Marine Cyanobacteria Compounds with Anticancer Properties: Implication of Apoptosis

Marine cyanobacteria have been proved to be an important source of potential anticancer drugs. Although several compounds were found to be cytotoxic to cancer cells in culture, the pathways by which cells are affected are still poorly elucidated. For some compounds, cancer cell death was attributed to an implication of apoptosis through morphological apoptotic features, implication of caspases and proteins of the Bcl-2 family, and other mechanisms such as interference with microtubules dynamics, cell cycle arrest and inhibition of proteases other than caspases

Cyclized NDGA modifies dynamic α-synuclein monomers preventing aggregation and toxicity.

Growing evidence implicates α-synuclein aggregation as a key driver of neurodegeneration in Parkinson's disease (PD) and other neurodegenerative disorders. Herein, the molecular and structural mechanisms of inhibiting α-synuclein aggregation by novel analogs of nordihydroguaiaretic acid (NDGA), a phenolic dibenzenediol lignan, were explored using an array of biochemical and biophysical methodologies. NDGA analogs induced modest, progressive compaction of monomeric α-synuclein, preventing aggregation into amyloid-like fibrils. This conformational remodeling preserved the dynamic adoption of α-helical conformations, which are essential for physiological membrane interactions. Oxidation-dependent NDGA cyclization was required for the interaction with monomeric α-synuclein. NDGA analog-pretreated α-synuclein did not aggregate even without NDGA-analogs in the aggregation mixture. Strikingly, NDGA-pretreated α-synuclein suppressed aggregation of naïve untreated aggregation-competent monomeric α-synuclein. Further, cyclized NDGA reduced α-synuclein-driven neurodegeneration in Caenorhabditis elegans. The cyclized NDGA analogs may serve as a platform for the development of small molecules that stabilize aggregation-resistant α-synuclein monomers without interfering with functional conformations yielding potential therapies for PD and related disorders

ON THE MECHANISM OF ACTIVATION OF DESIGNED ENEDIYNES WITH SELECTIVE CYTOTOXICITY

A number of novel enediyne compounds such as 3 equipped with a 2-(phenylsulfonyl)ethoxycarbonyl protecting group on the nitrogen atom have demonstrated selective cytotoxicity against a variety of cancer cell lines. Compounds 4-6 possessing one or two methyl group(s) at the C2 position of the sulfone residue have been synthesized and tested, showing reduced cytotoxity as compared to 3, suggesting that a beta-elimination mechanism as the main initial step for the activation of these cytotoxic agents. The differential in the cytotoxicity of compounds 4 and 5 with opposite chirality at C2 suggests the possible existence of tumor-associated factors in certain tumor cells that may activate these systems selectively

Isoform-selective PI3K inhibitors as novel therapeutics for the treatment of acute myocardial infarction. Biochem Soc Trans 35

Abstract In the present paper, we review the preclinical development of TG100-115, a PI3K (phosphoinositide 3-kinase) γ /δ isoform-specific inhibitor currently in clinical trials for the reduction of acute MI (myocardial infarction). An overview is presented outlining the pathogenesis of acute MI and the rationale for clinical use of PI3K γ /δ-specific inhibitors in this indication. TG100-115's broad anti-inflammatory activities are described, as well as its ability to discriminate between cellular signalling pathways downstream of receptor tyrosine kinase ligands such as vascular endothelial growth factor. Finally, we review TG100-115's potent cardioprotective activities as revealed in rigorous animal models of acute MI, and, based on these data, this compound's potential for clinical utility. MI (myocardial infarction) represents the heart's attempt to manage an I/R (ischaemia/reperfusion) injury. The acute phase of infarct development initiates with an ischaemic event, the loss of regional blood flow resulting from occlusion of a major coronary vessel, which then directly induces cardiomyocyte apoptosis as well as the up-regulation of proinflammatory mediators such as VEGF (vascular endothelial growth factor) and PAF (platelet-activating factor) Reperfusion injury, by contrast, unfolds in the clinic after re-establishment of macrovascular flow (via angioplasty and/ or thrombolysis). Reperfusion generates damage in large part by fostering myocardial inflammatio

Induction of apoptosis by enediyne antibiotic calicheamicin gammaII proceeds through a caspase-mediated mitochondrial amplification loop in an entirely Bax-dependent manner

Calicheamicin {theta} variantII is a member of the enediyne class of antitumor antibiotics that bind to DNA and induce apoptosis. These compounds differ, however, from conventional anticancer drugs as they bind in a sequence-specific manner noncovalently to DNA and cause sequence-selective oxidation of deoxyriboses and bending of the DNA helix. Calicheamicin is clinically employed as immunoconjugate to antibodies directed against, for example, CD33 in the case of gemtuzumab ozogamicin. Here, we show by the use of the unconjugated drug that calicheamicin-induced apoptosis is independent from death-receptor/FADD-mediated signals. Moreover, calicheamicin triggers apoptosis in a p53-independent manner as shown by the use of p53 knockout cells. Cell death proceeds via activation of mitochondrial permeability transition, cytochrome c release and activation of caspase-9 and -3. The overexpression of Bcl-xL or Bcl-2 strongly inhibited calicheamicin-induced apoptosis. Knockout of Bax abrogated cell death after calicheamicin treatment. Thus, the activation of mitochondria and execution of cell death occur through a fully Bax-dependent mechanism. Interestingly, caspase inhibition by the pancaspase-inhibitor zVAD-fmk interfered with mitochondrial activation by calicheamicin. This places caspase activation upstream of the mitochondria and indicates that calicheamicin-triggered apoptosis is enhanced through death receptor-independent activation of the caspase cascade, that is, an amplification loop that is required for full activation of the mitochondrial pathway