Shikonin Inhibits Cancer Through P21 Upregulation and Apoptosis Induction

Abstract

Shikonin is a natural naphthoquinone compound and has demonstrated potent anticancer activities; however, the underlying molecular mechanisms remained elusive. Here we report that Shikonin inhibited the growth of a wide range of human cancer cell lines, illustrating a broad anticancer effect. Mechanistically, we show that Shikonin arrested the cell cycle at the G2/M phase, inhibited the ERK-dependent cell growth signal, and induced cell death in both P53 wild type and mutant cancer cells, which collectively contributed to the growth inhibitory effect of Shikonin. A pan-apoptosis inhibitor largely suppressed Shikonin-induced cell death, suggesting an important role of apoptosis in this process. Intriguingly, Shikonin also activated autophagy and inhibition of autophagy by depleting critical autophagic genes further increased Shikonin-induced cell death, indicating a protective role of autophagy. In uncovering the molecular mechanisms underlying these effects of Shikonin, we found that Shikonin induced a robust upregulation of P21 independent of the P53 status, upregulated autophagy genes, as well as inhibited expression of genes required for cell growth. Using mouse tumor models, we confirmed the strong anticancer effect of Shikonin in vivo. Together, our data reveal a broad range of pharmacological functions of Shikonin, involving simultaneous growth inhibition, cell cycle arrest, autophagy activation and apoptosis induction through regulating expression of critical genes involved in these pathways. Our study may facilitate the development of Shikonin in cancer therapy as a single agent or in combination with other anticancer therapies.

Shikonin Reduces Growth of Docetaxel-Resistant Prostate Cancer Cells Mainly through Necroptosis

“…Growth and proliferation inhibition after treatment with SHI was associated with a cell cycle arrest of parental PC3 and DX-resistant DU145 cells in the G2/M phase, and an S-phase arrest in DX-resistant 22Rv1. Furthermore, in pancreatic, lung [ 25 ], breast [ 31 ], gastric cancer cells [ 26 ], and melanoma [ 49 ] the administration of SHI resulted in cell cycle arrest in the G2/M phase. In a study on therapy-sensitive PC3 and DU145 cells, SHI induced a shift to the G2/M phase [ 47 ].…”

“…It is isolated from the dried roots of Lithospermum erythrorhizon . Several studies show that SHI, in addition to its function as a color pigment, has antimicrobial [ 22 ], antiinflammatory [ 23 ], and antitumor [ 24 , 25 ] activity.…”

Shikonin Inhibits Tumor Growth of ESCC by suppressing PKM2 mediated Aerobic Glycolysis and STAT3 Phosphorylation

“…Many studies have reported that Shikonin has antitumor effect, which is mainly related to cycle, apoptosis, autophagy, necrosis and immune escape. The molecules and signaling pathways involved include Bcl-2, p53 [21], cIAP1/2 [22], P21 [23], PD-L1 [24], HIF1α/PKM2 [25], PI3K/ AKT /mTOR [26], MAPK [27], NF-κB/STAT3 [24] and so on. Compared with the previous reports, our study focused on the effect of Shikonin on glycolysis, which was consistent with the study of Zhao et al [8].…”

Chinese herbal medicine: Fighting SARS-CoV-2 infection on all fronts

“…Shikonin has already demonstrated a broad spectrum of pharmacological properties that show significant potential for therapeutic development ( Zhang et al, 2018b ). Specifically, shikonin exhibits significant pharmacological activities both in vitro and in vivo , including anti-inflammatory, anti-fungal, and anti-HIV effects ( Wang et al, 2020c ). Jin et al recently reported that shikonin can effectively inhibit the replication of SARS-CoV-2 M pro r in vitro with an EC 50 at 15.75 μM ( Jin et al, 2020 ).…”