gambogic-acid and Skin-Neoplasms

Cutaneous melanoma is the deadliest form of skin cancer, and gambogic acid (GA) exhibits potent anti-melanoma activity. However, clinical application of GA via intravenous injection and oral administration is limited by systemic toxicity and rapid metabolism in the blood. Here, we developed a new, topical route of GA delivery for anti-melanoma activity and reduction of systemic toxicity. The results indicated that the barrier of the stratum corneum (SC) and low diffusion of GA in the hydrophilic viable skin (epidermis and dermis) limited the GA penetration through intact skin. The combination of azone (AZ) and propylene glycol (PG) showed obvious synergistic effects on skin penetration by GA via improving the permeability of the SC and greatly increasing the skin accumulation of GA, thereby forming a high drug concentration in the skin and achieving a topical targeted treatment of melanoma. In addition, GA (AZ-PG) achieved the same anti-melanoma effect via topical delivery as via intravenous injection. Intravenous injection and oral administration of GA induced remarkable pathological changes in various organs in mice, whereas GA was not toxic to various organs or to the skin via topical delivery. These findings indicated that topical administration of GA is an alternative route for melanoma treatment.

Topics: Administration, Cutaneous; Animals; Melanoma; Mice; Skin; Skin Absorption; Skin Neoplasms; Xanthones

Anti-cutaneous melanoma activity of the skin-delivered gambogic acid (GA) has been reported in our previous study. However, it is difficult for GA to diffuse passively through intact skin without any enhancement means. In this study, a combination of chemical enhancers (EN: azone and propylene glycol) and physical ultrasound (US) was used to improve the percutaneous permeation of GA and enhance the anti-melanoma activity. The enhancement effect of the combination of EN and US (EN-US) on GA in vitro and in vivo was studied, and the enhancement mechanism and skin irritation were also evaluated. We showed that the parameters of US application at a constant frequency (30 kHz) with a duty cycle of 100% and intensity of 1.75 W/cm

Topics: Administration, Cutaneous; Animals; Melanoma; Mice; Permeability; Skin; Skin Absorption; Skin Neoplasms; Xanthones

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Extracellular Signal-Regulated MAP Kinases; Humans; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Melanoma; Melanoma, Cutaneous Malignant; Mice; Neoplasm Invasiveness; Neoplasm Metastasis; Neovascularization, Pathologic; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; Skin Neoplasms; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2; Xanthones

To investigate the effect of a Chinese traditional medicine, gambogic acid (GA), on human malignant melanoma (MM) A375 cells and to study the mechanism of apoptosis induced by GA.. A375 cells were treated with GA at different doses and for different times, and their proliferation and viability were detected by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis induced by GA in A375 cells was observed by annexin-V/propidium iodide doubling staining flow cytometry assay and Hoechst staining. To further determine the molecular mechanism of apoptosis induced by GA, the changes in expression of Bcl-2 and Bax were detected by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot, and caspase-3 activity was measured by fluorescence resonance energy transfer (FRET) probe.. After incubation with GA, A375 cell proliferation was dramatically inhibited in a dose-dependent manner. After these cells had been exposed to GA for 24, 36 and 48 h, the IC(50) values were 1.57 +/- 0.05, 1.31 +/- 0.20, and 1.12 +/- 0.19 microg/mL, respectively. Treatment of A375 cells with GA (2.5-7.5 microg/mL) for 36 h resulted in an increased number of early apoptotic cells, which ranged from 27.6% to 41.9%, in a dose-dependent manner, compared with only 3.5% apoptotic cells in the non-GA-treated group. An increase in Bax and decrease in Bcl-2 expression were found by real-time RT-PCR and Western blot. Caspase-3 activity was increased in a dose-dependent manner, observed by FRET probe.. GA can inhibit the proliferation of A375 cells and induce their apoptosis, which may be related to the up-regulation of the Bax/Bcl-2 ratio and caspase-3 activity.

Topics: Apoptosis; bcl-2-Associated X Protein; Caspase 3; Cell Line, Tumor; Cell Survival; Dose-Response Relationship, Drug; Fluorescence Resonance Energy Transfer; Gene Expression Regulation, Neoplastic; Humans; Melanoma; Proto-Oncogene Proteins c-bcl-2; RNA, Messenger; Skin Neoplasms; Xanthones