Novel Multiple Apoptotic Mechanism of Shikonin in Human Glioma Cells

Chen, Ching‐Hsein; Lin, Miao‐Ling; Ong, Ping-Lin; Yang, Jen-Tsung

doi:10.1245/s10434-012-2324-4

Cited by 46 publications

(39 citation statements)

References 20 publications

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“…36 Furthermore, necroptosis is also activated by shikonin mediated by RIP-1 pathway and oxidative stress in human glioma cell lines, including U87MG cells. 37 In our study, shikonin inhibited cell growth of a panel of 13 EGFRexpressing cancer cell lines with IC 50 values much lower than that of erlotinib, which is a specific inhibitor of EGFR.…”

Section: Discussionmentioning

confidence: 99%

Shikonin and its derivatives inhibit the epidermal growth factor receptor signaling and synergistically kill glioblastoma cells in combination with erlotinib

et al. 2015

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Overexpression and mutation of the epidermal growth factor receptor (EGFR) gene play a causal role in tumorigenesis and resistance to treatment of glioblastoma (GBM). EGFR inhibitors such as erlotinib are currently used for the treatment of GBM; however, their efficacy has been limited due to drug resistance. New treatment strategies are therefore urgently needed. Shikonin, a natural naphthoquinone, induces both apoptosis and necroptosis in human glioma cells, but the effectiveness of erlotinib-shikonin combination treatment as well as the underlying molecular mechanisms is unknown yet. In this study, we investigated erlotinib in combination with shikonin and 14 shikonin derivatives in parental U87MG and transfected U87MG.DEGFR GBM cells. Most of the shikonin derivatives revealed strong cytotoxicity. Shikonin together with five other derivatives, namely deoxyshikonin, isobutyrylshikonin, acetylshikonin, b,b-dimethylacrylshikonin and acetylalkannin showed synergistic cytotoxicity toward U87MG.DEGFR in combination with erlotinib. Moreover, the combined cytotoxic effect of shikonin and erlotinib was further confirmed with another three EGFR-expressing cell lines, BS153, A431 and DK-MG. Shikonin not only dose-dependently inhibited EGFR phosphorylation and decreased phosphorylation of EGFR downstream molecules, including AKT, P44/42MAPK and PLCc1, but also together with erlotinib synergistically inhibited DEGFR phosphorylation in U87MG.DEGFR cells as determined by Loewe additivity and Bliss independence drug interaction models. These results suggest that the combination of erlotinib with shikonin or its derivatives might be a potential strategy to overcome drug resistance to erlotinib.Glioblastoma (GBM) is the most common primary brain tumor in adults and one of the deadliest human cancers with a median survival rate of 12 months despite aggressive therapies (i.e., urgical resection, radiotherapy and chemotherapy) due to their highly invasive and neurologically destructive nature.

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Section: Discussionmentioning

confidence: 99%

Shikonin and its derivatives inhibit the epidermal growth factor receptor signaling and synergistically kill glioblastoma cells in combination with erlotinib

et al. 2015

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“…Despite having immunomodulatory effects, 9 SHK, as a highly liposoluble naphthoquinone pigment, can inhibit pyruvate kinase M2 activity, 12,13 upregulate p53 activity and downregulate cyclin-dependent protein kinase 4 activity, 14 upregulate BCL2-associated X protein (BAX) and downregulate B-cell lymphoma 2 (BCL2), 6 and inhibit extracellular signal-regulated kinases (ERK) and protein kinase B pathways. 15 All these studies confirm that SHK can induce significant cytotoxicity, while its cytotoxic impacts are not specific to cancer cells.…”

Section: Introductionmentioning

confidence: 99%

“…In fact, SHK is a naturally occurring naphthoquinone with profound inhibitory effects on cancer cell proliferation both in vivo and in vitro. 6,53 Chen et al reported in 2012 that SHK can induce generation of reactive oxygen species, depletion of glutathione, disruption of mitochondrial transmembrane potential, upregulation of p53, cleavage of poly(adenosine diphosphate [ADP]-ribose) polymerase, catalase downregulation, super oxide dismutases (SOD1) upregulation, BCL2 downregulation, and BAX upregulation in U87MG glioma cells. 6 In human glioma cells, SHK-induced necroptosis appears to occur through multiple pathways, while it has also been shown to inhibit the glycolytic path in cancers through inhibiting pyruvate kinase-M2 (PKM2).…”

mentioning

confidence: 99%

“…6,53 Chen et al reported in 2012 that SHK can induce generation of reactive oxygen species, depletion of glutathione, disruption of mitochondrial transmembrane potential, upregulation of p53, cleavage of poly(adenosine diphosphate [ADP]-ribose) polymerase, catalase downregulation, super oxide dismutases (SOD1) upregulation, BCL2 downregulation, and BAX upregulation in U87MG glioma cells. 6 In human glioma cells, SHK-induced necroptosis appears to occur through multiple pathways, while it has also been shown to inhibit the glycolytic path in cancers through inhibiting pyruvate kinase-M2 (PKM2). 13 Similarly, skin epidermal JB6 P+ cells treated with SHK showed marked induction of apoptosis through suppression of PKM2 activation, and decreased level of lactate as a glycolysis marker, thus mitochondrial dysfunction.…”

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Shikonin-loaded antibody-armed nanoparticles for targeted therapy of ovarian cancer

Barar

Sandaltzopoulos

Liu

et al. 2014

IJN

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Conventional chemotherapy of ovarian cancer often fails because of initiation of drug resistance and/or side effects and trace of untouched remaining cancerous cells. This highlights an urgent need for advanced targeted therapies for effective remediation of the disease using a cytotoxic agent with immunomodulatory effects, such as shikonin (SHK). Based on preliminary experiments, we found SHK to be profoundly toxic in ovarian epithelial cancer cells (OVCAR-5 and ID8 cells) as well as in normal ovarian IOSE-398 cells, endothelial MS1 cells, and lymphocytes. To limit its cytotoxic impact solely to tumor cells within the tumor microenvironment (TME), we aimed to engineer SHK as polymeric nanoparticles (NPs) with targeting moiety toward tumor microvasculature. To this end, using single/double emulsion solvent evaporation/diffusion technique with sonication, we formulated biodegradable NPs of poly(lactic-co-glycolic acid) (PLGA) loaded with SHK. The surface of NPs was further decorated with solubilizing agent polyethylene glycol (PEG) and tumor endothelial marker 1 (TEM1)/endosialin-targeting antibody (Ab) through carbodiimide/N-hydroxysuccinimide chemistry. Having characterized the physicochemical and morphological properties of NPs, we studied their drug-release profiles using various kinetic models. The biological impact of NPs was also evaluated in tumor-associated endothelial MS1 cells, primary lymphocytes, and epithelial ovarian cancer OVCAR-5 cells. Based on particle size analysis and electron microscopy, the engineered NPs showed a smooth spherical shape with size range of 120 to 250 nm and zeta potential value of −30 to −40 mV. Drug entrapment efficiency was ~80%–90%, which was reduced to ~50%–60% upon surface decoration with PEG and Ab. The liberation of SHK from NPs showed a sustained-release profile that was best fitted with Wagner log-probability model. Fluorescence microscopy and flow cytometry analysis showed active interaction of Ab-armed NPs with TEM1-positive MS1 cells, but not with TEM1-negative MS1 cells. While exposure of the PEGylated NPs for 2 hours was not toxic to lymphocytes, long-term exposure of the Ab-armed and PEGylated NPs was significantly toxic to TEM1-positive MS1 cells and OVCAR-5 cells. Based on these findings, we propose SHK-loaded Ab-armed PEGylated PLGA NPs as a novel nanomedicine for targeted therapy of solid tumors.

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“…Здесь же заметим, что способность из-менять трансмембранный потенциал показана для структурного аналога эхинохрома А шиконина (5,8-дигидрокси-3(1´-гидрокси-4-метилпент-3-енил)-1,4-нафтохинон) [52]. Изучение влияния гистохрома на биофизические свойства электро-возбудимых клеток выявило гиперполяризую-щий эффект 2,3,5,6,8-пентагидрокси-7-этил-1,4-нафтохинона [25].…”

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The cellular and molecular mechanisms providing therapeutic efficiency of gistokhrom

Talalaeva

Сергеевна²,

Zverev

et al. 2017

Rev Clin Pharm Drug Ther

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The review presents the screening of the therapeutic effects of the Russia drug “Histochrome”, active substance of which is quinoid pigment marine - echinochrome A (2,3,5,6,8-pentahydroxy-7-ethyl-1,4-naphthoquinone). Assessing the pharmacological aspects of the drug authors have focused on cellular and molecular mechanisms of action of histochrome. The parallel between echinochrome A pharmacodynamics and its biological effects proves promising directions for expansion of the clinical application of the preparation “Histochrome”. (For citation: Talalaeva OS, Zverev YaF, Bryukhanov VM. The cellular and molecular mechanisms providing therapeutic efficiency of gistokhrom. Reviews on Clinical Pharmacology and Drug Therapy. 2017;15(4):58-68. doi: 10.17816/RCF15458-68).

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Novel Multiple Apoptotic Mechanism of Shikonin in Human Glioma Cells

Abstract: These studies are the first to show that shikonin-induced apoptosis occurs through multiple pathways in human glioma cells. We conclude that shikonin may be used as a potential chemotherapeutic agent against human glioma.

Cited by 46 publications

References 20 publications

Shikonin and its derivatives inhibit the epidermal growth factor receptor signaling and synergistically kill glioblastoma cells in combination with erlotinib

Shikonin and its derivatives inhibit the epidermal growth factor receptor signaling and synergistically kill glioblastoma cells in combination with erlotinib

Shikonin-loaded antibody-armed nanoparticles for targeted therapy of ovarian cancer

The cellular and molecular mechanisms providing therapeutic efficiency of gistokhrom

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