Shikonin Induces Apoptosis, Necrosis, and Premature Senescence of Human A549 Lung Cancer Cells through Upregulation of p53 Expression

Yeh, Yu-Min; Liu, Tsun Jui; Lai, Hui Chin

doi:10.1155/2015/620383

Cited by 44 publications

(24 citation statements)

References 52 publications

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“…The half-maximal inhibitory concentration of SHK in A549 cells, as determined using an MTT assay, has previously been determined to be 3.52±0.17 µg/ml (46). To confirm the effect of ATP reduction in A549 cells, the expression of MRP1, P-gp and BCRP was analyzed in the present study following combination treatment with SHK and AD.…”

Section: Discussionmentioning

confidence: 84%

Shikonin enhances Adriamycin antitumor effects by inhibiting efflux pumps in A549 cells

Liu¹,

Sun²

2017

Oncology Letters

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Abstract. Shikonin (SHK) is a natural naphthoquinone pigment isolated from Lithospermum erythrorhizon, that has been reported to suppress the growth of a number of cancer cell types. Adriamycin (AD) is typically used as an effective anticancer agent; however, it has the propensity to induce drug resistance. The aim of the present study was to investigate the effects of SHK alone and in combination with AD on lung adenocarcinoma cells and the underlying molecular mechanisms of their effects. Colony formation, MTT and propidium iodide staining assays demonstrated that the co-treatment of A549 cells with SHK and AD significantly decreased cell viability and potently induced apoptosis. The mitochondrial membrane potential was assessed using 5,5', 6,6'-tetrachloro-1,1',3,3'-tetraethyl-benzimidazolylcarbocyanine iodide staining and fluorescence microscopy. Cells co-treated with SHK and AD exhibited marked mitochondrial membrane damage. In addition, co-treatment with SHK and AD significantly reduced ATP levels in A549 cells compared with the control. Western blot analysis revealed that SHK enhanced the antitumor effects of AD by inhibiting the expression of ATP-binding cassette transporters. These results suggest that the inhibition of glycolysis could be an effective approach for lung cancer treatment. Therefore, SHK has the potential to be used as an anticancer agent in the treatment of lung adenocarcinoma, and thus warrants further investigation and development.

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Section: Discussionmentioning

confidence: 84%

Shikonin enhances Adriamycin antitumor effects by inhibiting efflux pumps in A549 cells

Liu¹,

Sun²

2017

Oncology Letters

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“…A number of natural products extracted from plants, and showing low toxicity, including taxol, quercetin, curcumin, and shikonin, have been shown to induce or suppress complicated signaling pathways to inhibit cancer cell growth in vitro [13,14]. Shikonin, a natural naphthoquinone pigment, suppresses the growth of various cancer cells including those of lung cancer [15], pancreatic cancer [16], and gastric cancer [17]. However, the exact molecular mechanism of Shikonin-induced toxicity remains incompletely elucidated in human melanoma A375 cells.…”

Section: Discussionmentioning

confidence: 99%

Shikonin induces apoptosis and prosurvival autophagy in human melanoma A375 cells via ROS-mediated ER stress and p38 pathways

Liu

Kang

Niu

et al. 2019

Artificial Cells, Nanomedicine, and Biotechnology

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2019) Shikonin induces apoptosis and prosurvival autophagy in human melanoma A375 cells via ROS-mediated ER stress and p38 pathways, Artificial Cells, Nanomedicine, and Biotechnology, 47:1, 626-635, ABSTRACT Shikonin, a botanical drug extracted from Lithospermum erythrorhizon, exhibits anti-cancer effects in various cancer cell lines. However, the mechanisms underlying these effects have not been completely elucidated yet. Here, we showed that Shikonin induces apoptosis and autophagy in A375 cells and inhibits their proliferation. Shikonin caused G2/M phase arrest through upregulation of p21 and downregulation of cyclin B1. Shikonin significantly triggered ER stress-mediated apoptosis by upregulating the expression of p-eIF2a, CHOP, and cleaved caspase-3. It also induced protective autophagy by activating the p38 pathway, followed by an increase in the levels of p-p38, LC3B-II, and Beclin 1. Upon suppression of autophagy by 3-methyladenine, Shikonin-induced apoptosis was enhanced in A375 cells. Moreover, after pretreatment with N-acetyl-cysteine, Shikonin increased the production of reactive oxygen species that are involved in regulating ER stress-mediated apoptosis and p38-activated autophagy, as evidenced by the reversion of cell viability and apoptosis and a decrease in p-eIF2a, CHOP, p-p38, LC3B-II, and Beclin 1 levels. Thus, we demonstrated that Shikonin induced apoptosis and autophagy in A375 cells via the activation of ROS-mediated ER stress and p38 pathways, indicating that Shikonin can serve as a potential agent for human melanoma therapy. ARTICLE HISTORY

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“…Bcl-2, Bax and p53 affect the proliferation, apoptosis, occurrence and development of PCa (22,23). Among the genes involved in the regulation of cell apoptosis, Bcl-2 is currently recognized as an anti-apoptotic gene (24), which participates in the occurrence of tumors by inhibiting cell apoptosis and prolonging cell survival (25). The present results revealed that treatment with DPPT significantly reduced p-Akt protein expression, and increased p53 and Bax protein expression in DU-145 cells.…”

Section: Discussionmentioning

confidence: 99%

Anticancer effect of deoxypodophyllotoxin induces apoptosis of human prostate cancer cells

Zhou

et al. 2016

Oncology Letters

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Abstract. Deoxypodophyllotoxin (DPPT) is extracted and separated from citrus-related plants, including Podophyllum (P.) peltatum, P. pleianthum, P. emodi (also called P. hexandrum) and Diphylleia grayi. DPPT has significant antitumor and antiviral activity. However, due to its strong toxicity and side effects, its use is limited in practical applications. The in vitro antitumor efficacy of DPPT on human prostate cancer (PCa) cells remains to be determined. The present study investigated the anticancer effect of DPPT on human PCa cells and its potential mechanism. The data revealed that DPPT markedly reduced cell proliferation and activated the caspase-3 expression level by an increase in apoptotic cell death in DU-145 cells. In addition, treatment with DPPT markedly downregulated the levels of phosphorylated Akt and activated the p53/B-cell lymphoma 2 associated X protein (Bax)/phosphatase and tensin homolog (PTEN) signaling pathway in DU-145 cells, suggesting that caspase-mediated pathways were involved in DPPT-induced apoptosis. The present study suggested the role of DPPT as a novel chemotherapeutic drug for human PCa, which may function through the Akt/p53/Bax/PTEN signaling pathway.

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Shikonin Induces Apoptosis, Necrosis, and Premature Senescence of Human A549 Lung Cancer Cells through Upregulation of p53 Expression

Cited by 44 publications

References 52 publications

Shikonin enhances Adriamycin antitumor effects by inhibiting efflux pumps in A549 cells

Shikonin enhances Adriamycin antitumor effects by inhibiting efflux pumps in A549 cells

Shikonin induces apoptosis and prosurvival autophagy in human melanoma A375 cells via ROS-mediated ER stress and p38 pathways

Anticancer effect of deoxypodophyllotoxin induces apoptosis of human prostate cancer cells

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