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Antaroide, a Novel Natural Nine-Membered Macrolide, Inhibits Melanin Biosynthesis in B16F10 Murine Melanoma Cells.

ABSTRACT:

1

). The chemical structure was established through the interpretation of MS, UV, and NMR spectroscopic data. Antaroide is a nine-membered macrolide with lactone and lactam moieties. To investigate its applicability in skin whitening cosmetics, its anti-melanogenic activity in B16F10 murine melanoma cells was examined. As a result, antaroide displayed strong inhibitory activities against melanin synthesis and also attenuated the dendrite formation induced by the ?-melanocyte stimulating hormone (?-MSH). Antaroide suppressed the mRNA expression of the melanogenic enzymes such as tyrosinase, TRP-1 and TRP-2. This suggests that it may serve as a transcriptional regulator of melanogenesis. Collectively, the discovery of this novel natural nine-membered macrolide and its anti-melanogenic activity could give new insights for the development of skin whitening agents.

SUBMITTER: Ryu MJ

PROVIDER: S-EPMC7771842 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Antaroide, a Novel Natural Nine-Membered Macrolide, Inhibits Melanin Biosynthesis in B16F10 Murine Melanoma Cells.

Ryu Min-Ji MJ Baek Eun-Ki EK Kim Soyeon S Seong Chi Nam CN Yang Inho I Lim Kyung-Min KM Nam Sang-Jip SJ

Biomolecules & therapeutics 20210101 1

<h4>1</h4>). The chemical structure was established through the interpretation of MS, UV, and NMR spectroscopic data. Antaroide is a nine-membered macrolide with lactone and lactam moieties. To investigate its applicability in skin whitening cosmetics, its anti-melanogenic activity in B16F10 murine melanoma cells was examined. As a result, antaroide displayed strong inhibitory activities against melanin synthesis and also attenuated the dendrite formation induced by the α-melanocyte stimulating ...[more]

PMID: 33077699

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Project description:Skin hyperpigmentation disorders arise due to excessive production of the macromolecular pigment melanin catalyzed by the enzyme tyrosinase. Recently, the therapeutic use of curcumin for inhibiting tyrosinase activity and production of melanin have been recognized, but poor stability and solubility have limited its use, which has inspired synthesis of curcumin analogs. Here, we investigated four novel chemically modified curcumin (CMC) derivatives (CMC2.14, CMC2.5, CMC2.23 and CMC2.24) and compared them to the parent compound curcumin (PC) for inhibition of in vitro tyrosinase activity using two substrates for monophenolase and diphenolase activities of the enzyme and for diminution of cellular melanogenesis. Enzyme kinetics were analyzed using Lineweaver-Burk and Dixon plots and nonlinear curve-fitting to determine the mechanism for tyrosinase inhibition. Copper chelating activity, using pyrocatechol violet dye indicator assay, and antioxidant activity, using a DPPH radical scavenging assay, were also conducted. Next, the capacity of these derivatives to inhibit tyrosinase-catalyzed melanogenesis was studied in B16F10 mouse melanoma cells and the mechanisms of inhibition were elucidated. Inhibition mechanisms were studied by measuring intracellular tyrosinase activity, cell-free and intracellular α-glucosidase enzyme activity, and effects on MITF protein level and cAMP maturation factor. Our results showed that CMC2.24 showed the greatest efficacy as a tyrosinase inhibitor of all the CMCs and was better than PC as well as a popular tyrosinase inhibitor-kojic acid. Both CMC2.24 and CMC2.23 inhibited tyrosinase enzyme activity by a mixed mode of inhibition with a predominant competitive mode. In addition, CMC2.24 as well as CMC2.23 showed a comparable robust efficacy in inhibiting melanogenesis in cultured melanocytes. Furthermore, after removal of CMC2.24 or CMC2.23 from the medium, we could demonstrate a partial recovery of the suppressed intracellular tyrosinase activity in the melanocytes. Our results provide a proof-of-principle for the novel use of the CMCs that shows them to be far superior to the parent compound, curcumin, for skin depigmentation.

Project description:BackgroundMelanoma is one of the most invasive and aggressive types of cancer with a very poor prognosis. Surgery remains the most efficient treatment prior melanoma invasion and metastasis formation. However, therapy becomes a challenge once the cancer cells colonized other tissues. At present, there are two main classes of therapies acting with a certain efficiency on metastatic melanoma: immune check point inhibitors (anti-PD1/PDL1) and targeted therapy such as Vemurafenib. Unfortunately, these therapies are not fully responsive, induce resistance and/or generate unwanted side effects. In this respect, it is important to continue to discover new cancer therapeutics. Here, we show that daphnane diterpenes type of compounds can prevent melanoma metastasis by inhibiting metastasis-associated matrix metalloproteinases expression without cytotoxicity.MethodsEvaluation of the anti-metastasis effect of daphnane diterpenes-rich Thymelaea hirsuta extract (TH) and its bioactive component gnidilatidin was carried out in vitro using B16 murine melanoma cells and in vivo using male C57BL/6 J mice. Global gene expression in B16 cells was done using DNA microarray, validated using real-time PCR, to further understand the effect of daphnane diterpenes, specifically daphnane diterpenoid gnidilatidin.ResultsOral administration of daphnane diterpenes-rich Thymelaea hirsuta extract (TH) suppressed MMP2 and MMP9 expression, decreasing lung tumor in mice injected with B16 murine melanoma cells. Validation of these observations in vitro showed reduced B16 cells migration, adhesion, and invasion. Results of microarray analysis of B16 cells treated with daphnane diterpenoid gnidilatidin from TH revealed an upregulation of tumor suppressor Egr1 while inhibiting metastasis-associated genes Id2 and Sytl2 expression. A downregulation of the melanoma oncogene microphthalmia-associated transcription factor (Mitf) was observed, and most likely caused by the inhibition of Id2, a gene that regulated HLH transcription factors such as MITF and also reported to promote tumor cell migration and invasion.ConclusionsDaphnane diterpenes have inhibitory effect on the metastatic potential of B16 melanoma cells, and the results of this study provided evidence for their potential for use in the prevention and inhibition of melanoma metastasis.

Dataset Information

Antaroide, a Novel Natural Nine-Membered Macrolide, Inhibits Melanin Biosynthesis in B16F10 Murine Melanoma Cells.

1

Publications

Antaroide, a Novel Natural Nine-Membered Macrolide, Inhibits Melanin Biosynthesis in B16F10 Murine Melanoma Cells.

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