Shikonin targets cytosolic thioredoxin reductase to induce ROS-mediated apoptosis in human promyelocytic leukemia HL-60 cells

Duan, Dongzhu; Zhang, Baoxin; Yao, Juan; Liu, Yaping; Fang, Jianguo

doi:10.1016/j.freeradbiomed.2014.02.016

Cited by 157 publications

(164 citation statements)

References 71 publications

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“…Recent studies confirmed that shikonin has the potential to induce apoptosis in a variety of human tumor cell lines, including leukemia cell lines in vitro and in vivo, with minimal or no toxicity to healthy human cells [9][10][11].…”

Section: Introductionmentioning

confidence: 89%

“…[7,8]. Recent studies confirmed that shikonin has the potential to induce apoptosis in a variety of human tumor cell lines, including leukemia cell lines in vitro and in vivo, with minimal or no toxicity to healthy human cells [9][10][11]. 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].…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Introductionmentioning

confidence: 89%

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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“…For instance, shikonin inhibits cancer cell proliferation by targeting tumor specific pyruvate kinase-M2 (PKM2) [5]. Other mechanisms involve shikonin induced proteasome inhibition, NFkB inhibition, Thioredoxin reductase (TrxR1) inhibition [37][38][39]. In addition shikonin also sensitizes cancer cells towards chemotherapeutic drugs used for cancer therapy [40,41].…”

Section: Discussionmentioning

confidence: 99%

Anti-Leukemic Activity of Shikonin: Role of ERP57 in Shikonin Induced Apoptosis in Acute Myeloid Leukemia

Trivedi

Müller

Rathore

et al. 2016

Cell Physiol Biochem

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Background/Aims: ER-Stress and activation of unfolded protein response belong to the major factors involved in chemoresistance in cancer cells. In this study we investigated the effect of shikonin on the survival of acute myeloid leukemia cells and the role of ER-stress protein ERP57, a protein disulfide isomerase, in improvement of chemotherapy. Methods: Using MTT assay we studied cytotoxic effects of shikonin on HL-60 cells. The flow cytometry was adopted to examine the shikonin induced mode of cell death in HL-60 cells. The overall protein expression alteration resulting from shikonin treatment was investigated using proteomics methods. Western blotting was performed to quantify the alteration in protein expression in HL-60 after shikonin treatment. Silencing and overexpression studies were carried out to highlight the therapeutic role of ERP57 in shikonin effect on AML cells. Results: Shikonin induces apoptosis in HL-60 cells without significant effect on Primary cells from healthy volunteers. The apoptotic effect was dose and time dependent and was accompanied by strong alteration in cell proteome. Among the proteins targeted by shikonin, ERP57 was significantly downregulated in HL-60 after treatment. Compared to healthy control ERP57 was found to be highly expressed in AML cell line HL60 and was downregulated after shikonin treatment. Overexpression of ERP57 protected HL-60 from shikonin induced apoptosis, whereas knockdown of ERP57 expression resulted in increase in shikonin induced apoptosis. Conclusions: Our results demonstrate that ERP57 plays a crucial role in resistance towards shikonin induced apoptosis in AML cells. Targeting of ERP57 might offer a new therapeutic option for the treatment of acute myeloid leukemia.

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“…Recent studies have identified several traditional Chinese herbal remedies capable of inducing apoptosis in cancer cells by increasing the level of reactive oxygen species (ROS) (16)(17)(18). ROS are oxygen-containing chemically reactive molecules that can cause considerable damage to key cellular molecules, such as lipids, proteins and DNA (19,20).…”

Section: Reactive Oxygen Species Detectionmentioning

confidence: 99%

Guizhi Fuling Wan as a Novel Agent for Intravesical Treatment for Bladder Cancer in a Mouse Model

Shen

Chang

et al. 2016

Mol Med

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Alternative intravesical agents are required to overcome the side effects currently associated with the treatment of bladder cancer. This study used an orthotopic bladder cancer mouse model to evaluate Guizhi Fuling Wan (GFW) as an intravesical agent. The effects of GFW were compared with those of mitomycin-C (Mito-C) and bacille Calmette-Guérin (BCG). We began by evaluating the response of the mouse bladder cancer cell line MB49 to GFW treatment, with regard to cell viability, cell cycle progression and apoptosis. MB49 cells were subsequently implanted into the urothelial walls of the bladder in female C57BL/6 mice. The success of the model was confirmed by the appearance of hematuria and tumor growth in the bladder. Intravesical chemotherapy was administered in accordance with a published protocol. In vitro data revealed that GFW arrested MB49 cell cycle in the G0/G1 phase, resulting in the suppression of cell proliferation and induced apoptosis. One possible mechanism underlying these effects is an increase in intracellular reactive oxygen species (ROS) levels leading to the activation of ataxia telangiectasia-mutated (ATM)/checkpoint kinase 2 (CHK2) and ATM/P53 pathways, thereby mediating cell cycle progression and apoptosis, respectively. This mouse model demonstrates the effectiveness of GFW in the tumor growth, with results comparable to those achieved by using BCG and Mito-C. Furthermore, GFW was shown to cause only mild hematuria. The low toxicity of the compound was confirmed by a complete lack of lesions on bladder tissue, even after 10 consecutive treatments using high concentrations of GFW. These results demonstrate the potential of GFW for the intravesical therapy of bladder cancer.

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Shikonin targets cytosolic thioredoxin reductase to induce ROS-mediated apoptosis in human promyelocytic leukemia HL-60 cells

Cited by 157 publications

References 71 publications

Comparative Study of PEGylated and Conventional Liposomes as Carriers for Shikonin

Comparative Study of PEGylated and Conventional Liposomes as Carriers for Shikonin

Anti-Leukemic Activity of Shikonin: Role of ERP57 in Shikonin Induced Apoptosis in Acute Myeloid Leukemia

Guizhi Fuling Wan as a Novel Agent for Intravesical Treatment for Bladder Cancer in a Mouse Model

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