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

ArticleinCancer Letters 259(1):82-98 · February 2008with18 Reads
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.
    • "Plumbagin (5-hydroxy, 2-methyl, 1,4-naphthoquinone, PB) is used widely in experimental systems. Anti-proliferative activity of plumbagin has been proved in breast cancers, cervical cancers, lung cancers, melanomas, prostate cancers and ovarian cancers but with varying sensitivities wherein an IC 50 < 5 M was effective in breast, prostate, ovarian and cervical cancers, but an IC 50 > 14 M was effective in case of lung cancers and melanomas (Hsu et al., 2006; Kuo et al., 2006; Powolny and Singh, 2008; Srinivas et al., 2004a Srinivas et al., , 2004b Wang et al., 2008; Xu and Lu, 2010). We have earlier shown that the anti-carcinogenic activity of PB in human cervical cancer cells is mainly through ROS induction which then activates a plethora of downstream targets to produce a number of varied cellular effects (Srinivas et al., 2004b). "
    [Show abstract] [Hide abstract] ABSTRACT: The identification of various biomolecules in cancer progression and therapy has led to the exploration of the roles of two cardinal players, namely Nitric Oxide (NO) and Reactive Oxygen Species (ROS) in cancer. Both ROS and NO display bimodal fashions of functional activity in a concentration dependent manner, by inducing either pro- or anti- tumorigenic signals. Researchers have identified the potential capability of NO and ROS in therapies owing to their role in eliciting pro-apoptotic signals at higher concentrations and their ability to sensitize cancer cells to one another as well as to other therapeutics. We review the prospects of NO and ROS in cancer progression and therapy, and analyze the role of a combinatorial therapy wherein an NO donor (SNAP) is used to sensitize the oxidative damage repair defective, triple negative breast cancer cells (HCC 1937) to a potent ROS inducer. Preliminary findings support the potential to employ various combinatorial regimes for anti-cancer therapies with regard to exploiting the chemo-sensitization property of NO donors.
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    • "The photochemical interactions of the PS, light and molecular oxygen producing reactive oxygen species known as ROS, results in damage to organelles within malignant cells and can lead to tumor ablation [3]. Membranous organelles, including mitochondria, plasma membrane, and lysosomes, have been suggested to be the main sites of PDT damage [5]. Apoptosis and necrosis after PDT has been demonstrated in vitro and in vivo, but the mechanism of PDT-induced cell death is unknown [4,10,12]. "
    Full-text · Dataset · Feb 2016 · BMC Cancer
    • "MDM2 is an oncoprotein that can regulate the cell cycle and is a negative regulator of p21, which is required for cell cycle arrest in the G2/M2 phase [16, 17]. Several studies have reported that some compounds inducing ROS generation, including diallyl trisulfide [23], plumbagin [33], and diallyl disulfide [25], could induce cell cycle arrest at the G2/M phase in several cancer cells. Here, we also found the WZ35-induced G2/M arrest was reversed by co-treatment with an ROS scavenger (Fig. 5 ). "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Prostate cancer is the most commonly diagnosed malignancy among men. The Discovery of new agents for the treatment of prostate cancer is urgently needed. Compound WZ35, a novel analog of the natural product curcumin, exhibited good anti-prostate cancer activity, with an IC50 of 2.2 μM in PC-3 cells. However, the underlying mechanism of WZ35 against prostate cancer cells is still unclear. Methods: Human prostate cancer PC-3 cells and DU145 cells were treated with WZ35 for further proliferation, apoptosis, cell cycle, and mechanism analyses. NAC and CHOP siRNA were used to validate the role of ROS and ER stress, respectively, in the anti-cancer actions of WZ35. Results: Our results show that WZ35 exhibited much higher cell growth inhibition than curcumin by inducing ER stress-dependent cell apoptosis in human prostate cells. The reduction of CHOP expression by siRNA partially abrogated WZ35-induced cell apoptosis. WZ35 also dose-dependently induced cell cycle arrest in the G2/M phase. Furthermore, we found that WZ35 treatment for 30 min significantly induced reactive oxygen species (ROS) production in PC-3 cells. Co-treatment with the ROS scavenger NAC completely abrogated the induction of WZ35 on cell apoptosis, ER stress activation, and cell cycle arrest, indicating an upstream role of ROS generation in mediating the anti-cancer effect of WZ35. Conclusions: Taken together, this work presents the novel anticancer candidate WZ35 for the treatment of prostate cancer, and importantly, reveals that increased ROS generation might be an effective strategy in human prostate cancer treatment.
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