Efficacy of Shikonin against Esophageal Cancer Cells and its possible mechanisms <i>in vitro</i> and <i>in vivo</i>

Tang, Jian-Cai; Zhao, Jia; Long, Feng; Chen, Jian-Ye; Mu, Bo; Jiang, Zhen; Ren, Yonggan; Yang, Jian

doi:10.7150/jca.21224

Cited by 41 publications

(30 citation statements)

References 35 publications

(35 reference statements)

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“…The molecular mechanisms underlying the anti-cancer activity of Shikonin seemed to be complicated and may depend on the cellular context (Wang et al, 2019). So far, the reported cellular targets of Shikonin include the pyruvate kinase isoenzyme M2 (PKM2) (Chen et al, 2011;Lu et al, 2018;Tang et al, 2018b), the MAPK pathway (Mao et al, 2008;Zhao et al, 2015;Shan et al, 2017), HIF1a (Li et al, 2017;Han et al, 2018;Tang et al, 2018b), JNK (Zhai et al, 2017;Lin et al, 2018), PI3K/AKT (Zhang et al, 2015;Zhou et al, 2017;Ni et al, 2018;Tang et al, 2018b), STAT3 (Qiu et al, 2017;Tang et al, 2018a), p16INK4A and p73 (Jang et al, 2015), and PTEN (Nigorikawa et al, 2006;Chen et al, 2018;Zhang et al, 2018). These findings, at one hand, demonstrate that Shikonin can regulate various biological processes (Wang et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Shikonin Inhibits Cancer Through P21 Upregulation and Apoptosis Induction

et al. 2020

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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.

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Section: Introductionmentioning

confidence: 99%

Shikonin Inhibits Cancer Through P21 Upregulation and Apoptosis Induction

et al. 2020

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“…Shikonin is reported to inhibit cell growth by inducing cell cycle arrest and promoting apoptosis in human NSCLC A549, gallbladder cancer NOZ and EHGB-1, esophageal cancer EC109, and epidermoid carcinoma A-431 cells [601,[603][604][605]. It can also induce necroptosis via autophagy inhibition in human NSCLC A549 cells [593], and through ROS overproduction in human nasopharyngeal carcinoma 5-8F, and glioma SHG-44, U87 and U251 cells [606,607].…”

Section: Shikoninmentioning

confidence: 99%

Naturally occurring anti-cancer compounds: shining from Chinese herbal medicine

et al. 2019

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Numerous natural products originated from Chinese herbal medicine exhibit anti-cancer activities, including antiproliferative, pro-apoptotic, anti-metastatic, anti-angiogenic effects, as well as regulate autophagy, reverse multidrug resistance, balance immunity, and enhance chemotherapy in vitro and in vivo. To provide new insights into the critical path ahead, we systemically reviewed the most recent advances (reported since 2011) on the key compounds with anti-cancer effects derived from Chinese herbal medicine (curcumin, epigallocatechin gallate, berberine, artemisinin, ginsenoside Rg3, ursolic acid, silibinin, emodin, triptolide, cucurbitacin B, tanshinone I, oridonin, shikonin, gambogic acid, artesunate, wogonin, β-elemene, and cepharanthine) in scientific databases (PubMed, Web of Science, Medline, Scopus, and Clinical Trials). With a broader perspective, we focused on their recently discovered and/or investigated pharmacological effects, novel mechanism of action, relevant clinical studies, and their innovative applications in combined therapy and immunomodulation. In addition, the present review has extended to describe other promising compounds including dihydroartemisinin, ginsenoside Rh2, compound K, cucurbitacins D, E, I, tanshinone IIA and cryptotanshinone in view of their potentials in cancer therapy. Up to now, the evidence about the immunomodulatory effects and clinical trials of natural anti-cancer compounds from Chinese herbal medicine is very limited, and further research is needed to monitor their immunoregulatory effects and explore their mechanisms of action as modulators of immune checkpoints.

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“…Accumulating evidence suggests that shikonin can suppress tumor growth and overcome the resistance to chemotherapy drugs in tumor cells [10]. Tang et al [11] suggested that shikonin can significantly inhibit the proliferation of esophageal cancer cells by regulating the HIF1α/PKM2 signaling pathway. Shikonin can also suppress the inflammatory immune response by…”

Section: Mediators Of Inflammationmentioning

confidence: 99%

Effects of Shikonin on the Functions of Myeloid Dendritic Cells in a Mouse Model of Severe Aplastic Anemia

Zheng

Liu

Shao

et al. 2020

Mediators of Inflammation

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This study is aimed at investigating the effects of shikonin, a pyruvate kinase M2 (PKM2) inhibitor, on the functions of myeloid dendritic cells (mDCs) in a mouse model of severe aplastic anemia (AA) generated by total body irradiation and lymphocyte infusion. Flow cytometry and qPCR were used to determine the proportions of PKM2+ mDCs and other immune indicators in the AA mice. Glucose consumption level, pyruvate generation level, and ATP content were used to determine the level of glycolytic metabolism in the mDCs. The survival rates of AA mice were evaluated after the administration of shikonin or the immunosuppressive agent cyclosporin A. The AA mice displayed pancytopenia, decreased CD4+/CD8+ cell ratio, increased perforin and granzyme levels in CD8+ cells, increased costimulatory CD80 and CD86 expressions, and inadequate regulatory T cell number. In vivo animal experiments showed that the shikonin-mediated inhibition of the PKM2 expression in mice was associated with high survival rates. In addition, the administration of cyclosporin A or shikonin decreased the expression of cytotoxic molecules and costimulatory CD80 and CD86 on CD8+ cells. Taken together, the results of this study indicated that shikonin could inhibit the activation and proliferation of mDCs as well as the activation of downstream cytotoxic T cells by reducing the PKM2 level in mDCs.

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Efficacy of Shikonin against Esophageal Cancer Cells and its possible mechanisms in vitro and in vivo

Cited by 41 publications

References 35 publications

Shikonin Inhibits Cancer Through P21 Upregulation and Apoptosis Induction

Shikonin Inhibits Cancer Through P21 Upregulation and Apoptosis Induction

Naturally occurring anti-cancer compounds: shining from Chinese herbal medicine

Effects of Shikonin on the Functions of Myeloid Dendritic Cells in a Mouse Model of Severe Aplastic Anemia

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