In Vitro and In Vivo Anti-tumoral Effects of the Flavonoid Apigenin in Malignant Mesothelioma

Malignant mesothelioma (MM) is a tumor arising from mesothelium. MM patients’survival is poor. The polyphenol 4′,5,7,-trihydroxyflavone Apigenin (API) is a“multifunctional drug”. Several studies have demonstrated API anti-tumoral effects.However, little is known on thein vitroandin vivoanti-tumoral effects of API in MM.Thus, we analyzed thein vitroeffects of API on cell proliferation, cell cycle regulation, pro-survival signaling pathways, apoptosis, and autophagy of human and mouse MM cells.We evaluated thein vivoanti-tumor activities of API in mice transplanted with MM #40acells forming ascites. API inhibitedin vitroMM cells survival, increased reactive oxygenspecies intracellular production and induced DNA damage. API activated apoptosis butnot autophagy. API-induced apoptosis was sustained by the increase of Bax/Bcl-2 ratio,increase of p53 expression, activation of both caspase 9 and caspase 8, cleavage ofPARP-1, and increase of the percentage of cells in subG1 phase. API treatment affectedthe phosphorylation of ERK1/2, JNK and p38 MAPKs in a cell-type specific manner,inhibited AKT phosphorylation, decreased c-Jun expression and phosphorylation, andinhibited NF-κB nuclear translocation. Intraperitoneal administration of API increasedthe median survival of C57BL/6 mice intraperitoneally transplanted with #40a cells andreduced the risk of tumor growth. Our findings may have important implications for thedesign of MM treatment using API.