Shikonin induces glioma cell necroptosis in vitro by ROS overproduction and promoting RIP1/RIP3 necrosome formation

Lü, Bin; Gong, Xu; Wang, Zongqi; Ding, Ye; Wang, Chen; Luo, Tianfei; Piao, Meihua; Meng, Fankai; Chi, Guangfan; Luo, Yan; Ge, Pengfei

doi:10.1038/aps.2017.112

Cited by 110 publications

(79 citation statements)

References 39 publications

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“…Consistent with these studies, the present results indicated that shikonin-activated AMPK could scavenge LPS-induced ROS generation. Previous studies have also shown that shikonin can increase the intracellular ROS level via various mechanisms, leading to oxidative stress and cytotoxicity (34,58,59). However, the present results are inconsistent with these existing studies.…”

Section: Discussioncontrasting

confidence: 99%

Non‑cytotoxic doses of shikonin inhibit lipopolysaccharide‑induced TNF‑α expression via activation of the AMP‑activated protein kinase signaling pathway

Zhang

Gao

et al. 2020

Exp Ther Med

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Shikonin has been reported to exhibit a wide variety of medical functions. However, the strong non-selective cytotoxicity of shikonin can restrict its clinical application. The aim of the present study was to investigate the effects of shikonin at non-cytotoxic doses on the pro-inflammation functions of monocytes and macrophages. The present results suggested that the non-cytotoxic doses of shikonin effectively inhibited lipopolysaccharide (LPS)-induced reactive oxygen species production, NF-κB activation and TNF-α expression in RAW 264.7 mouse macrophages via AMP-activated protein kinase (AMPK) signaling pathway. In addition, the non-cytotoxic doses of shikonin downregulated LPS-induced TNF-α expression via AMPK signaling activation in primary murine bone marrow-derived macrophages, and also in monocytes cultured ex vivo from patients with chronic obstructive pulmonary disease (COPD). The present in vivo results indicated that the low-toxic dose of shikonin suppressed LPS-induced endotoxin shock and TNF-α expression in mice. Collectively, the present results may provide clinical and translational relevance for treating COPD and other TNF-α-related inflammatory disorders.

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Section: Discussioncontrasting

confidence: 99%

Non‑cytotoxic doses of shikonin inhibit lipopolysaccharide‑induced TNF‑α expression via activation of the AMP‑activated protein kinase signaling pathway

Zhang

Gao

et al. 2020

Exp Ther Med

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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]. Moreover, shikonin induces autophagy in human melanoma A375, pancreatic cancer BxPC-3, and hepatocellular carcinoma Bel-7402 and Huh7 cells [608][609][610].…”

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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“…Lu et al indicated that RIP1 or RIP3 blockade induced by Nec-1 and GSK872, respectively, not only reduces shikonin-mediated necroptosis in glioma cells but also decreases the generation of intracellular ROS. MnTBAP, a superoxide dismutase mimetic, inhibits ROS production and impedes RIP1 and RIP3 expression [86,87]. In addition, the removal of ROS by butylated hydroxyanisole (BHA), an antioxidant, significantly abrogates TNF-mediated necroptosis in the mouse fibrosarcoma L929 cell line [88].…”

Section: Crosstalk Between Ros and Necroptosismentioning

confidence: 99%

“…Shikonin (SK), a naphthoquinone compound extracted from Lithospermum erythrorhizon and the enantiomer of alkannin, triggers necroptosis by upregulating RIP1 and RIP3 [87,134]. Chen et al reported that SK leads to AsPC-1 human pancreatic tumor cell death through necroptosis; additionally, SK can improve the efficacy of gemcitabine in specific pathogen-free female nude mice (athymic, Balb/c nu/nu) [54].…”

Section: Treatments Targeting Necroptosismentioning

confidence: 99%

The Role of Necroptosis in ROS-Mediated Cancer Therapies and Its Promising Applications

Hsu

Chang

Lin

et al. 2020

Cancers

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Over the past decades, promising therapies targeting different signaling pathways have emerged. Among these pathways, apoptosis has been well investigated and targeted to design diverse chemotherapies. However, some patients are chemoresistant to these therapies due to compromised apoptotic cell death. Hence, exploring alternative treatments aimed at different mechanisms of cell death seems to be a potential strategy for bypassing impaired apoptotic cell death. Emerging evidence has shown that necroptosis, a caspase-independent form of cell death with features between apoptosis and necrosis, can overcome the predicament of drug resistance. Furthermore, previous studies have also indicated that there is a close correlation between necroptosis and reactive oxygen species (ROS); both necroptosis and ROS play significant roles both under human physiological conditions such as the regulation of inflammation and in cancer biology. Several small molecules used in experiments and clinical practice eliminate cancer cells via the modulation of ROS and necroptosis. The molecular mechanisms of these promising therapies are discussed in detail in this review.

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Shikonin induces glioma cell necroptosis in vitro by ROS overproduction and promoting RIP1/RIP3 necrosome formation

Cited by 110 publications

References 39 publications

Non‑cytotoxic doses of shikonin inhibit lipopolysaccharide‑induced TNF‑α expression via activation of the AMP‑activated protein kinase signaling pathway

Non‑cytotoxic doses of shikonin inhibit lipopolysaccharide‑induced TNF‑α expression via activation of the AMP‑activated protein kinase signaling pathway

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

The Role of Necroptosis in ROS-Mediated Cancer Therapies and Its Promising Applications

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Shikonin induces glioma cell necroptosis in vitro by ROS overproduction and promoting RIP1/RIP3 necrosome formation

Cited by 110 publications

References 39 publications

Non‑cytotoxic doses of shikonin inhibit lipopolysaccharide‑induced TNF‑&alpha; expression via activation of the AMP‑activated protein kinase signaling pathway

Non‑cytotoxic doses of shikonin inhibit lipopolysaccharide‑induced TNF‑&alpha; expression via activation of the AMP‑activated protein kinase signaling pathway

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

The Role of Necroptosis in ROS-Mediated Cancer Therapies and Its Promising Applications

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Non‑cytotoxic doses of shikonin inhibit lipopolysaccharide‑induced TNF‑α expression via activation of the AMP‑activated protein kinase signaling pathway

Non‑cytotoxic doses of shikonin inhibit lipopolysaccharide‑induced TNF‑α expression via activation of the AMP‑activated protein kinase signaling pathway