Submit to IJMS Review for IJMS Propose a Special Issue

Journal Menu

Journal Browser

Commemorative Issue in Honor of Professor Milan R. Uskokovic: Role of Vitamin D in Cancer Therapeutics

Special Issue Editors
Special Issue Information
Keywords
Benefits of Publishing in a Special Issue
Published Papers

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (11 May 2016) | Viewed by 76011

Share This Special Issue

Special Issue Editors

Dr. Efigenia Arias

E-Mail Website
Guest Editor

Department of Obstetrics and Gynecology-CIMUS, Clinic Universitary Hospital Santiago de Compostela University of Santiago de Compostela, Santiago de Compostela 15782, Spain
Interests: vitamin D; vitamin D receptor; vitamin D analogues; Pit-1; POU1F1; breast cancer

Prof. Dr. Roman Perez-Fernandez

E-Mail Website
Guest Editor

Department of Physiology-Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), University of Santiago de Compostela, 15782 Santiago de Compostela, Spain
Interests: vitamin D; vitamin D receptor; vitamin D analogues; Pit-1; POU1F1; breast cancer

Special Issue Information

Dear Colleagues,

This Special Issue is dedicated to Professor Milan R. Uskokovic * on the occasion of the first anniversary of his passing away.

Multiple studies have shown vitamin D’s involvement in certain processes beyond calcium and bone homeostasis, such as inflammation, immune response, and cancer. Epidemiological studies have demonstrated an inverse association between cancer incidence and sunlight exposure, suggesting that vitamin D deficiency may play a role in cancer development. Studies to date have failed to demonstrate this association; nevertheless, there is strong experimental evidence of antiproliferative and proapoptotic effects of vitamin D and its derivatives, indicating these compounds as potential anticancer treatments. Numerous vitamin D analogues have been synthesized which maintain antiproliferative properties while reducing calcemic side effects. These have been used alone or in combination with chemotherapeutic agents for cancer treatment. However, in order to design better clinical trials, it is still necessary to further assess optimal dosage, therapeutic schedules and patient profile.

Vitamin D and its derivatives is an active field of investigation in cancer therapeutics. This Special Issue, entitled “Role of Vitamin D in Cancer Therapeutics”, will cover a selection of recent research topics and current review articles in the field of vitamin D for cancer prevention and treatment. Experimental and clinical papers, up-to-date review articles, and commentaries are all welcome.

Prof. Dr. Roman Perez-Fernandez
Dr. Maria E. Arias
Guest Editors

* Professor Uskokovic, a leading researcher in Vitamin D synthesis, died on May 11th 2015. He studied chemical engineering at the Belgrade Polytechnic University (Yugoslavia), and moved to Clark University (Worcester, MA, USA) to obtain his Ph.D. in organic chemistry, and then to Upper Montclair, New Jersey, where he resided until 2011. He has 66 patents to his name and was the Director of Natural Products Research at Hoffmann La Roche (Nutley, NJ, USA). Among his accomplishments, he was on the advisory or editorial boards of six professional journals, a member of the American Chemical Society, and the New York Academy of Sciences, and a Regents Professor at the University of California. A laboratory at the Brown University, School of Medicine, Women and Infants Hospital of Rhode Island, was dedicated in honor of his research mentorship. He made substantial contributions to the development of vitamin D analogs, studying its clinical applications and generously collaborating with researchers around the world.

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

vitamin D analogues
calcitriol
vitamin D and derivatives
vitamin D receptor (VDR) and polymorphisms
cancer and vitamin D
vitamin D and chemotherapy
vitamin D and chemoprevention

Benefits of Publishing in a Special Issue

Ease of navigation: Grouping papers by topic helps scholars navigate broad scope journals more efficiently.
Greater discoverability: Special Issues support the reach and impact of scientific research. Articles in Special Issues are more discoverable and cited more frequently.
Expansion of research network: Special Issues facilitate connections among authors, fostering scientific collaborations.
External promotion: Articles in Special Issues are often promoted through the journal's social media, increasing their visibility.
e-Book format: Special Issues with more than 10 articles can be published as dedicated e-books, ensuring wide and rapid dissemination.

Further information on MDPI's Special Issue polices can be found here.

Published Papers (12 papers)

Download All Papers

Order results

Result details

Show export options Show export options

Select all

Export citation of selected articles as:

Research

Jump to: Review

2196 KiB

Open AccessArticle

1α,25(OH)₂D₃ Suppresses the Migration of Ovarian Cancer SKOV-3 Cells through the Inhibition of Epithelial–Mesenchymal Transition

by Yong-Feng Hou, Si-Hai Gao, Ping Wang, He-Mei Zhang, Li-Zhi Liu, Meng-Xuan Ye, Guang-Ming Zhou, Zeng-Li Zhang and Bing-Yan Li

Int. J. Mol. Sci. 2016, 17(8), 1285; https://doi.org/10.3390/ijms17081285 - 19 Aug 2016

Cited by 41 | Viewed by 6451

Abstract

Ovarian cancer is the most lethal gynecological malignancy due to its high metastatic ability. Epithelial-mesenchymal transition (EMT) is essential during both follicular rupture and epithelium regeneration. However, it may also accelerate the progression of ovarian carcinomas. Experimental studies have found that 1α,25-dihydroxyvitamin-D3 [1α,25(OH)₂D₃] can inhibit the proliferation of ovarian cancer cells. In this study, we investigated whether 1α,25(OH)₂D₃ could inhibit the migration of ovarian cancer cells via regulating EMT. We established a model of transient transforming growth factor-β1(TGF-β1)-induced EMT in human ovarian adenocarcinoma cell line SKOV-3 cells. Results showed that, compared with control, 1α,25(OH)₂D₃ not only inhibited the migration and the invasion of SKOV-3 cells, but also promoted the acquisition of an epithelial phenotype of SKOV-3 cells treated with TGF-β1. We discovered that 1α,25(OH)₂D₃ increased the expression of epithelial marker E-cadherin and decreased the level of mesenchymal marker, Vimentin, which was associated with the elevated expression of VDR. Moreover, 1α,25(OH)₂D₃ reduced the expression level of transcription factors of EMT, such as slug, snail, and β-catenin. These results indicate that 1α,25(OH)₂D₃ suppresses the migration and invasion of ovarian cancer cells by inhibiting EMT, implying that 1α,25(OH)₂D₃ might be a potential therapeutic agent for the treatment of ovarian cancer. Full article

(This article belongs to the Special Issue Commemorative Issue in Honor of Professor Milan R. Uskokovic: Role of Vitamin D in Cancer Therapeutics)

► Show Figures

Graphical abstract

2415 KiB

Open AccessArticle

Prodifferentiation Activity of Novel Vitamin D₂ Analogs PRI-1916 and PRI-1917 and Their Combinations with a Plant Polyphenol in Acute Myeloid Leukemia Cells

by Matan Nachliely, Ehud Sharony, Narasimha Rao Bolla, Andrzej Kutner and Michael Danilenko

Int. J. Mol. Sci. 2016, 17(7), 1068; https://doi.org/10.3390/ijms17071068 - 5 Jul 2016

Cited by 12 | Viewed by 5970

Abstract

1α,25-dihydroxyvitamin D₃ (1,25D3) is a powerful differentiation inducer for acute myeloid leukemia (AML) cells. However, 1,25D3 doses required for differentiation of AML cells may cause lethal hypercalcemia in vivo. There is evidence that vitamin D₂ is less toxic than vitamin D₃ in animals. Here, we determined the differentiation effects of novel analogs of 1α,25-dihydroxyvitamin D₂ (1,25D2), PRI-1916 and PRI-1917, in which the extended side chains of their previously reported precursors (PRI-1906 and PRI-1907, respectively) underwent further 24Z (24-cis) modification. Using four human AML cell lines representing different stages of myeloid maturation (KG-1a, HL60, U937, and MOLM-13), we found that the potency of PRI-1916 was slightly higher or equal to that of PRI-1906 while PRI-1917 was significantly less potent than PRI-1907. We also demonstrated that 1,25D2 was a less effective differentiation agent than 1,25D3 in these cell lines. Irrespective of their differentiation potency, all the vitamin D₂ derivatives tested were less potent than 1,25D3 in transactivating the DR3-type vitamin D response elements. However, similar to 1,25D3, both 1,25D2 and its analogs could strongly cooperate with the plant polyphenol carnosic acid in inducing cell differentiation and inhibition of G1–S cell cycle transition. These results indicate that the 24Z modification has contrasting effects on the differentiation ability of PRI-1906 and PRI-1907 and that the addition of a plant polyphenol could result in a similar extent of cell differentiation induced by different vitamin D compounds. The enhanced antileukemic effects of the tested combinations may constitute the basis for the development of novel approaches for differentiation therapy of AML. Full article

(This article belongs to the Special Issue Commemorative Issue in Honor of Professor Milan R. Uskokovic: Role of Vitamin D in Cancer Therapeutics)

► Show Figures

Graphical abstract

2439 KiB

Open AccessArticle

The Effect of Analogues of 1α,25-Dihydroxyvitamin D₂ on the Regrowth and Gene Expression of Human Colon Cancer Cells Refractory to 5-Fluorouracil

by Jacek Neska, Paweł Swoboda, Małgorzata Przybyszewska, Agnieszka Kotlarz, Narasimha Rao Bolla, Joanna Miłoszewska, Monika Anna Grygorowicz, Andrzej Kutner and Sergiusz Markowicz

Int. J. Mol. Sci. 2016, 17(6), 903; https://doi.org/10.3390/ijms17060903 - 14 Jun 2016

Cited by 13 | Viewed by 5603

Abstract

This study aimed to evaluate the capacity of hypocalcemic analogues of 1α,25-dihydroxyvitamin D₂ (1,25D2) and 1α,25-dihydroxyvitamin D₃ (1,25D3) to inhibit regrowth and regulate the stemness-related gene expression in colon cancer cells undergoing renewal after exposure to 5-fluorouracil (5-FU). All of the tested analogues of 1,25D2 equally potently decreased the clonogenicity and the proliferative activity of HT-29 cells which survived the exposure to 5-FU, but differently regulated gene expression of these cells during their renewal. 1,25D2 and analogues (PRI-1907 and PRI-1917), as well as 1,25D3 and analogue PRI-2191, decreased the relative expression level of several stemness-related genes, such as NANOG, OCT3/4, PROM1, SOX2, ALDHA1, CXCR4, in HT-29/5-FU cells during their renewal, in comparison to untreated HT-29/5-FU cells. The other 1,25D2 analogues (PRI-1906 and PRI-1916) were not capable of downregulating the expression of these stemness-related genes as the analogues PRI-1907 and PRI-1917 did. All of the tested vitamin D analogues upregulated CDH1, the gene encoding E-cadherin associated with epithelial phenotype. Out of the series of analogues studied, side-chain branched analogues of 1,25D2 (PRI-1907, PRI-1917) and the analogue of 1,25D3 (PRI-2191) might be used to target cancer cells with stem-like phenotypes that survive conventional chemotherapy. Full article

(This article belongs to the Special Issue Commemorative Issue in Honor of Professor Milan R. Uskokovic: Role of Vitamin D in Cancer Therapeutics)

► Show Figures

Graphical abstract

3193 KiB

Open AccessArticle

The Vitamin D Analog, MART-10, Attenuates Triple Negative Breast Cancer Cells Metastatic Potential

by Kun-Chun Chiang, Ta-Sen Yeh, Shin-Cheh Chen, Jong-Hwei S. Pang, Chun-Nan Yeh, Jun-Te Hsu, Li-Wei Chen, Sheng-Fong Kuo, Masashi Takano, Atsushi Kittaka, Tai C. Chen, Chi-Chin Sun and Horng-Heng Juang

Int. J. Mol. Sci. 2016, 17(4), 606; https://doi.org/10.3390/ijms17040606 - 21 Apr 2016

Cited by 23 | Viewed by 7160

Abstract

Regarding breast cancer treatment, triple negative breast cancer (TNBC) is a difficult issue. Most TNBC patients die of cancer metastasis. Thus, to develop a new regimen to attenuate TNBC metastatic potential is urgently needed. MART-10 (19-nor-2α-(3-hydroxypropyl)-1α,25(OH)₂D₃), the newly-synthesized 1α,25(OH)₂D₃ analog, has been shown to be much more potent in cancer growth inhibition than 1α,25(OH)₂D₃ and be active in vivo without inducing obvious side effect. In this study, we demonstrated that both 1α,25(OH)₂D₃ and MART-10 could effectively repress TNBC cells migration and invasion with MART-10 more effective. MART-10 and 1α,25(OH)₂D₃ induced cadherin switching (upregulation of E-cadherin and downregulation of N-cadherin) and downregulated P-cadherin expression in MDA-MB-231 cells. The EMT(epithelial mesenchymal transition) process in MDA-MB-231 cells was repressed by MART-10 through inhibiting Zeb1, Zeb2, Slug, and Twist expression. LCN2, one kind of breast cancer metastasis stimulator, was also found for the first time to be repressed by 1α,25(OH)₂D₃ and MART-10 in breast cancer cells. Matrix metalloproteinase-9 (MMP-9) activity was also downregulated by MART-10. Furthermore, F-actin synthesis in MDA-MB-231 cells was attenuated as exposure to 1α,25(OH)₂D₃ and MART-10. Based on our result, we conclude that MART-10 could effectively inhibit TNBC cells metastatic potential and deserves further investigation as a new regimen to treat TNBC. Full article

(This article belongs to the Special Issue Commemorative Issue in Honor of Professor Milan R. Uskokovic: Role of Vitamin D in Cancer Therapeutics)

► Show Figures

Figure 1

2327 KiB

Open AccessArticle

Biological Evaluation of Double Point Modified Analogues of 1,25-Dihydroxyvitamin D₂ as Potential Anti-Leukemic Agents

by Aoife Corcoran, Sharmin Nadkarni, Kaori Yasuda, Toshiyuki Sakaki, Geoffrey Brown, Andrzej Kutner and Ewa Marcinkowska

Int. J. Mol. Sci. 2016, 17(2), 91; https://doi.org/10.3390/ijms17020091 - 1 Feb 2016

Cited by 10 | Viewed by 5547

Abstract

Structurally similar double-point modified analogues of 1,25-dihydroxyvitamin D₂ (1,25D₂) were screened in vitro for their pro-differentiating activity against the promyeloid cell line HL60. Their affinities towards human full length vitamin D receptor (VDR) and metabolic stability against human vitamin D 24-hydroxylase (CYP24A1) were also tested. The analogues (PRI-1730, PRI-1731, PRI-1732, PRI-1733 and PRI-1734) contained 5,6-trans modification of the A-ring and of the triene system, additional hydroxyl or unsaturation at C-22 in the side chain and reversed absolute configuration (24-epi) at C-24 of 1,25D₂. As presented in this paper, introduction of selected structural modifications simultaneously in two distinct parts of the vitamin D molecule resulted in a divergent group of analogues. Analogues showed lower VDR affinity in comparison to that of the parent hormones, 1,25D₂ and 1,25D₃, and they caused effective HL60 cell differentiation only at high concentrations of 100 nM and above. Unexpectedly, introducing of a 5,6-trans modification combined with C-22 hydroxyl and 24-epi configuration switched off entirely the cell differentiation activity of the analogue (PRI-1734). However, this analogue remained a moderate substrate for CYP24A1, as it was metabolized at 22%, compared to 35% for 1,25D₂. Other analogues from this series were either less (12% for PRI-1731 and PRI-1733) or more (52% for PRI-1732) resistant to the enzymatic deactivation. Although the inactive analogue PRI-1734 failed to show VDR antagonism, when tested in HL60 cells, its structure might be a good starting point for our design of a vitamin D antagonist. Full article

(This article belongs to the Special Issue Commemorative Issue in Honor of Professor Milan R. Uskokovic: Role of Vitamin D in Cancer Therapeutics)

► Show Figures

Graphical abstract

2271 KiB

Open AccessArticle

Antiproliferative Activity of Double Point Modified Analogs of 1,25-Dihydroxyvitamin D₂ Against Human Malignant Melanoma Cell Lines

by Anna Piotrowska, Justyna Wierzbicka, Sharmin Nadkarni, Geoffrey Brown, Andrzej Kutner and Michał A. Żmijewski

Int. J. Mol. Sci. 2016, 17(1), 76; https://doi.org/10.3390/ijms17010076 - 8 Jan 2016

Cited by 24 | Viewed by 5853

Abstract

Vitamin D is a lipid soluble steroid hormone with pleiotropic biological properties, including regulation of cell proliferation, differentiation and apoptosis. As to these desirable anticancer actions, 1,25-dihydroxyvitamins D and analogs have been reported to inhibit the proliferation and to induce differentiation of a wide variety of cancer cell types, including human malignant melanoma. However, there is a need for novel and more efficacious vitamin D analogs, and how best to design such is still an open issue. A series of double point modified (DPM) analogs of 1,25-dihydroxyvitamin D₂ (1,25(OH)₂D₂) induced differentiation of the vitamin D receptor (VDR) positive A375 and VDR negative SK-MEL 188b human malignant melanoma cell lines. Surprisingly, the dose of 1,25(OH)₂D₂ required to inhibit the proliferation of the A375 melanoma cell line by was several fold lower than that required in the case of 1,25(OH)₂D₃. To evaluate the impact of the modification in the side chain (additional 22-hydroxyl) and in the A-ring (5,6-trans modification), the regular side-chain of vitamin D₂ or D₃ was retained in the structure of our analogs. As expected, 5,6-trans modification was advantageous to enhancing the anti-proliferative activity of analogs, but not as a single point modification (SPM). Very unexpectedly, the additional 22-hydroxyl in the side-chain reduced significantly the anti-proliferative activity of both the natural and 5,6-trans series analogs. Finally, an induction of pigmentation in melanoma SK-MEL 188b cells was observed to sensitized cells to the effect of vitamin D analogs. Full article

(This article belongs to the Special Issue Commemorative Issue in Honor of Professor Milan R. Uskokovic: Role of Vitamin D in Cancer Therapeutics)

► Show Figures

Graphical abstract

2484 KiB

Open AccessArticle

Vitamin D Analogs Potentiate the Antitumor Effect of Imatinib Mesylate in a Human A549 Lung Tumor Model

by Ewa Maj, Beata Filip-Psurska, Marta Świtalska, Andrzej Kutner and Joanna Wietrzyk

Int. J. Mol. Sci. 2015, 16(11), 27191-27207; https://doi.org/10.3390/ijms161126016 - 13 Nov 2015

Cited by 24 | Viewed by 6820

Abstract

In previous papers, we presented data on studies on the anticancer activity of the vitamin D₃ analogs, named PRI-2191 and PRI-2205, in different cancer models. In this study, we showed the improved antiproliferative activity of a combination of imatinib mesylate (Gleevec, GV) and cytostatic agents in in vitro studies, when used with a third compound, namely PRI-2191, in an A549 human lung cancer model. Furthermore, we analyzed the influence of both PRI-2191, as well as PRI-2205 on the anticancer activity of GV in mice bearing A549 tumors. The route of PRI-2191 analog administration showed a significant impact on the outcome of GV treatment: subcutaneous injection was more efficient and less toxic than oral gavage. Moreover, both vitamin D compounds increased the anticancer activity of GV; however, they might also potentiate some adverse effects. We also evaluated in tumor tissue the expression of VEGF, PDGF-BB, vitamin D receptor, CYP27B1, CYP24, p53 and Bcl-2, as well as PDGF receptors: α and β. We observed the upregulation of p53 expression and the downregulation of Bcl-2, as well as VEGF in A549 tumors as a result of the tested treatment. However, vitamin D analogs did not significantly influence the expression of these proteins. Full article

(This article belongs to the Special Issue Commemorative Issue in Honor of Professor Milan R. Uskokovic: Role of Vitamin D in Cancer Therapeutics)

► Show Figures

Graphical abstract

4366 KiB

Open AccessArticle

Antiproliferative Activity and in Vivo Toxicity of Double-Point Modified Analogs of 1,25-Dihydroxyergocalciferol

by Justyna Trynda, Eliza Turlej, Magdalena Milczarek, Anita Pietraszek, Michał Chodyński, Andrzej Kutner and Joanna Wietrzyk

Int. J. Mol. Sci. 2015, 16(10), 24873-24894; https://doi.org/10.3390/ijms161024873 - 20 Oct 2015

Cited by 24 | Viewed by 5667

Abstract

Analogs of 1,25-dihydroxyergocalciferol, modified in the side-chain and in the A-ring, were tested for their antiproliferative activity against a series of human cancer cell lines in vitro and in vivo toxicity. The proliferation inhibition caused by the analogs was higher than that of the parent compounds, while the toxicity, measured as the serum calcium level, was lower. All analogs were able to induce, in HL-60 and MV4-11 leukemic cells, G₀/G₁ cell cycle arrest and differentiation expressed as morphological signs typical for monocytes. The analogs also induced the expression of CD11b and/or CD14 cell-differentiation markers. The most potent analogs, PRI-5105, PRI-5106, PRI-5201 and PRI-5202, were also able to induce vitamin D receptor (VDR) protein expression, mainly in the cytoplasmic fraction of HL-60 or MV4-11 cells. The most active analogs were the 19-nor ones with an extended and rigidified side-chain (PRI-5201 and PRI-5202), as in the former analogs PRI-1906 and PRI-1907. Epimerization at C-24 (PRI-5101) or introduction of an additional hydroxyl at C-23 (PRI-5104) reduced the toxicity of the analog with retained antiproliferative activity. Full article

(This article belongs to the Special Issue Commemorative Issue in Honor of Professor Milan R. Uskokovic: Role of Vitamin D in Cancer Therapeutics)

► Show Figures

Graphical abstract

2344 KiB

Open AccessArticle

Expression of Vitamin D Receptor (VDR) Positively Correlates with Survival of Urothelial Bladder Cancer Patients

by Wojciech Jóźwicki, Anna A. Brożyna, Jerzy Siekiera and Andrzej T. Slominski

Int. J. Mol. Sci. 2015, 16(10), 24369-24386; https://doi.org/10.3390/ijms161024369 - 15 Oct 2015

Cited by 33 | Viewed by 6369

Abstract

Vitamin D3 shows tumoristatic and anticancer effects by acting through the vitamin D receptor (VDR), while hydroxylation of 25-hydroxyvitamin D3 at position 1α by CYP27B1 is an essential step in its activation. The expression of both the VDR and CYP27B1 has been found in many normal and cancer tissues, but there is a lack of information about its expression in human bladder cancers. The aim of the present research was to examine whether the expression of the VDR and CYP27B1 in bladder cancer was related to the prognostic markers and disease outcome. We analyzed VDR and CYP27B1 in samples of tumor and normal tissues obtained from 71 urinary bladder cancer patients. The highest VDR immunostaining was found in normal epithelium and was significantly lower in bladder cancer cells (p < 0.001 with Mann–Whitney U test). VDR expression was lowest in more advanced (pT2b–pT4) (p = 0.005 with Mann–Whitney U test) and metastasizing cancers (p < 0.05 and p = 0.004 with Mann–Whitney U test for nuclear and cytoplasmic VDR immunostaining, respectively). The lack of cytoplasmic and nuclear VDR was also related to shorter overall survival (for cytoplasmic VDR immunolocalization 13.3 vs. 55.3 months of survival, HR = 1.92, p = 0.04 and for nuclear VDR immunostaining 13.5 vs. 55.3 months of survival, HR = 2.47, p = 0.002 with Mantel-Cox test). In cases with the lack of high cytoplasmic VDR staining the non-classic differentiations (NDs) was observed in higher percentage of tumor area. CYP27B1 expression was lower in cancer cells than in normal epithelial cells (p = 0.03 with Mann–Whitney U test), but its expression did not correlate with tumor stage (pT), metastasizing, grade, mitotic activity or overall survival. In conclusion, expression of the VDR and CYP27B1 are deregulated in urothelial bladder cancers. Although our results showing a relationship between the decreased VDR expression and prognostic markers and survival time indicate potential usefulness of VDR as a new indicator of a poorer prognosis, further studies are needed in different patient cohorts by independent groups to validate this hypothesis. We also suggest that vitamin D-based therapies may represent an adjuvant strategy in treatment for bladder cancers expressing VDR. Full article

(This article belongs to the Special Issue Commemorative Issue in Honor of Professor Milan R. Uskokovic: Role of Vitamin D in Cancer Therapeutics)

► Show Figures

Graphical abstract

Review

Jump to: Research

1302 KiB

Open AccessReview

Could Vitamin D Analogues Be Used to Target Leukemia Stem Cells?

by Idoia García-Ramírez, Alberto Martín-Lorenzo, Inés González-Herrero, Guillermo Rodriguez-Hernández, Carolina Vicente-Dueñas and Isidro Sánchez-García

Int. J. Mol. Sci. 2016, 17(6), 889; https://doi.org/10.3390/ijms17060889 - 6 Jun 2016

Cited by 2 | Viewed by 4762

Abstract

Leukemic stem cells (LSCs) are defined as cells that possess the ability to self-renew and give rise to the differentiated cancer cells that comprise the tumor. These LSCs seem to show chemo-resistance and radio-resistance leading to the failure of conventional cancer therapies. Current therapies are directed at the fast growing tumor mass leaving the LSC fraction untouched. Eliminating LSCs, the root of cancer origin and recurrence, is considered to be a hopeful approach to improve survival or even to cure cancer patients. In order to achieve this, the characterization of LSCs is a prerequisite in order to develop LSC-based therapies to eliminate them. Here we review if vitamin D analogues may allow an avenue to target the LSCs. Full article

(This article belongs to the Special Issue Commemorative Issue in Honor of Professor Milan R. Uskokovic: Role of Vitamin D in Cancer Therapeutics)

► Show Figures

Graphical abstract

244 KiB

Open AccessReview

The Use of 1α,25-Dihydroxyvitamin D₃ as an Anticancer Agent

by Ewa Marcinkowska, Graham R. Wallace and Geoffrey Brown

Int. J. Mol. Sci. 2016, 17(5), 729; https://doi.org/10.3390/ijms17050729 - 13 May 2016

Cited by 28 | Viewed by 5514

Abstract

The notion that vitamin D can influence the incidence of cancer arose from epidemiological studies. The major source of vitamin D in the organism is skin production upon exposure to ultra violet-B. The very first observation of an inverse correlation between exposure of individuals to the sun and the likelihood of cancer was reported as early as 1941. In 1980, Garland and Garland hypothesised, from findings from epidemiological studies of patients in the US with colon cancer, that vitamin D produced in response to sun exposure is protective against cancer as opposed to sunlight per se. Later studies revealed inverse correlations between sun exposure and the occurrence of prostate and breast cancers. These observations prompted laboratory investigation of whether or not vitamin D had an effect on cancer cells. Vitamin D is not active against cancer cells, but the most active metabolite 1α,25-dihydroxyvitamin D₃ (1,25D) has profound biological effects. Here, we review the anticancer action of 1,25D, clinical trials of 1,25D to date and the prospects of the future therapeutic use of new and low calcaemic analogues. Full article

(This article belongs to the Special Issue Commemorative Issue in Honor of Professor Milan R. Uskokovic: Role of Vitamin D in Cancer Therapeutics)

1861 KiB

Open AccessReview

Nucleotide Excision Repair and Vitamin D—Relevance for Skin Cancer Therapy

by Elzbieta Pawlowska, Daniel Wysokinski and Janusz Blasiak

Int. J. Mol. Sci. 2016, 17(4), 372; https://doi.org/10.3390/ijms17040372 - 6 Apr 2016

Cited by 26 | Viewed by 9264

Abstract

Ultraviolet (UV) radiation is involved in almost all skin cancer cases, but on the other hand, it stimulates the production of pre-vitamin D3, whose active metabolite, 1,25-dihydroxyvitamin D3 (1,25VD3), plays important physiological functions on binding with its receptor (vitamin D receptor, VDR). UV-induced DNA damages in the form of cyclobutane pyrimidine dimers or (6-4)-pyrimidine-pyrimidone photoproducts are frequently found in skin cancer and its precursors. Therefore, removing these lesions is essential for the prevention of skin cancer. As UV-induced DNA damages are repaired by nucleotide excision repair (NER), the interaction of 1,25VD3 with NER components can be important for skin cancer transformation. Several studies show that 1,25VD3 protects DNA against damage induced by UV, but the exact mechanism of this protection is not completely clear. 1,25VD3 was also shown to affect cell cycle regulation and apoptosis in several signaling pathways, so it can be considered as a potential modulator of the cellular DNA damage response, which is crucial for mutagenesis and cancer transformation. 1,25VD3 was shown to affect DNA repair and potentially NER through decreasing nitrosylation of DNA repair enzymes by NO overproduction by UV, but other mechanisms of the interaction between 1,25VD3 and NER machinery also are suggested. Therefore, the array of NER gene functioning could be analyzed and an appropriate amount of 1.25VD3 could be recommended to decrease UV-induced DNA damage important for skin cancer transformation. Full article

(This article belongs to the Special Issue Commemorative Issue in Honor of Professor Milan R. Uskokovic: Role of Vitamin D in Cancer Therapeutics)

► Show Figures

Journal Menu

Journal Browser

Commemorative Issue in Honor of Professor Milan R. Uskokovic: Role of Vitamin D in Cancer Therapeutics

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Benefits of Publishing in a Special Issue

Published Papers (12 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI