Overcoming resistance to apoptosis in cancer therapy

A fundamental characteristic of cancer cells is suppression of apoptosis and increased cell survival. These properties, when combined with deregulated cell proliferation, are the basic requirements for development of cancer. Increased deregulated cell proliferation by itself paradoxically may trigger cell death pathways which prevent outgrowth of the cancer cell unless the cell death pathways are inhibited. Another consequence of the latter may he resistance to treatments that depend on induction of apoptosis in the cancer cell. These widely held concepts have given rise to intense study of the antiapoptotic mechanisms generated in different cancer cells that are driven by different oncogenic stimuli and how these mechanisms may operate against different therapies used against cancers. The mechanisms by which different therapies induce apoptosis are in turn poorly understood and answers to both questions are needed in development of effective treatment approaches. In the following sections, we review recent information about regulation of apoptosis, how oncogenes interact with apoptotic pathways, and some of the therapeutic opportunities that are developing as a consequence of this information. Emphasis is given to studies on melanoma as a model system in these developments

Simvastatin enhances irinotecan-induced apoptosis in prostate cancer via inhibition of MCL-1

Prostate cancer is one of the most common malignant tumors around the world. Hyperlipidemia is considered as one of the most important risk factors for the development of prostate cancer. Simvastatin is widely used for the treatment of hyperlipidemia and was previously shown to induce apoptosis in several cancer types including lung, colon, pancreas, breast, and prostate cancer. In this study we aimed to explore the potential role of simvastatin in enhancing irinotecan-induced apoptosis in prostate cancer cells. In addition, the underlying molecular mechanisms driving this potential effect of simvastatin were also explored. PC3 cells were treated with simvastatin, irinotecan or combination. Cell viability was assessed by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) colorimetric assay. Flow cytometry technique was used to analyze apoptosis and cell cycle progression. Western blot was used for detection of protein expression. Results showed that simvastatin has a significant anti-proliferative activity on PC3 cells. Combined treatment of simvastatin with irinotecan exhibited a significant inhibition of PC3 cell growth compared to each treatment alone. Flow cytometry analysis showed that PC3 cell treatment with simvastatin and irinotecan combination demonstrated a remarkable increase in the percentage of apoptotic cells and those accumulated at G0/G1 phase when compared to each treatment alone. Moreover, induction of apoptosis was caspase-independent. Western blot showed that apoptosis was accompanied by upregulation of GRP-78 level and downregulation of Mcl-1 levels in a time-dependent manner. The results of this study demonstrated that combined treatment of simvastatin with chemotherapeutic agents such as irinotecan resulted in enhancement of growth inhibition and induction of prostate cancer cell apoptosis

Altholactone Displays Promising Antimicrobial Activity

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5-Fluorouracil-induced apoptosis in colorectal cancer cells is caspase-9-dependent and mediated by activation of protein kinase C-d

Elucidation of the molecular mechanisms by which 5-fluorouracil (5-FU) induces apoptosis is required in order to understand the resistance of colorectal cancer (CRC) cells to 5-FU. In the current study, 5-FU-induced apoptosis was assessed using the propidium iodide method. Involvement of protein kinase C (PKC) was assessed by evaluating the extent of their activation in CRC, following treatment with 5-FU, using biochemical inhibitors and western blot analysis. The results revealed that 5-FU induces varying degrees of apoptosis in CRC cells; HCT116 cells were identified to be the most sensitive cells and SW480 were the least sensitive. In addition, 5-FU-induced apoptosis was caspase-dependent as it appeared to be initiated by caspase-9. Furthermore, PKCe was marginally expressed in CRC cells and no changes were observed in the levels of cleavage or phosphorylation following treatment with 5-FU. The treatment of HCT116 cells with 5-FU increased the expression, phosphorylation and cleavage of PKCd. The inhibition of PKCd was found to significantly inhibit 5-FU-induced apoptosis. These results indicated that 5-FU induces apoptosis in CRC by the activation of PKCd and caspase-9. In addition, the levels of PKCd activation may determine the sensitivity of CRC to 5-FU

Antibacterial activity of statins: a comparative study of Atorvastatin, Simvastatin, and Rosuvastatin

Abstract Background Statins have several effects beyond their well-known antihyperlipidemic activity, which include immunomodulatory, antioxidative and anticoagulant effects. In this study, we have tested the possible antimicrobial activity of statins against a range of standard bacterial strains and bacterial clinical isolates. Methods Minimum inhibitory concentrations (MIC) values were evaluated and compared among three members of the statins drug (atorvastatin, simvastatin, and rosuvastatin). Results It was revealed that statins are able to induce variable degrees of antibacterial activity with atorvastatin, and simvastatin being the more potent than rosuvastatin. Methicillin-sensitive staphylococcus aureus (MSSA), methicillin-resistant staphylococcus aureus (MRSA), vancomycin-susceptible enterococci (VSE), vancomycin-resistant enterococcus (VRE), acinetobacter baumannii, staphylococcus epidermidis, and enterobacter aerogenes, were more sensitive to both atorvastatin, and simvastatin compared to rosuvastatin. On the other hand, escherichia coli, proteus mirabilis, and enterobacter cloacae were more sensitive to atorvastatin compared to both simvastatin and rosuvastatin. Furthermore, most clinical isolates were less sensitive to statins compared to their corresponding standard strains. Conclusion Our findings might raise the possibility of a potentially important antibacterial class effect for statins especially, atorvastatin and simvastatin.</p

Generation of the First Structure-Based Pharmacophore Model Containing a Selective “Zinc Binding Group” Feature to Identify Potential Glyoxalase-1 Inhibitors

Within this study, a unique 3D structure-based pharmacophore model of the enzyme glyoxalase-1 (Glo-1) has been revealed. Glo-1 is considered a zinc metalloenzyme in which the inhibitor binding with zinc atom at the active site is crucial. To our knowledge, this is the first pharmacophore model that has a selective feature for a “zinc binding group” which has been customized within the structure-based pharmacophore model of Glo-1 to extract ligands that possess functional groups able to bind zinc atom solely from database screening. In addition, an extensive 2D similarity search using three diverse similarity techniques (Tanimoto, Dice, Cosine) has been performed over the commercially available “Zinc Clean Drug-Like Database” that contains around 10 million compounds to help find suitable inhibitors for this enzyme based on known inhibitors from the literature. The resultant hits were mapped over the structure based pharmacophore and the successful hits were further docked using three docking programs with different pose fitting and scoring techniques (GOLD, LibDock, CDOCKER). Nine candidates were suggested to be novel Glo-1 inhibitors containing the “zinc binding group” with the highest consensus scoring from docking