Salviolone from Salvia miltiorrhiza Roots Impairs Cell Cycle Progression, Colony Formation, and Metalloproteinase-2 Activity in A375 Melanoma Cells: Involvement of P21(Cip1/Waf1) Expression and STAT3 Phosphorylation

Abstract

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.

Exploring the Potential Mechanism of Danshen in the Treatment of Concurrent Ischemic Heart Disease and Depression Using Network Pharmacology, Molecular Docking, and Molecular Dynamics Simulation

“…Salviolone, the first tropolone compound isolated from Danshen, has several pharmacological effects, including antioxidant, inhibition of cancer cell growth, migration, and invasion. 53,54 However, there have been few investigations on salviolone in IHD and depression, and it is worthwhile to conduct further relevant tests in the future.…”

Hyperforin Elicits Cytostatic/Cytotoxic Activity in Human Melanoma Cell Lines, Inhibiting Pro-Survival NF-κB, STAT3, AP1 Transcription Factors and the Expression of Functional Proteins Involved in Mitochondrial and Cytosolic Metabolism

“…Anchorage-independent growth of A375, FO-1 and SK-Mel-28 melanoma cells was analyzed by colony formation in soft agar, as previously described [ 78 ]. Firstly, the bottom layer of 6 well-plates was filled with 1% low gelling temperature agarose (Sigma-Merck, Milan, Italy) dissolved in 2× DMEM, 20% FBS and 2% antibiotic, antimycotic solution.…”

Salviolone protects against high glucose‐induced proliferation, oxidative stress, inflammation, and fibrosis of human renal mesangial cells by upregulating membrane metalloendopeptidase expression

“…Salvia miltiorrhiza is frequently used for treatment of diabetic nephropathy with safe and effective properties (Xie et al, 2021). Salviolone (Figure 1a) is one of bioactive components from the roots of S. miltiorrhiza with anti‐cancer, anti‐inflammatory, and anti‐proliferative activities (Liu et al, 2021; Zanre et al, 2022; Zhang et al, 2018). Hence, we hypothesized that salviolone might prevent renal mesangial cell dysfunction.…”