Icariside II induces apoptosis of melanoma cells through the downregulation of survival pathways.

Abstract

This study evaluated the antitumor effects of icariside II (IS), isolated from Herba Epimedii, on in vitro and in vivo models of melanoma and determined its mechanism of apoptosis. Mouse (B16) and human (A375, SK-MEL-5) melanoma cell lines were treated with IS at different concentrations (0-100 μM). Cell viability and proliferation was detected by WST-1 assay and with the xCELLigence system, respectively. Apoptosis was measured by the annexin-V/PI flow cytometric assay. Western blot was used to measure cleaved caspase 3, survivin, P-STAT3, P-ERK and P-AKT. B16 and A375 cells were injected subcutaneously into C57BL/6J and BALB/c-nu mice, respectively. After 1 wk, IS solution at (50 mg/kg, 100 mg/kg) was administered by intraperitoneal injection 3 times for a week. Tumor size was measured with an electronic digital caliper. IS inhibited the proliferation of melanoma cells in a dose- and time-dependent manner. Treatment of A375 cells with IS resulted in an increased number of apoptotic cells ranging from 5.6% to 26.3% mirrored by increases in cleaved caspase-3 and a decrease in survivin expression. IS significantly inhibited the activation of the JAK-STAT3 and MAPK pathways but promoted an unsustained activation peak of the PI3K-AKT pathway. IS administration (50 mg/kg) resulted in a 47.5% decreased tumor volume in A375 bearing mice. Furthermore, IS administration (50 mg/kg, 100 mg/kg) resulted in 41% and 49% decreased tumor volume in B16 bearing mice, respectively. IS dramatically inhibited the proliferation of melanoma cells in vivo and in vitro through the regulation of apoptosis. These effects demonstrate the ability of IS to effectively overcome the survival signals of tumor cells, which support further preclinical evaluation of IS in cancer as a new potential chemotherapeutic agent.

• Authors: Jinfeng Wu, Jinhua Xu, Erika A Eksioglu, Xianghong Chen, Junmin Zhou, Nicole Fortenbery, Sheng Wei, Jingcheng Dong
• Journal: Nutrition and cancer (Nutr Cancer) Vol. 65 Issue 1 Pg. 110-7 ( 2013) ISSN: 1532-7914 [Electronic] United States
• PMID: 23368920 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Phytogenic
• BIRC5 protein, human
• Flavonoids
• Inhibitor of Apoptosis Proteins
• STAT3 Transcription Factor
• Survivin
• baohuoside I
• Proto-Oncogene Proteins c-akt
• Extracellular Signal-Regulated MAP Kinases
• Caspase 3

Topics

• Animals
• Antineoplastic Agents, Phytogenic (pharmacology)
• Apoptosis (drug effects)
• Caspase 3 (metabolism)
• Cell Line, Tumor
• Dose-Response Relationship, Drug
• Down-Regulation (drug effects)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Female
• Flavonoids (pharmacology)
• Humans
• Inhibitor of Apoptosis Proteins (metabolism)
• Melanoma (drug therapy, metabolism, pathology)
• Melanoma, Experimental (drug therapy, metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• Proto-Oncogene Proteins c-akt (metabolism)
• STAT3 Transcription Factor (antagonists & inhibitors)
• Signal Transduction (drug effects)
• Survivin