al. 2019

Cells

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“…A pilot study of neoadjuvant paricalcitol in patients with resectable PDAC found 10-100 fold increased T cell migration into tumors after 28 days of treatment ( 193 ). Furthermore, a number of reviews suggest utilization of VDAs to inhibit immune-suppressive activity of stromal cells and the hope is that this will improve response to checkpoint inhibitors in patients with PDAC ( 194 , 195 ).…”

Section: Hypercalcemic Effect Of Vdr Ligandsmentioning

confidence: 99%

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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“…The density and impenetrability of the PDAC tumor microenvironment limit access to and prevent robust exposure of OVs to the proliferating PDAC cells. To overcome the specific challenges associated with the density of the PDAC microenvironment, the use of Vitamin D in conjunction with therapeutic agents or the use of hyaluronidase is currently being investigated for the potential to increase OV exposure to the tumor microenvironment and facilitate enhanced therapeutic efficacy [ 31 , 45 ]. One can also predict the challenges posed to other common strategies of immune system modulation through viral-induced transfection being limited due to PDAC microenvironment immunosuppression and lack of neoantigen expression.…”

Section: Introduction To Oncolytic Virusesmentioning

confidence: 99%

The Present Status of Immuno-Oncolytic Viruses in the Treatment of Pancreatic Cancer

Haller

Monaco

Essani

2020

Viruses

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Pancreatic ductal adenocarcinoma (PDAC) is the fifth leading cause of cancer-related death in Western countries. The incidence of PDAC has increased over the last 40 years and is projected to be the second leading cause of cancer death by 2030. Despite aggressive treatment regimens, prognosis for patients diagnosed with PDAC is very poor; PDAC has the lowest 5-year survival rate for any form of cancer in the United States (US). PDAC is very rarely detected in early stages when surgical resection can be performed. Only 20% of cases are suitable for surgical resection; this remains the only curative treatment when combined with adjuvant chemotherapy. Treatment regimens excluding surgical intervention such as chemotherapeutic treatments are associated with adverse effects and genetherapy strategies also struggle with lack of specificity and/or efficacy. The lack of effective treatments for this disease highlights the necessity for innovation in treatment options for patients diagnosed with early- to late-phase PDAC and immuno-oncolytic viruses (OVs) have been of particular interest since 2006 when the first oncolytic virus was approved as a therapy for nasopharyngeal cancers in China. Interest resurged in 2015 when T-Vec, an oncolytic herpes simplex virus, was approved in the United States for treatment of advanced melanoma. While many vectors have been explored, few show promise as treatment for pancreatic cancer, and fewer still have progressed to clinical trial evaluation. This review outlines recent strategies in the development of OVs targeting treatment of PDAC, current state of preclinical and clinical investigation and application.

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A New Role for Vitamin D: The Enhancement of Oncolytic Viral Therapy in Pancreatic Cancer

Cited by 15 publications

References 81 publications

Calcitriol Attenuates Doxorubicin-Induced Cardiac Dysfunction and Inhibits Endothelial-to-Mesenchymal Transition in Mice

Calcitriol Attenuates Doxorubicin-Induced Cardiac Dysfunction and Inhibits Endothelial-to-Mesenchymal Transition in Mice

New Roles for Vitamin D Superagonists: From COVID to Cancer

The Present Status of Immuno-Oncolytic Viruses in the Treatment of Pancreatic Cancer

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