Melanoma is a highly malignant solid
tumor characterized by an elevated growth and propagation rate. Since, often,
melanoma treatment cannot prevent recurrences and the appearance of
metastasis, new anti-
melanoma agents need to be discovered. Salvia miltiorrhiza roots are a source of
diterpenoid derivatives, natural compounds with several
biological activities, including antiproliferative and anticancer effects. Seven
diterpenoid derivatives were purified from S. miltiorrhiza roots and identified by NMR and MS analysis.
Tanshinone IIA and
cryptotanshinone were detected as the main components of S. miltiorrhiza root
ethanol extract. Although their antitumor activity is already known, they have been confirmed to induce a reduction in A375 and MeWo
melanoma cell growth. Likewise,
salviolone has been shown to impair the viability of
melanoma cells without affecting the growth of normal melanocytes. The underlying anticancer activity of
salviolone has been investigated and compared to that of
cryptotanshinone in A375 cells, showing an increased P21
protein expression in a P53-dependent manner. In that way,
salviolone, even more than
cryptotanshinone, displays a multitarget effect on cell-cycle-related
proteins. Besides, it modulates the phosphorylation level of the signal transducer and activator of transcription (STAT)3. Unexpectedly,
salviolone and
cryptotanshinone induce sustained activation of the
extracellular signal-regulated kinases (ERK)1/2 and the
protein kinase B (Akt). However, the blockage of ERK1/2 or Akt activities suggests that
kinase activation does not hinder their ability to inhibit A375 cell growth. Finally,
salviolone and
cryptotanshinone inhibit to a comparable extent some crucial
malignancy features of A375
melanoma cells, such as colony formation in soft
agar and metalloproteinase-2 activity. In conclusion, it has been shown for the first time that
salviolone, harboring a different molecular structure than
tanshinone IIA and
cryptotanshinone, exhibits a pleiotropic effect against
melanoma by hampering cell cycle progression, STAT3 signaling, and malignant phenotype of A375
melanoma cells.