Identification of new shikonin derivatives as STAT3 inhibitors

Qiu, Han‐Yue; Fu, Jiangyan; Yang, Minkai; Han, Hongwei; Wang, Pengfei; Zhang, Yahan; Lin, Hongyan; Tang, Cheng-Yi; Qi, Jinliang; Yang, Rongwu; Wang, Xiaoming; Zhu, Hai‐Liang; Yang, Yonghua

doi:10.1016/j.bcp.2017.10.009

Cited by 36 publications

(19 citation statements)

References 37 publications

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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 one of the main active ingredient of traditional chinese medicines Recently, some studies indicate that shikonin has potential anti-tumor effects by inducing programmed cell death, inhibition of cancer cell proliferation, anti-angiogenesis, and shikonin also circumvents cancer drug resistance by inducing necroptotic death. [53][54][55][56][57] In the current study, we found that shikonin induced programmed cell death in colorectal carcinoma cells by activating the expression and dimerization of Galectin-1. We confirmed that shikonin treatment could induce ROS accumulation and apoptosis in human colorectal cancer cells by inhibiting autophagic flux of these tumor cells.…”

Section: Discussionmentioning

confidence: 92%

Shikonin induces colorectal carcinoma cells apoptosis and autophagy by targeting galectin-1/JNK signaling axis

Zhang¹,

Fu²,

Wang³

et al. 2020

Int. J. Biol. Sci.

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Colorectal carcinoma (CRC) is the third most common malignant tumor pathology worldwide. Despite progress in surgical procedures and therapy options, CRC is still a considerable cause of cancer-related mortality. In this study, we tested the antitumor effects of shikonin in CRC and tried to identify its potential mechanism. The potential target, molecular mechanism as well as in vitro and in vivo antitumor effects of shikonin in CRC cells were determined by an integrative protocol including quantitative proteomics, RT-PCR, western blotting, RNA interference and overexpression, apoptosis and autophagy assays, etc. Galectin-1 was a potential target of shikonin from the iTRAQ-based proteomic analysis in shikonin-treated SW620 cell. The overexpression and RNA silencing of galectin-1 in two CRC cells suggested that the shikonin sensitivity was correlation to galectin-1 levels. The ROS accumulation induced by shikonin was important to the formation of galectin-1 dimers. Dimer galectin-1 was found to be associated with the activation of JNK and downstream apoptosis or autophagy. Moreover, through functional in vitro studies, we showed that differences in galectin-1 level affected tumor cell proliferation, migration, and invasion. In summary, shikonin induced CRC cells apoptosis and autophagy by targeting galectin-1 and JNK signaling pathway both in vitro and in vivo, which suggested a potential novel therapy target for CRC.

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“…These findings strongly suggest that inhibition of STAT3 signaling by shikonin may serve as an effective approach for melanoma treatment. It is of interest to note that several shikonin derivatives that target STAT3 have been identified, and some of them were proved to exert anticancer activities (Qiu et al, 2017a;Qiu et al, 2017b). After phosphorylation on tyrosine site 705, STAT3 homo-dimerized and translocate into the nucleus, where it mediates the transcription of target genes.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the STAT3 Signaling Pathway Contributes to the Anti-Melanoma Activities of Shikonin

Cao

Liu

Lai³

et al. 2020

Front. Pharmacol.

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Background: Malignant melanoma is an extremely aggressive and metastatic cancer, and highly resistant to conventional therapies. Signal transducer and activator of transcription 3 (STAT3) signaling promotes melanoma development and progression, which has been validated as an effective target in melanoma treatment. Natural naphthoquinone shikonin is reported to exert anti-melanoma effects. However, the underlying mechanisms have not been fully elucidated. Purpose: This study aims to evaluate the anti-melanoma activities of shikonin and explore the involvement of STAT3 signaling in these effects. Methods: Zebrafish tumor model was established to evaluate the anti-human melanoma effects of shikonin in vivo. MTT assay and colony formation assay were employed to investigate the anti-proliferative effects of shikonin on human melanoma A375 and A2058 cells. Flow cytometry was used to analyze cell cycle distribution and apoptosis induction. Wound healing assay and Transwell chamber assay were conducted to examine the cell migratory and invasive abilities. Immunofluorescence assay was used to observe F-actin, Tubulin, and STAT3 localization. Western blotting was used to determine the expression levels of proteins associated with apoptosis and key proteins in the STAT3 signaling pathway. Immunoblotting was performed in DSS cross-linked cells to determine the homo-dimerization of STAT3. Gelatin zymography was employed to evaluate the enzymatic activity of MMP-2 and MMP-9. Transient transfection was used to overexpress STAT3 in cell models. Results: Shikonin suppressed melanoma growth in cultured cells and in zebrafish xenograft models. Shikonin induced melanoma cells apoptosis, inhibited cell migration and invasion. Mechanistic study indicated that shikonin inhibited the phosphorylation and homo-dimerization of STAT3, thus reduced its nuclear localization. Further study showed that shikonin decreased the levels of STAT3-targeted genes Mcl-1, Bcl-2, MMP-2,

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Identification of new shikonin derivatives as STAT3 inhibitors

Cited by 36 publications

References 37 publications

Shikonin Inhibits Cancer Through P21 Upregulation and Apoptosis Induction

Shikonin Inhibits Cancer Through P21 Upregulation and Apoptosis Induction

Shikonin induces colorectal carcinoma cells apoptosis and autophagy by targeting galectin-1/JNK signaling axis

Inhibition of the STAT3 Signaling Pathway Contributes to the Anti-Melanoma Activities of Shikonin

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