Department of Neurosciences, Biomedicine and Movement Sciences, Biochemistry Section, University of Verona, Strada Le Grazie, 8, I-37134 Verona, Italy.
Department of Pharmacy, University of Salerno, via Giovanni Paolo II n.132, I-84084 Fisciano, Italy.
Int J Mol Sci. 2022 Jan 20;23(3):1121. doi: 10.3390/ijms23031121.
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. roots are a source of diterpenoid derivatives, natural compounds with several biological activities, including antiproliferative and anticancer effects. Seven diterpenoid derivatives were purified from roots and identified by NMR and MS analysis. Tanshinone IIA and cryptotanshinone were detected as the main components of 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.
黑色素瘤是一种高度恶性的实体肿瘤，其特征是生长和繁殖速度加快。由于黑色素瘤的治疗常常无法预防复发和转移的出现，因此需要发现新的抗黑色素瘤药物。 根是二萜衍生物的来源，二萜衍生物是具有多种生物活性的天然化合物，包括抗增殖和抗癌作用。从 根中分离并通过 NMR 和 MS 分析鉴定了七种二萜衍生物。丹参酮 IIA 和隐丹参酮被检测为 根乙醇提取物的主要成分。尽管它们的抗肿瘤活性已为人所知，但它们已被证实可降低 A375 和 MeWo 黑色素瘤细胞的生长。同样，柳酮也被证明可损害黑色素瘤细胞的活力，而不影响正常黑素细胞的生长。已经研究并比较了柳酮与隐丹参酮在 A375 细胞中的抗癌活性，结果表明柳酮以 P53 依赖的方式增加 P21 蛋白的表达。通过这种方式，柳酮甚至比隐丹参酮更能对细胞周期相关蛋白产生多靶点作用。此外，它还调节信号转导和转录激活因子（STAT）3 的磷酸化水平。出乎意料的是，柳酮和隐丹参酮诱导细胞外信号调节激酶（ERK）1/2 和蛋白激酶 B（Akt）的持续激活。然而，阻断 ERK1/2 或 Akt 的活性表明激酶的激活并不妨碍它们抑制 A375 细胞生长的能力。最后，柳酮和隐丹参酮以可比的程度抑制 A375 黑色素瘤细胞的一些关键恶性特征，例如软琼脂中的集落形成和金属蛋白酶-2 活性。总之，首次表明，柳酮具有与丹参酮 IIA 和隐丹参酮不同的分子结构，通过阻碍细胞周期进程、STAT3 信号和 A375 黑色素瘤细胞的恶性表型，对黑色素瘤具有多效作用。
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