A methyl derivative natural
triterpenoid amooranin (methyl-25-hydroxy-3-oxoolean-12-en-28-oate, AMR-Me) has been found to possess antiproliferative, proapoptotic, and antiinflammatory effects against established
tumor cells. Large-scale synthesis of pure
AMR-Me has eliminated the need of the natural
phytochemical for further development of
AMR-Me as an anticancer
drug. Metastatic
melanoma is a fatal form of cutaneous
malignancy with poor prognosis and limited therapeutic options. It was hypothesized that antitumor pharmacological effect of
AMR-Me could be linked to
AMR-Me-mediated suppression of the metastatic potential of B16F10 murine
melanoma.
AMR-Me was assessed for its antimetastatic efficacy by cell adhesion, migration, and invasion assays in B16F10 cells. The signaling crosstalk was explored by
gelatin zymography, Western blot, ELISA, and immunocytochemistry. The results elicited that
AMR-Me was successful in restricting the adhesion, migration, and invasion of highly metastatic cells. The antimetastatic potential of this compound may be attributed to the reduced expression of membrane type 1
metalloproteinase (MT1-MMP) and
matrix metalloproteinases (MMP-2 and MMP-9).
AMR-Me was found to downregulate
vascular endothelial growth factor (
VEGF)/phosphorylated forms of
focal adhesion kinase (pFAK397 )/Jun N-terminus
kinase (pJNK)/
extracellular signal-regulated kinase (pERK). This, in turn, inhibited
transcription factor nuclear factor-κB (NF-κB) and transactivation of
MMPs. Moreover, the activation of tissue inhibitors of
metalloproteinases (TIMP-1 and TIMP-2) might have influenced the downmodulation of
MT1-MMP, MMP-2, and MMP-9.
AMR-Me suppresses the activity of
MT1-MMP, MMP-2, and MMP-9 by downregulation of
VEGF/pFAK397 /pJNK/pERK/NF-κB and activation of
TIMP-1 and
TIMP-2 in metastatic
melanoma cell line, B16F10.
AMR-Me has the potential as an effective anticancer
drug for metastatic
melanoma which is a dismal disease.