Shikonin induces programmed necrosis-like cell death through the formation of receptor interacting protein 1 and 3 complex

Park, Seungyeon; Shin, Heesuk; Cho, YoungSik

doi:10.1016/j.fct.2012.12.017

Cited by 20 publications

(10 citation statements)

References 28 publications

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“…These results indicated that shikonin induced cell death in some osteosarcoma cell lines including K7 and U2OS via RIP1 and RIP3 dependent necroptosis pathway. Moreover, other reports have also shown that necroptosis could be induced via modulating RIP1 and RIP3 [16,22-24]. Also, there were results different from ours.…”

Section: Discussioncontrasting

confidence: 94%

“…Interestingly shikonin also exert two death modes of apoptosis and necroptosis in KL-60 cells depending on its concentrations [15]. Moreover, shikonin was demonstrated to mediated necrotic cell death via a RIP1-RIP3 complex similar to TNFα-directed necrotic cell death, and this pronecrotic complex was blocked by a reactive oxygen species (ROS) scavenger or Nec-1 concomitantly with protection against cell death [16]. In 2011, the first molecular target of shikonin was reported in which shikonin played a role in the anti-tumor effect by inhibiting pyruvate kinase-M2(PKM2).…”

Section: Introductionmentioning

confidence: 99%

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The anti-tumor effect of shikonin on osteosarcoma by inducing RIP1 and RIP3 dependent necroptosis

et al. 2013

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BackgroundOsteosarcoma is the most frequent primary malignant bone tumor, notorious for its lung metastasis. Shikonin, an effective constituent extracted from Chinese medicinal herb, was demonstrated to induce necroptosis in some cancers.MethodsMTT assay was performed to detect cell survival rate in vitro. Flow cytometry was used to analyze cell cycle and cell death. Western blot was performed to determine the expression levels of RIP1, RIP3, caspase-3, caspase-6 and PARP. The tibial primary and lung metastatic osteosarcoma models were used to evaluate the anti-tumor effect of shikonin in vivo.ResultsThe cell survival rate was decreased in a dose and time dependent manner when treated with shikonin. No major change in cell cycle was observed after shikonin treatment. The cell death induced by shikonin could be mostly rescued by specific necroptosis inhibitor necrostatin-1, but not by general caspase inhibitor Z-VAD-FMK. The number of necrotic cells caused by shikonin was decreased after being pretreated with Nec-1 detected by flow cytometry in K7 cells. After 8-hour treatment of shikonin, the expression levels of RIP1 and RIP3 were increased while caspase-3, caspase-6 and PARP were not activated in K7 and U2OS cells determined by Western blot. Size of primary tumor and lung metastasis in shikonin treated group were significantly reduced. The protein levels of RIP1 and RIP3 in primary tumor tissues were increased by shikonin. The overall survival of lung metastatic models was longer compared with control group (p < 0.001).ConclusionsShikonin had prompt but profound anti-tumor effect on both primary and metastatic osteosarcoma, probably by inducing RIP1 and RIP3 dependent necroptosis. Shikonin would be a potential anti-tumor agent on the treatment of primary and metastatic osteosarcoma.

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Section: Discussioncontrasting

confidence: 94%

Section: Introductionmentioning

confidence: 99%

The anti-tumor effect of shikonin on osteosarcoma by inducing RIP1 and RIP3 dependent necroptosis

et al. 2013

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“…Shikonin has antioxidant [1], anti-inflammatory [1,2,3], antithrombotic [1,2], antiviral [2,4], antimicrobial [1,2], as well as anticancer [2,5,6,7,8] potency and fosters wound healing [1,2,5]. The anticancer effect of Shikonin has been attributed at least in part to the stimulation of suicidal cell death or apoptosis [9,10,11,12,13,14,15,16,17]. Mechanisms involved in Shikonin-induced apoptosis include reactive oxidant species [18,19,20,21,22,23], altered gene expression [15], protein phosphorylation [18] and caspase activation [24].…”

Section: Introductionmentioning

confidence: 99%

In Vitro Induction of Erythrocyte Phosphatidylserine Translocation by the Natural Naphthoquinone Shikonin

Lupescu

Bissinger

Jilani

et al. 2014

Toxins

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Shikonin, the most important component of Lithospermum erythrorhizon, has previously been shown to exert antioxidant, anti-inflammatory, antithrombotic, antiviral, antimicrobial and anticancer effects. The anticancer effect has been attributed to the stimulation of suicidal cell death or apoptosis. Similar to the apoptosis of nucleated cells, erythrocytes may experience eryptosis, the suicidal erythrocyte death characterized by cell shrinkage and by phosphatidylserine translocation to the erythrocyte surface. Triggers of eryptosis include the increase of cytosolic Ca2+-activity ([Ca2+]i) and ceramide formation. The present study explored whether Shikonin stimulates eryptosis. To this end, Fluo 3 fluorescence was measured to quantify [Ca2+]i, forward scatter to estimate cell volume, annexin V binding to identify phosphatidylserine-exposing erythrocytes, hemoglobin release to determine hemolysis and antibodies to quantify ceramide abundance. As a result, a 48 h exposure of human erythrocytes to Shikonin (1 µM) significantly increased [Ca2+]i, increased ceramide abundance, decreased forward scatter and increased annexin V binding. The effect of Shikonin (1 µM) on annexin V binding was significantly blunted, but not abolished by the removal of extracellular Ca2+. In conclusion, Shikonin stimulates suicidal erythrocyte death or eryptosis, an effect at least partially due to the stimulation of Ca2+ entry and ceramide formation.

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“…The roots of traditional Chinese medicinal herb Lithospermum erythrorhizon are rich source of shikonin (Figure , Shikonin), which is an active red naphthoquinone compound. The compound is primarily used natural medicine for treating antibacterial, anti‐inflammatory, or antitumor drugs and for inhibition of HIV virus . Recently, the research interests of shikonin have gradually shifted to its derivatives, which further can potentially be used as drugs for cancer.…”

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confidence: 99%

Synthesis and Biological Evaluation of Heterocyclic Carboxylic Acyl Shikonin Derivatives

et al. 2013

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A series of shikonin derivatives (1-13) that were acylated selectively by various thiophene or indol carboxylic acids at the side chain of shikonin were synthesized, and their biological activities were also evaluated as potential tubulin inhibitors. Among them, compound 3 ((R)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-enyl 3-(1H-indol-3-yl)propanoate) and compound 8 ((R)-1-(5,8-dihydroxy-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-4-methylpent-3-enyl 2-(thiophen-3-yl)acetate) exhibited good antiproliferative activity of A875 (IC50 = 0.005 ± 0.001 μm, 0.009 ± 0.002 μm) and HeLa (IC50 = 11.84 ± 0.64 μm, 4.62 ± 0.31 μm) cancer cell lines in vitro, respectively. Shikonin (IC50 = 0.46 ± 0.002 μm, 4.80 ± 0.48 μm) and colchicine (IC50 = 0.75 ± 0.05 μm, 17.79 ± 0.76 μm) were used as references. Meanwhile, they also showed the most potent growth inhibitory activity against tubulin (IC50 of 3.96 ± 0.13 μm and 3.05 ± 0.30 μm, respectively), which were compared with shikonin (IC50 = 15.20 ± 0.25 μm) and colchicine (IC50 = 3.50 ± 0.35 μm). Furthermore, from the results of flow cytometer, we found compound 3 can really inhibit HeLa cell proliferation and has low cell toxicity. Based on the preliminary results, compound 3 with potent inhibitory activity in tumor growth may be a potential anticancer agent.

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Shikonin induces programmed necrosis-like cell death through the formation of receptor interacting protein 1 and 3 complex

Cited by 20 publications

References 28 publications

The anti-tumor effect of shikonin on osteosarcoma by inducing RIP1 and RIP3 dependent necroptosis

The anti-tumor effect of shikonin on osteosarcoma by inducing RIP1 and RIP3 dependent necroptosis

In Vitro Induction of Erythrocyte Phosphatidylserine Translocation by the Natural Naphthoquinone Shikonin

Synthesis and Biological Evaluation of Heterocyclic Carboxylic Acyl Shikonin Derivatives

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