Shikonin Directly Targets Mitochondria and Causes Mitochondrial Dysfunction in Cancer Cells

Wiench, Benjamin; Eichhorn, Tolga; Paulsen, Malte; Efferth, Thomas

doi:10.1155/2012/726025

Cited by 84 publications

(81 citation statements)

References 52 publications

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“…Shikonin has attracted increasing attention, as it exhibits numerous biological activities, such as anti-inflammatory, antiviral and anti-cancer actions (22)(23)(24). Hence, the effects of shikonin on MC3T3-E1 cells were evaluated in the current study.…”

Section: Discussionmentioning

confidence: 99%

Shikonin stimulates MC3T3-E1 cell proliferation and differentiation via the BMP-2/Smad5 signal transduction pathway

Fang

et al. 2016

Molecular Medicine Reports

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Abstract. Shikonin, the predominant naphthoquinone pigment isolated from the Chinese plant Lithospermum erythrorhizon, is anti-inflammatory, antiviral and exerts anticancer effects, amongst other biological activities. However, it is unknown whether shikonin affects bone formation. In the present study, the role of shikonin on cell proliferation was assessed via MTT assay, and shikonin was identified to markedly promote cell growth in a time-and dose-dependent manner in the MC3T3-E1 cell line. In addition, flow cytometric analysis was performed to evaluate the effect of shikonin on the cell cycle, and it was observed that shikonin markedly increased the percentage of S-phase MC3T3-E1 cells to accelerate the G 1 /S transition. To investigate the potential molecular mechanism by which shikonin enhances bone formation, the changes in bone morphogenic protein-2 (BMP-2), SMAD family member 5 (Smad5), runt related transcription factor 2 (Runx2), alkaline phosphatase (ALP) and osteocalcin (OC) expression levels induced by shikonin were investigated using western blot analysis and quantitative polymerase chain reaction. The results indicated that shikonin increased the BMP-2 and Smad5 mRNA levels, and upregulated Smad5 and Runx2 protein expression levels to promote osteoblast differentiation. Furthermore, ALP staining was performed, and revealed that shikonin enhanced ALP activity. These results indicate that shikonin promotes cell proliferation and differentiation of MC3T3-E1 cells via the BMP-2/Smad5 signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Shikonin stimulates MC3T3-E1 cell proliferation and differentiation via the BMP-2/Smad5 signal transduction pathway

Fang

et al. 2016

Molecular Medicine Reports

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“…These tubes were kept on a shaker at 37°C and 150 rpm. At designated time intervals (1,2,4,8,12,24,48, and 72 hours), these tubes were taken from the shaker and centrifuged at 9,000× g at 4°C for 5 minutes. Then, the supernatant was removed to estimate the amount of released drug using the Genesys 6 UV spectrophotometer, at a wavelength of 520 nm (SHK) and …”

Section: Release Kinetics Analysismentioning

confidence: 99%

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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“…This antitumor activity of shikonin may be attributed to its accumulation in the mitochondria of cancer cells, which disrupts mitochondrial function, and eventually causes apoptosis [12]. Our group investigated the inhibition of c-MYC expression and transcriptional activity by shikonin as a novel mechanism for killing leukemia cells [9], and more recently, the cytotoxic activity of shikonin to the Huh7 cancer cell line by a metabolite profiling approach which could set a basis for the elucidation of their antitumor activity was investigated [13].…”

Section: Introductionmentioning

confidence: 99%

Comparative Study of PEGylated and Conventional Liposomes as Carriers for Shikonin

Tsermentseli

Kontogiannopoulos

Papageorgiou

et al. 2018

Fluids

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Abstract:Liposomes are considered to be one of the most successful drug delivery systems.They apply nanotechnology to potentiate the therapeutic efficacy and reduce the toxicity of conventional medicines. Shikonin and alkannin, a pair of chiral natural naphthoquinone compounds, derived from Alkanna and Lithospermum species, are widely used due to their various pharmacological activities, mainly wound healing, antioxidant, anti-inflammatory and their recently established antitumor activity. The purpose of this study was to prepare conventional and PEGylated shikonin-loaded liposomal formulations and measure the effects of different lipids and polyethylene glycol (PEG) on parameters related to particle size distribution, the polydispersity index, the zeta potential, drug-loading efficiency and the stability of the prepared formulations. Three types of lipids were assessed (1,2-Dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC) and 1,2-distearoyl-sn-glycero-3-phospho-rac-(1-glycerol) (DSPG)), separately and in mixtures, forming anionic liposomes with good physicochemical characteristics, high entrapment efficiencies (varying from 56.5 to 89.4%), satisfactory in vitro release profiles and good physical stability. The addition of the negatively charged DSPG lipids to DOPC, led to an increment in the drug's incorporation efficiency and reduced the particle size distribution. Furthermore, the shikonin-loaded PEGylated sample with DOPC/DSPG, demonstrated the most satisfactory characteristics. These findings are considered promising and could be used for further design and improvement of such formulations.

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Shikonin Directly Targets Mitochondria and Causes Mitochondrial Dysfunction in Cancer Cells

Cited by 84 publications

References 52 publications

Shikonin stimulates MC3T3-E1 cell proliferation and differentiation via the BMP-2/Smad5 signal transduction pathway

Shikonin stimulates MC3T3-E1 cell proliferation and differentiation via the BMP-2/Smad5 signal transduction pathway

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

Comparative Study of PEGylated and Conventional Liposomes as Carriers for Shikonin

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