New vitamin D analogs as potential therapeutics in melanoma

Szyszka, Paulina; Żmijewski, Michał A.; Slominski, Andrzej

doi:10.1586/era.12.40

Cited by 38 publications

(69 citation statements)

References 99 publications

(236 reference statements)

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“…The endogenous VDR agonist 1,25-(OH) 2 D 3 has been used for the treatment of secondary hyperparathyroidism. 17 However, the therapeutic use of 1,25-(OH) 2 D 3 is often complicated by hypercalcemia and hyperphosphatemia. To overcome this limitation, synthetic VDR agonists were designed that bind to VDR with very high affinity and have a decreased risk of hypercalcemia and hyperphosphatemia.…”

Section: Introductionmentioning

confidence: 99%

Vitamin D receptor regulates TGF-β signalling in systemic sclerosis

et al. 2014

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Section: Introductionmentioning

confidence: 99%

Vitamin D receptor regulates TGF-β signalling in systemic sclerosis

et al. 2014

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“…Targeting of the vitamin D receptor represents a promising strategy for treatment of melanoma (Pinczewski and Slominski, 2010;Bro_ zyna et al, 2011;Szyszka et al, 2012), a deadly disease for which therapy is still unsatisfactory (Hauschild et al, 2012). Therefore, we tested whether the 1a-hydroxylation of 20,25(OH) 2 D3 and 20,26(OH) 2 D3, both good substrates for CYP27B1, altered their ability to inhibit melanoma colony formation in soft agar.…”

mentioning

confidence: 99%

Hydroxylation of CYP11A1-Derived Products of Vitamin D3 Metabolism by Human and Mouse CYP27B1

et al. 2013

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CYP11A1 can hydroxylate vitamin D3 at carbons 17, 20, 22, and 23, producing a range of secosteroids which are biologically active with respect to their ability to inhibit proliferation and stimulate differentiation of various cell types, including cancer cells. As 1a-hydroxylation of the primary metabolite of CYP11A1 action, 20S-hydroxyvitamin D3 [20(OH)D3], greatly influences its properties, we examined the ability of both human and mouse CYP27B1 to 1a-hydroxylate six secosteroids generated by CYP11A1. Based on their k cat /K m values, all CYP11A1-derived metabolites are poor substrates for CYP27B1 from both species compared with 25-hydroxyvitamin D3. No hydroxylation of metabolites with a 17a-hydroxyl group was observed. 17a,20-Dihydroxyvitamin D3 acted as an inhibitor on human CYP27B1 but not the mouse enzyme. We also tested CYP27B1 activity on 20,24-, 20,25-, and 20,26-dihydroxyvitamin D3, which are products of CYP24A1 or CYP27A1 activity on 20(OH)D3. All three compounds were metabolized with higher catalytic efficiency (k cat /K m ) by both mouse and human CYP27B1 than 25-hydroxyvitamin D3. CYP27B1 action on these new dihydroxy derivatives was confirmed to be 1a-hydroxylation by mass spectrometry and nuclear magnetic resonance analyses. Both 1,20,25-and 1,20,26-trihydroxyvitamin D3 were tested for their ability to inhibit melanoma (SKMEL-188) colony formation, and were significantly more active than 20(OH)D3. This study shows that CYP11A1-derived secosteroids are 1a-hydroxylated by both human and mouse CYP27B1 with low catalytic efficiency, and that the presence of a 17a-hydroxyl group completely blocks 1a-hydroxylation. In contrast, the secondary metabolites produced by subsequent hydroxylation of 20(OH)D3 at C24, C25, or C26 are very good substrates for CYP27B1.

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“…slnečný vitamín, je dobre známy svojou rozpustnosťou v tukoch. Má pleiotropický efekt na metabolizmus vápnika, fosforu, reguluje bunkový cyklus a apoptózu, stimuluje diferenciáciu rakovinových buniek v tumorových tkanivách, stimuluje angiogenézu, imunomoduláciu, má chemopreventívny účinok a podieľa sa na antibakteriálnej aktivite [7]. V posledných rokoch sa zdôrazňuje jeho vplyv na imunitný systém.…”

Section: Vitamín D 3 a Väzba Na Vdrunclassified

“…Alela A rs4516035 (A > G výmena v EcoRV reštrikčnom mieste) je prezentovaná ako alela zvýšeného melanómového rizika. Na druhej strane, nebolo pozorované žiadne prepojenie medzi dĺžkou reštrikčného fragmentu polymorfi zmu rs7975232 (G > T zámena v ApaI reštrikčnom mieste), podobne ako rs11568820 (G > A výmena v Cdx2 väzbovom mieste) a rizikom vzniku MM [7].…”

Section: Vitamín D 3 a Väzba Na Vdrunclassified

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Effect of Vitamin D Receptor Polymorphisms on the Development and Progression of Malignant Melanoma

Špaková¹,

Rabajdová²,

Zábavníková³

et al. 2014

Klin Onkol

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1 Ústav lekárskej a klinickej bio chémie LF UPJŠ a LABMED, a. s., Košice 2 Klinika plastickej, rekonštrukčnej a estetickej chirurgie LF UPJŠ a UN LP Košice SúhrnVýchodiská: Malígny melanóm patrí k najzhubnejším nádorovým ochoreniam zo všetkých ná-dorov kože mužov aj žien. Pravdepodobnosť vzniku malígneho melanómu závisí od vplyvu vonkajších faktorov a vzájomnej deregulácii interakcií genotypu a fenotypu. V súčasnosti sa čoraz väčšia pozornosť venuje štúdiu interakcií aktívnej formy vitamínu D 3 s receptorom, ako aj inhibičnému účinku polymorfi zmov receptoru vitamínu D 3 na viaceré signálne dráhy zapojené do proliferačných a metastatických procesov. Ciele: Táto prehľadová práca sa zameriava na popísanie vzťahu medzi faktormi, ktoré pôsobia na vznik maligného melanómu ovplyvnením Hedgehog signálnej dráhy (HH). Sumarizuje súčasné poznatky zaoberajúce sa malígnym melanómom v spojení s úlohou aktívnej formy vitamínu D 3 pri väzbe na receptor vitamínu D 3 (VDR) a vplyvu polymorfi zmov VDR na inhibíciu HH. Pochopenie daných mechanizmov a kritické zhodnotenie poznatkov sú dôležité pre aplikáciu primárnej, ako aj sekundárnej prevencie, respektíve pri použití chemoprevenčných látok vhodných pre predchádzanie vzniku malígneho melanómu. Kľúčové slová vitamín D 3 -Hedgehog signalizácia -melanóm -kalcitriol -rakovina kože SummaryBackground: Malignant melanoma is one of the most aggressive cutaneous tumors in men and women. The risk of developing a malignant melanoma depends on several external factors along with deregulation of mutual interaction of genotype and phenotype. Nowadays, growing attention is focused on the study of the interactions of the active form of vitamin D 3 with its receptor and inhibitory eff ect of vitamin D 3 receptor polymorphisms on multiple signaling pathways involved in proliferative and metastatic processes. Objectives: This review article addresses the relationship between factors involved in the development of malignant melanoma through Hedgehog signaling pathway (HH). It summarizes current knowledge of malignant melanoma in regard to the role of the active form of vitamin D 3 binding to vitamin D 3 receptor (VDR), as well as it describes the infl uence of polymorphisms of VDR on the inhibition of HH. Understanding of these mechanisms and critical assessment of available data is benefi cial to both primary and secondary prevention of malignant melanoma particularly by means of chemo-preventive substances.

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New vitamin D analogs as potential therapeutics in melanoma

Cited by 38 publications

References 99 publications

Vitamin D receptor regulates TGF-β signalling in systemic sclerosis

Vitamin D receptor regulates TGF-β signalling in systemic sclerosis

Hydroxylation of CYP11A1-Derived Products of Vitamin D3 Metabolism by Human and Mouse CYP27B1

Effect of Vitamin D Receptor Polymorphisms on the Development and Progression of Malignant Melanoma

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