Anticancer Agent Shikonin Is an Incompetent Inducer of Cancer Drug Resistance

Wu, Hao; Xie, Jiaxin; Pan, Qiangrong; Wang, Beibei; Hu, Danqing; Hu, Xun

doi:10.1371/journal.pone.0052706

Cited by 51 publications

(52 citation statements)

References 49 publications

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“…The IC 50 value was 12.75 ± 0.84 mol·L -1 after 72 h treatment, 24.82 ± 0.94 mol·L -1 after 48 h, and 61.41 ± 1.08 mol·L -1 after 24 h. In the present investigation, geraniin revealed growth inhibitory activity against A549 cells, which was superior to shikonin after treatments of 72 and 48 h and showed a similar result to shikonin after 24 h (Fig. 1) (Wu et al 2013). …”

Section: Cytotoxicity Of Geraniin In Vitrosupporting

confidence: 65%

Geraniin induces apoptotic cell death in human lung adenocarcinoma A549 cells in vitro and in vivo

Wang

Yin

et al. 2013

Can. J. Physiol. Pharmacol.

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Geraniin has previously been reported to possess extensive biological activity. In this study, we reported that geraniin is an inhibitor of tumor activity in vitro and in vivo. Geraniin suppressed the proliferation of A549 cells in a dose- and time-dependent manner. Geraniin arrested the cell cycle in the S phase and induced a significant accumulation of reactive oxygen species (ROS), as well as an increased percentage of cells with mitochondrial membrane potential (MMP) disruption. Western blot analysis showed that geraniin inhibited Bcl-2 expression and induced Bax expression to disintegrate the outer mitochondrial membrane and cause cytochrome c release. Mitochondrial cytochrome c release was associated with the activation of caspase-9 and caspase-3 cascades. Additionally, geraniin resulted in tumor growth inhibition in A549 xenografts. Our results indicate cytotoxic activity of geraniin towards cancer cells in vitro and in vivo.

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Section: Cytotoxicity Of Geraniin In Vitrosupporting

confidence: 65%

Geraniin induces apoptotic cell death in human lung adenocarcinoma A549 cells in vitro and in vivo

Wang

Yin

et al. 2013

Can. J. Physiol. Pharmacol.

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“…SHK is not toxic to normal cells (25), but exerts cytotoxic effects against various neoplastic cells, and has not been demonstrated to promote anticancer drug resistance (26). However, its effects against lung cancer remain unclear.…”

Section: Introductionmentioning

confidence: 99%

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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“…Shikonin can inhibit proliferation and induce apoptosis of human HepG2 cells (Yingkun et al, 2010). As an anticancer agent, shikonin circumvents cancer drug resistance in different cell lines (K562, MCF-7, and MDR cell K562/Adr) (Han et al, 2007;Wu et al, 2013). The results of the present study showed that shikonin inhibited proliferation and induced apoptosis of R-HepG2 cells.…”

Section: Discussionmentioning

confidence: 48%

Effect of shikonin on multidrug resistance in HepG2: The role of SIRT1

Jin

Ren

et al. 2014

Pharmaceutical Biology

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Context: Overexpression of SIRT1 is considered to enhance the resistance of HepG2 cells to irradiation. Shikonin, a naturally occurring naphthoquinone compound, displays anticancer effects and circumvents cancer drug resistance. Objectives: This study investigated the MDR reversal effect of shikonin induced by the overexpression of SIRT1. Materials and methods: The overexpression of SIRT1 in HepG2 cells was established by lentivirus infection. Five days after transduction, real-time quantitative polymerase chain reaction and western blotting were used to detect the expression of SIRT1 and MDR1/P-gp. Drug resistance was also evaluated by flow cytometry after rhodamine-123 staining. On day 5, the multidrug resistance cells were treated by shikonin (10 À7, 10 À6 , and 10 À5 mmol/L) one time. The cell viability was detected by the MTT assay, and apoptosis was evaluated by Hoechst 33342 staining and caspase-3 activity 24 h after shikonin treatment. Results: Overexpression of SIRT1 decreased rhodamine-123 staining and successfully produced the R-HepG2 cell line. Compared with HepG2, the expression of MDR1/P-gp mRNA (3.45 ± 0.35) and protein (1.40 ± 0.05) were both upregulated in R-HepG2. Shikonin inhibited cell viability (from 93.9 ± 2.1 to 66.7 ± 1.5%), induced apoptosis of R-HepG2 (apoptotic ratio from 3.5 ± 0.8 to 47.5 ± 2.7%, caspase-3 activity from 103.5 ± 1.9 to 329.2 ± 14.9%, respectively), downregulated the mRNA and protein expression of SIRT1 and MDR1/P-gp, and decreased rhodamin 123 efflux. Discussion and conclusion: In the present study, we demonstrated that shikonin is able to overcome drug resistance in hepatocellular carcinoma cells, and the mechanism is related to the SIRT1-MDR1/P-gp signaling pathway.

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Anticancer Agent Shikonin Is an Incompetent Inducer of Cancer Drug Resistance

Cited by 51 publications

References 49 publications

Geraniin induces apoptotic cell death in human lung adenocarcinoma A549 cells in vitro and in vivo

Geraniin induces apoptotic cell death in human lung adenocarcinoma A549 cells in vitro and in vivo

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

Effect of shikonin on multidrug resistance in HepG2: The role of SIRT1

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