A carbazole compound,9-ethyl-9H-carbaole-3-carbaldehyde,activates p53 pathway to promote melanoma cell apoptosis

Chemotherapy is an important treatment for patients with melanoma, but the application of traditional chemotherapy drugs is always limited by treatment-related mortality and drug resistance. In this study, we found a carbazole derivative,9-ethyl-9H-carbazole-3-carbaldehyde(ECCA), and evaluated the antitumor activity for melanoma both in vitro and in vivo. Compound ECCA possessed strong inhibitory activity against melanoma selectively, particularly for UACC62 cells, compared to human primary melanocytes. Moreover, compound ECCA inhibited UACC62 melanoma cell growth by inducing cell apoptosis as detected by Annexin/V staining assay. The cell apoptosis was dependent of caspase activities and significantly abrogated by the addition of caspases inhibitor, z-VAD-FMK. In vivo compound ECCA significantly suppressed tumor formation in melanoma xenograft mouse model by enhanced cell apoptosis and reduced cell growth. RNA-Seq analysis subjected the induction of cell apoptosis mainly on the activation of p53 signaling pathway. ECCA triggered a marked phosphorylation of p53 on Ser-15 and the loss function of p53 led to an decreased in ECCA-induced apoptosis and impaired cell viability. In addition, ECCA treatment enhanced the phosphorylation of p38 MAPK and c-Jun N-terminal kinase(JNK), but not for extracellular signal-regulated kinase(ERK). By p53 deficiency and p38 MAPK or JNK inhibitor, we found the rescued cell growth induced by inhibiting p38 MAPK or JNK was associated with the accumulation of p53 protein. Collectively, our study is the first to identify ECCA, a drug candidate with selective and enhanced anti-tumor activity, apoptosis-induced mechanism and acceptable safety in vivo.