Title

 

Authors

E. Panza¹, M. Tersigni¹, M. Iorizzi², M. Napolitano³,  G. Cirino¹ and A. Ianaro¹.

¹Dept of Experimental Pharmacology, University of Naples “Federico II”, Naples, Italy
²Dept of STAT, University of Molise, Pesche, Isernia, Italy
³Oncologic Immunology, National Tumour Institute, Fondazione Pascale, Naples, Italy

 

Abstract

Malignant melanoma is a highly aggressive tumour which frequently resists chemotherapy, therefore the search for new agents for its treatment is of great importance. In this study, individual constituents of Laurus nobilis L. leaves, previously isolated by our group [1], were assessed for their antiproliferative effect on several human melanoma cell lines. After a preliminary screening one compound, a megastigmane glycoside named Lauroside B (LB), was selected and its anti-cancer potency against human melanoma cell lines was investigated. LB greatly suppressed proliferation of three human melanoma cell lines: A375, WM115 and SK-Mel-28 in a time- and concentration-dependent manner. We further investigated LB mechanism of action using A375 as a representative cell line model. The LB-induced inhibition of human melanoma cell proliferation was due to the induction of apoptosis as demonstrated by FACS analysis with Annexin V/PI staining and further confirmed by the degradation of pro-caspase-3, the precursor form of caspase-3, and by the cleavage of its substrate, poly (ADP-ribose) polymerase (PARP). Growing evidence implicates NF-κB as an important contributor to metastasis and increased chemoresistance of melanoma. Recently, NF-κB activation has been connected with multiple aspects of oncogenesis, including the control of apoptosis, cell migration, cell cycle progression, and cell differentiation. Several reports have shown that in melanoma, the constitutive activation of NF-κB, often due to constitutive IKK activity [2,3],confers tumor survival capacity and the avoidance of apoptosis [4]. Thus, we hypothesized that the LB-induced apoptosis could be associated with suppression of NF-κB activation. Our results show that LB treatment inhibited IκB-α degradation and constitutive NF-κB DNA-binding activity. Finally, we demonstrated that exposure of human melanoma cells to LB negatively affected the expression, regulated by NF-κB, of two anti-apoptotic genes, XIAP and c-FLIP. Induction of apoptosis by LB in human aggressive melanoma cell lines has high pharmacological value and NF-κB inhibition is considered a promising strategy to improve the fight against cancer.
 
[1] De Marino et al. (2004) Megastigmane and phenolic components from Laurus nobilis L. leaves and their inhibitory effects on nitric oxide production. Journal of Agricultural and Food Chemistry52, 7525-753.
[2] Greten et al. (2004) The IKK/NF-kappaB activation pathway-a target for prevention and treatment of cancer. Cancer Letters 206, 193-199.
[3] Richmond et al. (2002) Nf-kappa B, chemokine gene transcription and tumour growth. Nature Reviews Immunology 2, 664-674.
[4] Baud et al. (2009) Is NF-kappaB a good target for cancer therapy? Hopes and pitfalls. Nature Reviews Drug Discovery 8, 33-40.