Cytotoxicity and antigenotoxicity evaluation of acetylshikonin and shikonin

Figat, Ramona; Zgadzaj, Anna; Geschke, Sylwia; Sieczka, Patrycja; Pietrosiuk, Agnieszka; Sommer, Sylwester; Skrzypczak, Agata

doi:10.1080/01480545.2018.1536710

Cited by 16 publications

(17 citation statements)

References 38 publications

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“…Thus, the strong cytotoxic activity and possible side effects have limited its potential as an anticancer drug [11,12,13]. Recently, several shikonin derivatives with relatively few side effects and minimal toxicity have been developed as potential chemotherapeutic agents against human cancer, such as acetylshikonin (ASH) [14]. ASH is less cytotoxic than shikonin to normal cells, and it can be concluded that ASH may be a potentially safer alternative to shikonin for cancer treatment [14,15].…”

Section: Introductionmentioning

confidence: 99%

“…Recently, several shikonin derivatives with relatively few side effects and minimal toxicity have been developed as potential chemotherapeutic agents against human cancer, such as acetylshikonin (ASH) [14]. ASH is less cytotoxic than shikonin to normal cells, and it can be concluded that ASH may be a potentially safer alternative to shikonin for cancer treatment [14,15]. Previous studies have shown that 10 μM ASH could induce ROS production and enhance the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK), which are in the major pathways of apoptotic cell death [15].…”

Section: Introductionmentioning

confidence: 99%

“…In addition, ASH (10 μM) inhibited the growth of human gastric carcinoma SGC-7901 cells in vitro and in vivo by inducing PUMA-dependent cell apoptosis, which indicated that ASH might sensitize tumor cells to apoptosis [17]. Although ASH has been found to be less toxic than shikonin, 10 μM ASH still has potential cytotoxicity towards normal cells [14]. Thus, we intend to treat HCC with relatively low doses of ASH in combination with TRAIL for evaluating the potential sensitizing effect of ASH to TRAIL-induced apoptosis.…”

Section: Introductionmentioning

confidence: 99%

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RETRACTED: Acetylshikonin Sensitizes Hepatocellular Carcinoma Cells to Apoptosis through ROS-Mediated Caspase Activation

Hong

et al. 2019

Cells

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The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has shown strong and explicit cancer cell-selectivity, which results in little toxicity toward normal tissues, and has been recognized as a potential, relatively safe anticancer agent. However, several cancers are resistant to the apoptosis induced by TRAIL. A recent study found that shikonin b (alkannin, 5,8-dihydroxy-2-[(1S)-1-hydroxy-4-methylpent-3-en-1-yl]naphthalene-1,4-dione) might induce apoptosis in TRAIL-resistant cholangiocarcinoma cells through reactive oxygen species (ROS)-mediated caspases activation. However, the strong cytotoxic activity has limited its potential as an anticancer drug. Thus, the current study intends to discover novel shikonin derivatives which can sensitize the liver cancer cell to TRAIL-induced apoptosis while exhibiting little toxicity toward the normal hepatic cell. The trypan blue exclusion assay, western blot assay, 4′,6-diamidino-2-phenylindole (DAPI) staining and the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay as well as the ‘comet’ assay, were used to study the underlying mechanisms of cell death and to search for any mechanisms of an enhancement of TRAIL-mediated apoptosis in the presence of ASH. Herein, we demonstrated that non-cytotoxic doses of acetylshikonin (ASH), one of the shikonin derivatives, in combination with TRAIL, could promote apoptosis in HepG2 cells. Further studies showed that application of ASH in a non-cytotoxic dose (2.5 μM) could increase intracellular ROS production and induce DNA damage, which might trigger a cell intrinsic apoptosis pathway in the TRAIL-resistant HepG2 cell. Combination treatment with a non-cytotoxic dose of ASH and TRAIL activated caspase and increased the cleavage of PARP-1 in the HepG2 cell. However, when intracellular ROS production was suppressed by N-acetyl-l-cysteine (NAC), the synergistic effects of ASH and TRAIL on hepatocellular carcinoma (HCC) cell apoptosis was abolished. Furthermore, NAC could alleviate p53 and the p53 upregulated modulator of apoptosis (PUMA) expression induced by TRAIL and ASH. Small (or short) interfering RNA (siRNA) targeting PUMA or p53 significantly reversed ASH-mediated sensitization to TRAIL-induced apoptosis. In addition, Bax gene deficiency also abolished ASH-induced TRAIL sensitization. An orthotopical HCC implantation mice model further confirmed that co-treated ASH overcomes TRAIL resistance in HCC cells without exhibiting potent toxicity in vivo. In conclusion, the above data suggested that ROS could induce DNA damage and activating p53/PUMA/Bax signaling, and thus, this resulted in the permeabilization of mitochondrial outer membrane and activating caspases as well as sensitizing the HCC cell to apoptosis induced by TRAIL and ASH treatment.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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RETRACTED: Acetylshikonin Sensitizes Hepatocellular Carcinoma Cells to Apoptosis through ROS-Mediated Caspase Activation

Hong

et al. 2019

Cells

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“…Acetylshikonin exerted toxic effects on DNA by binding to the minor groove of DNA and slightly intercalating into the DNA base pairs by using the fluorescence spectrometry with two kinds of probes and resonance light scattering spectroscopy (Li et al 2015). In another study, acetylshikonin increased methanesulfonate-induced genotoxicity, and had cytotoxic effect on a normal cell line (V79 cells; EC 50 ¼ 0.49 mg/L), based on LDH assay (Figat et al 2018). In acetylshikonin-treated Sprague-Dawley rats, reproductive toxicity effect was observed due to decrease in the populations of developing and mature follicles.…”

Section: Toxicity Of Acetylshikoninmentioning

confidence: 97%

“…In another study, acetylshikonin increased methanesulfonate-induced genotoxicity, and had cytotoxic effect on a normal cell line (V79 cells; EC 50 = 0.49 mg/L), based on LDH assay (Figat et al. 2018 ). In acetylshikonin-treated Sprague-Dawley rats, reproductive toxicity effect was observed due to decrease in the populations of developing and mature follicles.…”

Section: Toxicity Of Acetylshikoninmentioning

confidence: 99%

Pharmacology, toxicity and pharmacokinetics of acetylshikonin: a review

Zhang

Bai

Zeng

et al. 2020

Pharmaceutical Biology

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Context: Acetylshikonin, a naphthoquinone derivative, is mainly extracted from some species of the family Boraginaceae, such as Lithospermum erythrorhizon Sieb. et Zucc., Arnebia euchroma (Royle) Johnst., and Arnebia guttata Bunge. As a bioactive compound, acetylshikonin has attracted much attention because of its broad pharmacological properties. Objective: This review provides a comprehensive summary of the pharmacology, toxicity, and pharmacokinetics of acetylshikonin focussing on its mechanisms on the basis of currently available literature. Methods: The information of acetylshikonin from 1977 to 2020 was collected using major databases including Elsevier, Scholar, PubMed, Springer, Web of Science, and CNKI. Acetylshikonin, pharmacology, toxicity, pharmacokinetics, and naphthoquinone derivative were used as key words. Results: According to emerging evidence, acetylshikonin exerts a wide spectrum of pharmacological effects such as anticancer, anti-inflammatory, lipid-regulatory, antidiabetic, antibacterial, antifungal, antioxidative, neuroprotective, and antiviral properties. However, only a few studies have reported the adverse effects of acetylshikonin, with respect to reproductive toxicity and genotoxicity. Pharmacokinetic studies demonstrate that acetylshikonin is associated with a wide distribution and poor absorption. Conclusions: Although experimental data supports the beneficial effects of this compound, acetylshikonin cannot be considered as a therapy drug without further investigations, especially, on the toxicity and pharmacokinetics.

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Acetylshikonin promoting PI3K/Akt pathway and inhibiting SOX4 expression to delay intervertebral disc degeneration and low back pain

Huang

Lei

Zhao

et al. 2023

Journal Orthopaedic Research

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This study investigated the molecular mechanism by which acetylshikonin inhibits SOX4 expression via the PI3K/Akt pathway to delay intervertebral disc degeneration (IVDD) and low back pain (LBP). Bulk RNA‐seq, RT‐qPCR, Western blot analysis, immunohistochemical staining, small interfering RNA (siSOX4), lentivirus (lentiv‐SOX4hi), and imaging techniques were used to assess SOX4 expression and validate its upstream regulatory pathway. Acetylshikonin and siSOX4 were injected into the IVD to measure IVDD. SOX4 expression significantly increased in degenerated IVD tissues. TNF‐α increased SOX4 expression and apoptosis‐related proteins in nucleus pulposus cells (NPCs). siSOX4 reduced TNF‐α‐induced NPCs apoptosis, while Lentiv‐SOX4hi increased it. The PI3K/Akt pathway was significantly correlated with SOX4, and acetylshikonin upregulated PI3K/Akt pathway while inhibiting SOX4 expression. In the anterior puncture IVDD mouse model, SOX4 expression was upregulated, and acetylshikonin and siSOX4 delayed IVDD‐induced LBP. Acetylshikonin delays IVDD‐induced LBP by inhibiting SOX4 expression through the PI3K/Akt pathway. These findings offer potential therapeutic targets for future treatments.

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Cytotoxicity and antigenotoxicity evaluation of acetylshikonin and shikonin

Cited by 16 publications

References 38 publications

RETRACTED: Acetylshikonin Sensitizes Hepatocellular Carcinoma Cells to Apoptosis through ROS-Mediated Caspase Activation

RETRACTED: Acetylshikonin Sensitizes Hepatocellular Carcinoma Cells to Apoptosis through ROS-Mediated Caspase Activation

Pharmacology, toxicity and pharmacokinetics of acetylshikonin: a review

Acetylshikonin promoting PI3K/Akt pathway and inhibiting SOX4 expression to delay intervertebral disc degeneration and low back pain

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