Plumbagin induces cell cycle arrest and apoptosis through reactive oxygen species/c-Jun N-terminal kinase pathways in human melanoma A375.S2 cells

Department of Chemistry, University of Southern California, College of Letters, Arts, and Sciences, University Park Campus, Los Angeles, CA 90089, USA.
Cancer Letters (Impact Factor: 5.62). 02/2008; 259(1):82-98. DOI: 10.1016/j.canlet.2007.10.005
Source: PubMed


This study is the first to investigate the anticancer effect of plumbagin in human melanoma A375.S2 cells. Plumbagin exhibited effective cell growth inhibition by inducing cancer cells to undergo S-G2/M phase arrest and apoptosis. Further investigation revealed that plumbagin's inhibition of cell growth was also evident in a nude mice model. Blockade of cell cycle was associated with increased levels of p21, and reduced amounts of cyclin B1, cyclin A, Cdc2, and Cdc25C. Plumbagin also enhanced the levels of inactivated phosphorylated Cdc2 and Cdc25C. Plumbagin triggered the mitochondrial apoptotic pathway indicated by a change in Bax/Bcl-2 ratios, resulting in caspase-9 activation. We also found the generation of ROS is a critical mediator in plumbagin-induced cell growth inhibition. Plumbagin increased the activation of apoptosis signal-regulating kinase 1, JNK and extracellular signal-regulated kinase 1/2 (ERK1/2), but not p38. In addition, antioxidants vitamin C and catalase significantly decreased plumbagin-mediated c-Jun N-terminal kinase (JNK) activation and apoptosis. Moreover, blocking ERK and JNK by specific inhibitors suppressed plumbagin-triggered mitochondrial apoptotic pathway. Taken together, these results imply a critical role for ROS and JNK in the plumbagin's anticancer activity.

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    • "Plumbagin has been shown to exert anticancer (Gomathinayagam et al. 2008; Parimala and Sachdanandam 1993) and antiproliferative activities (Poosarla et al. 2011) in animal models as well as in in vitro cultures. Plumbagin has been shown to induce apoptosis in different cell types (Hsu et al. 2006; Srinivas et al. 2004; Wang et al. 2008) and inhibition of cell proliferation by inducing G2-M arrest and autophagic cell death. It is reported to be toxic for keratinocytes and cervical cancer cells by changing the redox status of the cells (Inbaraj and Chignell 2004; Nair et al. 2008). "
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    ABSTRACT: This study focused on enhancing the produc-tion of plumbagin, an anticancer compound, in embryo-genic cell suspension cultures of Plumbago rosea. Elicitation techniques have been reported to enhance plumbagin production. Cell suspension cultures raised from embryogenic calli induced from in vitro leaf explants were exposed to different concentrations of jasmonic acid, yeast extract and different auxin combinations. Influence of these on cell growth, biomass and plumbagin production was studied. To our knowledge this is the first report on elicitation of embryogenic cell suspension cultures of P. rosea for enhanced plumbagin production. Elicitor treated suspension cultures exhibited decreased culture viability and increased plumbagin synthesis. A maximum of 5.59-fold enhancement of plumbagin production was observed in cultures added with 1 mg L -1 naphthalene acetic acid after 6 days of incubation. Viability of cultures decreased with increased concentration of elicitors and prolonged incubation period. Application of elicitors in cell suspen-sion cultures induces defense related responses which lead to increased secondary metabolite production for making the cells adapt to the situation. If the stressed condition persists or is in intolerable level this will eventually lead to programmed cell death and loss of culture viability.
    Full-text · Article · Nov 2014 · Plant Cell Tissue and Organ Culture
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    • "Plumbagin, is a natural napthaquinone, possessing various pharmacological activities namely antimalarial, antimicrobial, anticancer, cardiotonic, antibiotic, and antineoplastic activities.[111325] Potential role of plumbagin, as an anti-cancer agent has been recognize[24262728] and its anti-cancer effects have been reported in diverse cancer models such as prostate[29], lung[3031], cervical[3233], ovarian[34] as well as melanoma.[34] "
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    ABSTRACT: Background: Plumbago rosea is used in traditional systems of medicine for the preparation of formulations used for treating inflammations, cough, bronchitis, and gastrointestinal disorders, and also in conjunction with cancer chemotherapy. In the present study, the cytotoxic and anti-proliferative effects of plumbagin, and the ethanolic root extract of P. rosea (ETPR) was evaluated on SK-MEL 28 melanoma cell lines and human lymphocytes. Materials and Methods: MTT and apoptotic assays were used for the evaluation of cytotoxic and anti-proliferative effects, respectively. In addition, the effect of Plumbagin and ETPR in down regulation of BCL-2 expression is investigated using RT-PCR analysis. Results: Both plumbagin and ETPR dose-dependently decreased the cell viability more potently in melanoma cell lines. P. rosea extract demonstrated significant synergy in inhibiting BCL-2 expression than plumbagin. Moreover plumbagin showed more toxicity in human lymphocytes. Conclusion: Plumbagin has anti-cancer potential, but the side effects limits its use; yet plumbagin, in combination with other ingredients in Plumbago rosea extract, displays significant synergy leading to a stronger anticancer effect with significantly less toxicity.
    Full-text · Article · Aug 2014 · Pharmacognosy Research
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    • "Data presented here indicated that 5 and 10 μM plumbagin were able to inhibit cell proliferation and induce apoptosis in cancer cells. The range of concentrations used was consistent with many other studies that investigated the antitumour effect of plumbagin in cultured cancer cells [13,35,43]. "
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    ABSTRACT: Background Plumbagin, a quinonoid constituent isolated from the root of Plumbago zeylanica L., has been proven to possess anti-tumor activity both in vitro and in vivo. However, its anti-tumor properties for human tongue carcinoma have not been reported. This study aimed to investigate the inhibitory effect and the underlying mechanism of plumbagin on the growth of human tongue carcinoma cells. Material/Methods Cell proliferation ability was detected by EdU incorporation assay and colony formation assay. Cell-cycle distribution was determined by flow cytometric analysis using propidium iodide (PI) staining. Cellular apoptosis was then evaluated by flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Western blotting was applied to assay the expression of Bax and Bcl-2. Results Plumbagin inhibited the growth and proliferation of Tca8113 cells in vitro in a concentration- and time-dependent manner. The cell cycles of plumbagin-treated Tca8113 cells were arrested at the G2/M phase. Cells treated with plumbagin presented the characteristic morphological changes of apoptosis. The ratio of Bax/Bcl-2 was raised by plumbagin in a concentration-dependent manner. Conclusions These results indicate that plumbagin induces the apoptosis of Tca8113 cells through mitochondria-mediated pathway.
    Full-text · Article · Aug 2013
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