Antitumor Effects of Vitamin D Analogs on Hamster and Mouse Melanoma Cell Lines in Relation to Melanin Pigmentation

Wasiewicz, Tomasz; Szyszka, Paulina; Cichorek, M; Tuckey, Robert C.; Slominski, Andrzej; Żmijewski, Michał A.

doi:10.3390/ijms16046645

Cited by 44 publications

(73 citation statements)

References 78 publications

(129 reference statements)

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“…Importantly, 20(OH)D 3 , 21(OH)pD and calcipotriol have less or no influence on calcium levels compared to 1,25(OH) 2 D 3 [8, 23, 24, 26, 116, 117], indicating biased effects on the VDR as proposed previously [8]. For instance, of the secosteroids tested 20(OH)D 3 displayed the strongest stimulation of VDR expression (Figure 6D).…”

Section: Discussionsupporting

confidence: 59%

“…Experiments were performed as described before [26]. Briefly, HaCaT keratinocytes were seeded in 96-well plates (8,000 per well), cultured for 24 h and then treated with serial dilutions of the compounds being tested for an additional 24 h (Scheme 1A).…”

Section: Methodsmentioning

confidence: 99%

“…The hydroxyvitamin D 3 metabolites produced by these pathways, including the major product, 20(OH)D 3 , are biologically active in both in vitro (reviewed in [8]) and in vivo [22] models. Since they are less prone to induce hypercalcemia than 1,25(OH) 2 D 3 [23, 24], they deserve special attention as potential therapeutics for the treatment of leukemia [23], melanoma [10, 11, 25, 26] and colorectal cancer [27]. …”

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confidence: 99%

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Vitamin D derivatives enhance cytotoxic effects of H2O2 or cisplatin on human keratinocytes

et al. 2016

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Although the skin production of vitamin D is initiated by ultraviolet radiation type B (UVB), the role vitamin D plays in antioxidative or pro-oxidative responses remains to be elucidated.. We have used immortalized human HaCaT keratinocytes as a model of proliferating epidermal cells to test the influence of vitamin D on cellular response to H2O2 or the anti-cancer drug, cisplatin. Incubation of keratinocytes with 1,25(OH)2D3 or its low calcemic analogues, 20(OH)D3, 21(OH)pD or calcipotriol, sensitized cells to ROS resulting in more potent inhibition of keratinocyte proliferation by H2O2 in the presence of vitamin D compounds. These results were supported by cell cycle and apoptosis analyses, and measurement of the mitochondrial transmembrane potentials (MMP), however some unique properties of individual secosteroids were observed. Furthermore, in HaCaT keratinocytes treated with H2O2, 1,25(OH)2D3, 21(OH)pD and calcipotriol stimulated the expression of SOD1 and CAT genes, but not SOD2, indicating a possible role of mitochondria in ROS-modulated cell death. 1,25(OH)2D3 also showed a short-term, protective effect on HaCaT keratinocytes, as exemplified by the inhibition of apoptosis and the maintenance of MMP. However, with prolonged incubation with H2O2 or cisplatin, 1,25(OH)2D3 caused an acceleration in the death of the keratinocytes. Therefore, we propose that lead vitamin D derivatives can protect the epidermis against neoplastic transformation secondary to oxidative or UV-induced stress through activation of vitamin D-signaling. Furthermore, our data suggest that treatment with low calcemic vitamin D analogs or the maintenance of optimal level of vitamin D by proper supplementation, can enhance the anticancer efficacy of cisplatin

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Section: Discussionsupporting

confidence: 59%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Vitamin D derivatives enhance cytotoxic effects of H2O2 or cisplatin on human keratinocytes

et al. 2016

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“…Treatment of primary keratinocytes with 21(OH)pD, which only has a 2C side chain, did not stimulate the expression of CYP24A1 , a major target of the activated VDR, suggesting an alternative pathway may be activated by this secosteroid. This is consistent with previous studies showing that treatment of melanoma cells with 21(OH)pD does not stimulate the translocation of VDR to the nucleus (Zmijewski et al, 2011) nor cause stimulation of CYP24A1 expression (Wasiewicz et al, 2015), despite inhibiting melanoma cell proliferation (Zmijewski et al, 2011; Wasiewicz et al, 2015). The lack of stimulation of VDR translocation and expression of CYP24A1 and INV genes by 21(OH)pD can be explained by the recent in silico prediction that 21(OH)pD interacts poorly with the VDR, having the lowest docking score of the vitamin D analogs examined (Kim et al, 2012).…”

Section: Discussionsupporting

confidence: 93%

Bioactive forms of vitamin D selectively stimulate the skin analog of the hypothalamus-pituitary-adrenal axis in human epidermal keratinocytes

Wierzbicka

Żmijewski

Piotrowska

et al. 2016

Molecular and Cellular Endocrinology

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Ultraviolet radiation B stimulates both the production of vitamin D3 in the skin and the activation of the skin analog of the hypothalamic-pituitary-adrenal axis (HPA) as well as the central HPA. Since the role of vitamin D3 in the regulation of the HPA is largely unknown, we investigated the impact of 1,25(OH)2D3 and its noncalcemic analogs, 20(OH)D3 and 21(OH)pD, on the expression of the local HPA in human epidermal keratinocytes. The noncalcemic analogs showed similar efficacy to 1,25(OH)2D3 in stimulating the expression of neuropeptides, CRF, urocortins and POMC, and their receptors, CRFR1, CRFR2, MC1R, MC2R, MC3R and MC4R. Interestingly, unlike other secosteroids, the activity of 21(OH)pD did not correlate with induction of differentiation, suggesting a separate but overlapping mechanism of action. Thus, biologically active forms of vitamin D can regulate different elements of the local equivalent of the HPA with implications for the systemic HPA.

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“…It is well recognized that inhibition of melanogenesis should improve the efficacy of melanoma therapy [9][10][11]. Indeed, melanoma is an extremely aggressive tumor among skin cancer, with high metastatic potential and considerable resistance to cytotoxic agents [12].…”

Section: Introductionmentioning

confidence: 99%

Antitumoral, antioxidant, and antimelanogenesis potencies of Hawthorn, a potential natural agent in the treatment of melanoma

et al. 2016

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The lack of an efficient agent that does not have the disadvantage of low activity (kojic acid), high cytotoxicity, and mutagenicity (hydroquinone), poor skin penetration (arbutin), or low stability in formulation (glabridin) led us to continue our research on new antipigmentation/skin-lightening agents. Therefore, research of natural products that can modulate the metabolism of pigmentation is of great interest. Otherwise, malignant melanoma is one of the most aggressive forms of skin cancer, with high metastatic potential, and currently, there is no effective chemotherapy against invasive melanoma. Therefore, it is necessary to develop new drugs with potent activity and weak side effects against melanoma. The in-vitro anticancer effect of hawthorn was analyzed against B16F10 melanoma cells using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The effect of isolated compounds from hawthorn on melanogenesis in B16F10 melanoma cells was investigated by measuring the amounts of melanin and tyrosinase spectrophotometrically at 475 nm. Balb/c mice models inoculated with B16F10 mouse tumor cells were used to evaluate the in-vivo antitumoral potential of hawthorn by assessing its effect on the growth of transplanted tumors. The antioxidant potential of tested samples was evaluated in B16F10 and primary human keratinocyte cells using a cellular antioxidant activity assay. Hawthorn tested samples inhibited effectively the growth of melanoma cells in vitro. Furthermore, it appears that tested samples from hawthorn reduced melanogenesis by inhibiting the tyrosinase activity of B16F10 cells in a dose-dependent manner. In-vivo studies showed that hawthorn total oligomer flavonoids extract treatment at a dose of 150 mg/kg body weight for 21 days in implanted tumor mice resulted in significant inhibition of the tumor growth volume and weight. In addition, tested samples showed significant cellular antioxidant capacity against the reactive oxygen species in B16F10 and primary human keratinocyte cells. Our results indicate that hawthorn could be considered as a promising agent for the treatment of melanoma as it shows antitumor activity in vitro and in vivo. Moreover, hawthorn constituents are shown to be highly effective at inhibiting tyrosinase-mediated melanogenesis in vitro on melanoma cells by preventing oxidation in these cells and without affecting the viability of normal human keratinocyte cells. Then, hawthorn might also be used as a new candidate of natural skin depigmenting agents in skin care products.

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Antitumor Effects of Vitamin D Analogs on Hamster and Mouse Melanoma Cell Lines in Relation to Melanin Pigmentation

Cited by 44 publications

References 78 publications

Vitamin D derivatives enhance cytotoxic effects of H2O2 or cisplatin on human keratinocytes

Vitamin D derivatives enhance cytotoxic effects of H2O2 or cisplatin on human keratinocytes

Bioactive forms of vitamin D selectively stimulate the skin analog of the hypothalamus-pituitary-adrenal axis in human epidermal keratinocytes

Antitumoral, antioxidant, and antimelanogenesis potencies of Hawthorn, a potential natural agent in the treatment of melanoma

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