mangostin and Skin-Neoplasms

α-Mangostin (αM), a traditional natural product with promising application of treating a series of diseases, was limited use in clinical due to its hydrophobicity. Herein, MPEG-PCL nanomicelles were used to embed the αM for resolving hydrophobicity and improving the anti-melanoma effect of the αM. The anti-melanoma activity and potential mechanisms of biodegradable αM/MPEG-PCL nanomicelles were investigated. The αM/MPEG-PCL nanomicelles possessed a stronger effect on anti-melanoma compared to the free αM both in vitro and in vivo with a low cytotoxicity in non-tumor cell lines. In the research of mechanisms, the αM/MPEG-PCL nanomicelles inhibited the proliferation of melanoma cell, induced apoptosis via both apoptosis pathways of intrinsic and exogenous in vitro, as well as suppressed tumor growth and restrained angiogenesis in vivo, which implied that the αM/MPEG-PCL nanomicelles have potential application as a novel chemotherapeutic agent in melanoma therapy.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Drug Delivery Systems; Human Umbilical Vein Endothelial Cells; Humans; Hydrophobic and Hydrophilic Interactions; Melanoma; Membrane Potential, Mitochondrial; Micelles; Nanoparticles; Polyesters; Polyethylene Glycols; Rats; Rats, Sprague-Dawley; Skin Neoplasms; Xanthones

α-Mangostin is a dietary xanthone that displays various biological activities, and numerous reports have shown its efficacy in cancer prevention and inhibition. As most agents have been shown to be ineffective as single-agent therapy for malignant melanoma (MM), the principle of targeted chemotherapy for MM is to use effective inhibitors and combination methods. In this study, we tested the cytotoxicity of several kinase inhibitors, including the glycogen synthase kinase (GSK)-3 inhibitor CHIR99021, and rapamycin, in combination with a dietary xanthone, α-mangostin, by screening from a kinase inhibitor library for melanogenesis in SK-MEL-2 MM cells, and verified these by clone formation efficiency, terminal dUTP nick end labelling, and expression of apoptosis-related proteins. We also explored the molecular mechanisms for the apoptosis-inducing effects reported. We found a marked synergistic effect of CHIR99021 or rapamycin in combination with α-mangostin, which we verified through apoptosis-related methods. These data provide a strong rationale for the use of α-mangostin as an adjunct to GSK-3 inhibitor or mammalian target of rapamycin inhibitor treatment. The intrinsic mechanism behind α-mangostin might be inhibition of phosphatidylinositol 3-kinase/AKT signalling and autophagy, and induction of reactive oxygen species generation.

Topics: Apoptosis; Autophagy; Cell Line, Tumor; Cell Proliferation; Cytotoxins; Drug Synergism; Drug Therapy, Combination; Glycogen Synthase Kinase 3; Humans; Melanoma; Melanoma, Cutaneous Malignant; Protein Kinase Inhibitors; Pyridines; Pyrimidines; Sirolimus; Skin Neoplasms; TOR Serine-Threonine Kinases; Xanthones

Skin cancer is the most common form of cancer responsible for considerable morbidity and mortality, the treatment progress of which remains slow though. Therefore, studies identifying anti-skin cancer agents that are innocuous are urgently needed. α-Mangostin, a natural product isolated from the pericarp of mangosteen fruit, has potent anti-cancer activity. However, its role in skin cancer remains unclear. The aim of this study was to evaluate the treatment effect of α-mangostin on skin tumorigenesis induced by 9,10-dimethylbenz[a]anthracene (DMBA)/TPA in mice and the potential mechanism. Treatment with α-mangostin significantly suppressed tumor formation and growth, and markedly reduced the incidence rate. α-Mangostin not only inhibited the expressions of pro-inflammatory factors, but also promoted the production of anti-inflammatory factors in tumor and blood. It induced autophagy of skin tumor and regulated the expressions of autophagy-related proteins. The protein expressions of LC3, LC3-II and Beclin1 increased whereas those of LC3-I and p62 decreased after treatment with α-mangostin. Moreover, α-mangostin promoted the apoptosis of skin tumor dose-dependently by up-regulating of Bax, cleaved caspase-3, cleaved PARP and Bad, and down-regulating of Bcl-2 and Bcl-xl. Furthermore, showed α-mangostin inhibited the PI3K/AKT/mTOR (mammalian target of rapamycin) signaling pathway, as evidenced by decreased expressions of phospho-PI3K (p-PI3K), p-Akt and p-mTOR, but did not affect the expressions of t-PI3K, t-Akt or t-mTOR. Collectively, α-mangostin suppressed murine skin tumorigenesis induced by DMBA/TPA through inhibiting inflammation and promoting autophagy and apoptosis by regulating the PI3K/Akt/mTOR signaling pathway, as a potential candidate for future clinical therapy.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Antineoplastic Agents; Apoptosis; Autophagy; Carcinogens; Dose-Response Relationship, Drug; Female; Inflammation; Mice; Mice, Inbred ICR; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Random Allocation; Signal Transduction; Skin Neoplasms; TOR Serine-Threonine Kinases; Xanthones

Melanogenesis is a key pathway for the regulation of skin pigmentation and the development of skin-lightening/skin-whitening drugs or cosmetics. In this study, we found that β-mangostin from seedcases of Garcinia mangostana inhibited α-melanocyte-stimulating hormone (α-MSH)-mediated melanogenesis in B16F10 melanoma cells and a three-dimensional human skin model. β-Mangostin significantly inhibited the protein level of tyrosinase induced by α-MSH in UPS (ubiquitin proteasome system)-independent and lysosome-dependent manner. The inhibition of autophagy by 3-methyladenine treatment or ATG5 knockdown effectively recovered premelanosome protein as well as tyrosinase degraded by the β-mangostin treatment. However, rapamycin, a representative non-selective autophagy inducer, triggered autophagy in α-MSH-stimulated cells, which was characterized by a considerable decrease in p62, but it was unable to inhibit melanogenesis. Melanosome-engulfing autophagosomes were observed using transmission electron microscopy. Furthermore, previously formed melanin could be degraded effectively in an autophagy-dependent manner in β-mangostin-treated cells. Taken together, our results suggest that β-mangostin inhibits the melanogenesis induced by α-MSH via an autophagy-dependent mechanism, and thus, the depigmentation effect of β-mangostin may depend on autophagy targeted at the melanosome rather than non-selective autophagy.

Topics: Adenine; alpha-MSH; Animals; Autophagy; Cell Survival; Garcinia mangostana; Humans; Inflammation; Melanins; Melanocytes; Melanoma; Melanoma, Experimental; Melanosomes; Mice; Microscopy, Electron, Transmission; Monophenol Monooxygenase; Pigmentation; Plant Extracts; Proteasome Endopeptidase Complex; Seeds; Skin; Skin Neoplasms; Ubiquitin; Xanthones

This study aimed at investigating the anti-invasive activities of α-mangostin on human melanoma SK-MEL-28 and squamous cell carcinoma A-431 cell lines.. Cytotoxicity was tested by the crystal violet assay; anti-invasive activity was detected by the wound healing, cell-matrix adhesion, and boyden chamber assays; and gene regulatory effects by qRT-PCR. Treatments were at non-toxic concentrations (0-1.25 μg/ml for A-431 cells and 0-2.5 μg/ml for SK-MEL-28 cells).. α-Mangostin inhibited motility, adhesion, migration and invasion. Invasive ability was reduced to 4% and 20% following α-mangostin treatment compared with untreated A-431 and SK-MEL-28 cells, respectively. Inhibition of gene expression of MMP-2, MMP-9, NF-κB, and Akt1 was involved in the anti-invasive activities on A-431 cells. Inhibition of MMP-2, NF-κB and IκBα was involved for SK-MEL-28 cells.. α-Mangostin suppressed the metastatic processes of SK-MEL-28 and A-431 cell lines by differentially regulating metastasis-related genes, showing potential as an anti-metastatic agent.

Topics: Carcinoma, Squamous Cell; Cell Adhesion; Cell Line, Tumor; Cell Movement; Garcinia mangostana; Gene Expression; Humans; Melanoma; Neoplasm Invasiveness; Neoplasm Metastasis; Plant Extracts; Skin Neoplasms; Xanthones