Induction of apoptosis by sanguinarine in C6 rat glioblastoma cells is associated with the modulation of the Bcl-2 family and activation of caspases through downregulation of extracellular signal-regulated kinase and Akt

Department of Biomaterial Control (BK21 program), Dongeui University Graduate School, Busan, South Korea.
Anti-Cancer Drugs (Impact Factor: 1.78). 10/2007; 18(8):913-21. DOI: 10.1097/CAD.0b013e328117f463
Source: PubMed


Sanguinarine is a benzophenanthridine alkaloid that is derived from the root of Sanguinaria canadensis and other poppy fumaria species, and is known to have antimicrobial, antiinflammatory and antioxidant properties. This study investigated the possible mechanisms through which sanguinarine exerts its antiproliferative action in cultured C6 rat glioblastoma cells. The exposure of C6 cells to sanguinarine resulted in growth inhibition and the induction of apoptosis in a dose-dependent manner, as measured by the MTT assay, fluorescence microscopy, agarose gel electrophoresis and annexin-V-based assay. The sanguinarine treatment induced the proteolytic activation of caspases and ICAD/DFF45, which was associated with the modulation of the Bcl-2 family, concomitant degradation of poly(ADP ribose) polymerase and phospholipase C-gamma1 protein, and DNA fragmentation. z-DEVD-fmk, a caspase-3-specific inhibitor, blocked poly(ADP ribose) polymerase degradation, DNA fragmentation and increased the survival rate of sanguinarine-treated C6 cells. Moreover, the activity of extracellular signal-regulated kinase and Akt was downregulated in sanguinarine-treated cells, and PD98059, a specific extracellular signal-regulated kinase inhibitor, and phosphatidylinositol 3'-kinase/Akt inhibitors, LY294002 and wortmanin, sensitized the cells to sanguinarine-induced apoptosis, indicating that the downregulation of the extracellular signal-regulated kinase and Akt signaling pathway may play a key role in sanguinarine-induced apoptosis in C6 cells.

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    • "It has been shown to act as a potent inhibitor of NF-κB acti- vation, IκBα phosphorylation and degradation (Chaturvedi et al., 1997). The alkaloid is a potential lead compound in cancer therapy inducing apoptosis in a variety of cancer cells through various mechanisms (Adhami et al., 2004; Ahsan, Reagan-Shaw, Breur, & Ahmad, 2007; Debiton, Madelmont, Legault, & Barthomeuf, 2003; Han et al., 2007; Hussain et al., 2007; Kim et al., 2008). Nucleic acid binding and topoisomerase inhibition properties of sanguinarine have also been linked to its pronounced anticancer activity (Holy, Lamont, & Perkins, 2006; Maiti & Suresh Kumar, 2007, 2009, 2010). "
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    ABSTRACT: The interaction of the natural plant alkaloid and anticancer agent sanguinarine with tRNA(phe) has been investigated by spectroscopic and calorimetric techniques. Sanguinarine iminium binds to tRNA(phe) cooperatively; alkanolamine does not bind but in presence of large tRNA(phe) concentration, a conversion from alkanolamine to iminium occurs resulting in concomitant binding of the latter. The binding affinity of the iminium to tRNA(phe) obtained from isothermal titration calorimetry was of the order of 10(5) M(-1), which is close to that evaluated from spectroscopy. The binding was driven largely by negative enthalpy and a smaller but favourable positive entropy change. The binding was dependent on the [Na(+)] concentration, but had a larger non-electrostatic contribution to the Gibbs energy. A small heat capacity value and the enthalpy-entropy compensation in the energetics of the interaction characterized the binding of the iminium form to tRNA(phe). This study confirms that the tRNA(phe) binding moiety is the iminium form of sanguinarine.
    Journal of biomolecular Structure & Dynamics 06/2012; 30(2):223-34. DOI:10.1080/07391102.2012.677774 · 2.92 Impact Factor
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    • "In contrast to primary mouse spleen cells, leukemic L1210 cells showed slightly higher sensitivity to sanguinarine, suggesting that cytotoxic and DNA damaging effects of sanguinarine are more selective against mouse leukemic cells and primary mouse spleen cells [188]. Han et al. [189] investigated the possible mechanism through which sanguinarine exerts its antiproliferative action in cultured rat glioblastoma cells and suggested the induction of apoptosis to be due to the downregulation of the extra cellular signal regulated kinase and Akt signaling pathway. The effect of sanguinarine on the human cells line HeLa (Cervix carcinoma cells) has been studied [190] and the results showed a strong killing effect of sanguinarine which was explained as a consequence of its easy penetration through cell membrane owing to nonpolar pesudobase formation and to a high degree of molecular planarity. "
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    ABSTRACT: Bioactive alkaloids occupy an important position in applied chemistry and play an indispensable role in medicinal chemistry. Amongst them, isoquinoline alkaloids like berberine, palmatine and coralyne of protoberberine group, sanguinarine of the benzophenanthridine group, and their derivatives represent an important class of molecules for their broad range of clinical and pharmacological utility. In view of their extensive occurrence in various plant species and significantly low toxicities, prospective development and use of these alkaloids as effective anticancer agents are matters of great current interest. This review has focused on the interaction of these alkaloids with polymorphic nucleic acid structures (B-form, A-form, Z-form, H(L)-form, triple helical form, quadruplex form) and their topoisomerase inhibitory activity reported by several research groups using various biophysical techniques like spectrophotometry, spectrofluorimetry, thermal melting, circular dichroism, NMR spectroscopy, electrospray ionization mass spectroscopy, viscosity, isothermal titration calorimetry, differential scanning calorimetry, molecular modeling studies, and so forth, to elucidate their mode and mechanism of action for structure-activity relationships. The DNA binding of the planar sanguinarine and coralyne are found to be stronger and thermodynamically more favoured compared to the buckled structure of berberine and palmatine and correlate well with the intercalative mechanism of sanguinarine and coralyne and the partial intercalation by berberine and palmatine. Nucleic acid binding properties are also interpreted in relation to their anticancer activity.
    Journal of nucleic acids 01/2010; 2010. DOI:10.4061/2010/593408
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    ABSTRACT: Previous studies have suggested that phytomedicinal preparations from bloodroot (Sanguinaria canadensis L.) may harbor immunomodulatory properties. The purpose of this investigation was to determine the effects of alcohol tinctures and water infusions generated from bloodroot flowers, leaves, rhizomes, and roots on human peripheral blood mononuclear cell (PBMC) cytokine production and proliferation in vitro. PBMCs were collected from 16 healthy young adults and cultured with bloodroot extracts or respective controls for interleukins-1β, -2, -8, -10, interferon-γ, and tumor necrosis factor. Proliferative capabilities of both PBMCs and K562 cells (an immortalized human myelogenous leukemia cell line) following extract treatment were determined. High-pressure liquid chromatography was used to quantify berberine, chelerythrine, and sanguinarine in the extracts and to correlate extract composition with observed effects. Overall, infusions demonstrated greater immunomodulatory capabilities than tinctures, and flower- and root-based extracts showed greater immunomodulatory properties than leaf- or rhizome-based extracts (some effects seen with root-based extracts may be due to endotoxin). Several extracts were able to augment PBMC proliferation and diminish K562 proliferation, suggesting a selective anti-carcinogenic activity. The rhizome alcohol tincture had a markedly stronger effect against K562 cells than other extracts. Chelerythrine, sanguinarine, and endotoxin (but not berberine) sometimes correlated with observed effects. The in vitro activities demonstrated here suggest bloodroot extracts may have potential as therapeutic immunomodulators.
    Journal of Herbs Spices & Medicinal Plants 01/2009; 15(1):45. DOI:10.1080/10496470902787485
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