Hormetic effect of low doses of rapamycin triggers anti-aging cascades in WRL-68 cells by modulating an mTOR-mitochondria cross-talk.

BACKGROUND: Rapamycin is hormetic in nature-it demonstrates contrasting effects at high and low doses. It is toxic at moderate/high doses, while it can restrain aging and extend lifespan at low doses. However, it is not fully understood how rapamycin governs cellular aging. On the other hand, aging is putatively correlated to mitochondrial dysregulation. Although previous studies have suggested that hormetic (low) doses of rapamycin can cause partial/incomplete inhibition of mTOR, the actual modus operandi of how such partial mTOR inhibition might modulate the mTOR-mitochondria cross-talk remained to be deciphered in the context of cellular aging. The present study was designed to understand the hormetic effects of rapamycin on cellular factors that govern aging-associated changes in mitochondrial facets, such as functional and metabolic homeostases, sustenance of membrane potential, biogenesis, mitophagy, and oxidative injury to mitochondrial macromolecules. METHODS AND RESULTS: WRL-68 cells treated (24 h) with variable doses of rapamycin were studied for estimating their viability, apoptosis, senescence, mitochondrial density and Δψm. Expression levels of key functional proteins were estimated by immunofluorescence/immunoblots. Oxidative damage to mtDNA/mtRNA/proteins was measured in mitochondrial lysates. We demonstrated that hormetic doses (0.1 and 1 nM) of rapamycin can alleviate aging-associated mitochondrial dyshomeostasis in WRL-68 cells, such as oxidative injury to mitochondrial nucleic acids and proteins, as well as disequilibrium of mitochondrial density, membrane potential, biogenesis, mitophagy and overall metabolism. CONCLUSIONS: We established that low doses of rapamycin can hormetically amend the mTOR-mitochondria cross-talk, and can consequently promote anti-aging outcome in cells.

Microtubule motors in centrosome homeostasis: A target for cancer therapy?

Cancer is a grievous concern to human health, owing to a massive heterogeneity in its cause and impact. Dysregulation (numerical, positional and/or structural) of centrosomes is one of the notable factors among those that promote onset and progression of cancers. In a normal dividing cell, a pair of centrosomes forms two poles, thereby governing the formation of a bipolar spindle assembly. A large number of cancer cells, however, harbor supernumerary centrosomes, which mimic the bipolar arrangement in normal cells by centrosome clustering (CC) into two opposite poles, thus developing a pseudo-bipolar spindle assembly. Manipulation of centrosome homeostasis is the paramount pre-requisite for the evasive strategy of CC in cancers. Out of the varied factors that uphold centrosome integrity, microtubule motors (MiMos) play a critical role. Categorized as dyneins and kinesins, MiMos are involved in cohesion of centrosomes, and also facilitate the maintenance of the numerical, positional and structural integrity of centrosomes. Herein, we elucidate the decisive mechanisms undertaken by MiMos to mediate centrosome homeostasis, and how dysregulation of the same might lead to CC in cancer cells. Understanding the impact of MiMos on CC might open up avenues toward a credible therapeutic target against diverse cancers.

A novel indenone derivative selectively induces senescence in MDA-MB-231 (breast adenocarcinoma) cells.

Triple-negative breast cancer is the most aggressive form of breast cancer with limited intervention options. Moreover, a number of belligerent therapeutic strategies adopted to treat such aggressive forms of cancer have demonstrated detrimental side effects. This necessitates exploration of targeted chemotherapeutics. We assessed the efficacy of a novel indenone derivative (nID) [(±)-N-(2-(-5-methoxy-1-oxo-3-(2-oxo-2-phenylethyl)-2,3-dihydro-1H-inden-2-yl)ethyl)-4-methylbenzenesulfonamide], synthesized by a novel internal nucleophile-assisted palladium-catalyzed hydration-olefin insertion cascade; against triple-negative breast cancer cells (MDA-MB-231). On 24 h treatment, the nID caused decline in the viability of MDA-MB-231 and MDA-MB-468 cells, but did not significantly (P < 0.05) affect WRL-68 (epithelial-like) cells. In fact, the nID demonstrated augmentation of p53 expression, and consequent p53-dependent senescence in both MDA-MB-231 and MDA-MB-468 cells, but not in WRL-68 cells. The breast cancer cells also exhibited reduced proliferation, downregulated p65/NF-κB and survivin, along with augmented p21Cip1/WAF1 expression, on treatment with the nID. This ensued cell cycle arrest at G1 stage, which might have driven the MDA-MB-231 cells to senescence. We observed a selectivity of the nID to target MDA-MB-231 cells, whereas WRL-68 cells did not show any considerable effect. The results underscored that the nID has potential to be developed into a cancer therapeutic.

Friend turned foe: A curious case of disrupted endosymbiotic homeostasis promoting the Warburg effect in sepsis.

Sepsis is a grievous health concern with limited understanding of its precise etiology. Although studies on sepsis have implicated the Warburg effect (mitigation of mitochondrial oxidative phosphorylation, as evident from aerobic glycolysis), we propose that an evolutionary perspective might further unravel its etiology. The endosymbiotic theory suggests that evolution of a eukaryotic cell is a consequence of the fruitful association between an archaea (Asgard) and an alphaproteobacterium (Rickettsia). We hypothesize that, during pathological conditions like sepsis, such endosymbiotic homeostasis between the two systems is perturbed. We underscore the fact (supported by in silico homology analyses) that during sepsis, the Asgard component of a cell is promoted to trigger aerobic glycolysis as well as the innate immune response (spearheaded by the TLR pathway), while suppressing the Rickettsia counterpart, thereby promoting the Warburg effect. It might be this discord between the two endosymbiotic partners (Asgard and Rickettsia-derived cellular components) that promotes sepsis.

Hexavalent chromium-induced autophagic death of WRL-68 cells is mitigated by aqueous extract of Cuminum cyminum L. seeds.

In this study, we assessed the potential of aqueous extract (CSEaq) of Cuminum cyminum L. (cumin) seeds in protecting WRL-68 cells from hexavalent chromium [Cr(VI)]-induced oxidative injury. Cells exposed to Cr(VI) (10 µM CrO3) for 24 h demonstrated a twofold increase in ROS, which, in turn, led to extensive oxidative stress, consequently causing colossal decline in cell viability (by 58.82 ± 9.79%) and proliferation (as was evident from a reduced expression of Ki-67, a proliferation marker). Immunofluorescence studies showed that Cr(VI) diminished the expressions of mTOR and survivin in WRL-68 cells. It also led to a substantial elevation of BECN1 expression, which suggested autophagy. Overall, our results indicated that 24 h exposure of WRL-68 cells to Cr(VI) caused oxidative stress-induced autophagic cell death. CSEaq was found to protect WRL-68 cells from the same fate by refurbishing their viability and proliferation in a dose-dependent manner. The extract reduced ROS in these cells, which consequently decreased the degree of autophagic cell death by restoring expressions of mTOR, survivin and BECN1 to their respective normal levels. Biochemical assays revealed that CSEaq is rich in phenolic constituents. Total phenolic content of CSEaq demonstrated positive correlations with (i) its antioxidant potential, (ii) its alleviation of cellular oxidative stress and (iii) its cytoprotective efficacy in Cr(VI)-treated WRL-68 cells. We also identified the major phenolic constituents of CSEaq. Our study suggested that polyphenols in CSEaq might be responsible for protecting WRL-68 cells from Cr(VI)-governed oxidative assault that would have otherwise led to survivin/mTOR-mediated autophagic death.

Gene therapy for the mitochondrial genome: Purging mutations, pacifying ailments.

In the recent years, the reported cases of mitochondrial disorders have reached a colossal number. These disorders spawn a sundry of pathological conditions, which lead to pernicious symptoms and even fatality. Due to the unpredictable etiologies, mitochondrial diseases are putatively referred to as "mystondria" (mysterious diseases of mitochondria). Although present-day research has greatly improved our understanding of mitochondrial disorders, effective therapeutic interventions are still at the precursory stage. The conundrum becomes further complicated because these pathologies might occur due to either mitochondrial DNA (mtDNA) mutations or due to mutations in the nuclear DNA (nDNA), or both. While correcting nDNA mutations by using gene therapy (replacement of defective genes by delivering wild-type (WT) ones into the host cell, or silencing a dominant mutant allele that is pathogenic) has emerged as a promising strategy to address some mitochondrial diseases, the complications in correcting the defects of mtDNA in order to renovate mitochondrial functions have remained a steep challenge. In this review, we focus specifically on the selective gene therapy strategies that have demonstrated prospects in targeting the pathological mutations in the mitochondrial genome, thereby treating mitochondrial ailments.

Cancer chemotherapeutics in rheumatoid arthritis: A convoluted connection.

Chemotherapy is one of the most popular therapeutic strategies to treat cancer. However, cancer chemotherapeutics have often been associated with impairment of the immune system, which might consequently lead to an augmented risk of autoimmune disorders, such as rheumatoid arthritis. Though the accurate mechanistic facets of rheumatoid arthritis induction have not been interpreted yet, a conglomeration of genetic and environmental factors might promote its etiology. What makes the scenario more challenging is that patients with rheumatoid arthritis are at a significantly elevated risk of developing various types of cancer. It is intriguing to note that diverse cancer chemotherapy drugs are also commonly used to treat symptoms of rheumatoid arthritis. However, a colossal multitude of such cancer therapeutics has demonstrated highly varied results in rheumatoid arthritis patients, including both beneficial and adverse effects. Herein, we attempt to present a holistic account of the variegated modalities of this complex tripartite cross-talk between cancer, rheumatoid arthritis and chemotherapy drugs in order to decode the sinuous correlation between these two appalling pathological conditions.

CNS Hemangiopericytoma: A Systematic Review of 523 Patients.

BACKGROUND: Central nervous system (CNS) hemangiopericytomas are rare mesenchymal tumors of the brain. In the absence of randomized clinical trials or large studies, the only information we have about the natural history and the management is from isolated clinical case series. They have suggested that surgery is beneficial, with conflicting results on the role of complete resection and adjuvant radiation. We have conducted a systematic review of clinical case series of CNS hemangiopericytoma analyzing the biology of the tumor and the best follow-up and management strategy. METHODS: Fifteen pertinent clinical case series on newly diagnosed CNS hemangiopericytoma were selected by a review of literature. A total of 523 patients were analyzed for age, sex, mode of recurrence and metastases, and survival after complete/incomplete resection with or without radiation. RESULTS: The mean age was found to be 44.17 (±3.59) years. The incidence was higher in male individuals younger than 45 years and in older female individuals. Complete resection and adjuvant radiation significantly improved survival in comparison with incomplete resection and no radiation, respectively (P<0.0001). Furthermore, a significant trend of the tumor to recur locally compared with extraneural and neural axis metastases was noted (P<0.0001). The mean time for distant metastases was seen to be 91.33 (±12.66) months. CONCLUSIONS: Complete resection followed by adjuvant radiation improves survival. Extraneural metastases, especially to lung, bone, and liver, are not uncommon and can occur late in the disease course for which continued follow-up is required. There is also a need to establish a systemic treatment regimen to control the distant metastases.

Cancer nanotheranostics: Strategies, promises and impediments.

Cancer has remained one of the most indomitable conundrums for scientists over centuries due to its multifarious etiology. While improved therapeutic and diagnostic approaches have commendably augmented the rate of survival of cancer patients, a holistic riddance from the ailment is still implausible. Hence, further explorations to scout for novel strategies of cancer therapy and diagnosis are necessary. Theranostics (amalgamation of therapy and diagnostics) has emerged as one of the avant-garde strategies, which provides a two-pronged advantage in cancer management. This integrative approach has found immense relevance in light of nanotechnology. Nanoparticles can be customized (loaded with a mélange of therapeutic drugs and diagnostic probes) to develop theranostic properties, thereby constructing nanotheranostic agents. These nano-composites are lucrative tools for cancer cell obliteration and simultaneous monitoring of the drug action, and can also be tailored for targeted drug delivery. Nanotheranostic agents have emerged as a prudent ploy for synchronized cancer intervention and detection of the 'route and reach' of the drugs. In this review, we discuss the diversified state-of-the-art facets of theranostic nanoparticles, including various nanoparticle-based platforms as well as the plethora of reported therapeutic drugs, aptamers, markers and diagnostic molecules that have found use in the precincts of nanotheranostics.

Novel Pactamycin Analogs Induce p53 Dependent Cell-Cycle Arrest at S-Phase in Human Head and Neck Squamous Cell Carcinoma (HNSCC) Cells.

Pactamycin, although putatively touted as a potent antitumor agent, has never been used as an anticancer drug due to its high cytotoxicity. In this study, we characterized the effects of two novel biosynthetically engineered analogs of pactamycin, de-6MSA-7-demethyl-7-deoxypactamycin (TM-025) and 7-demethyl-7-deoxypactamycin (TM-026), in head and neck squamous cell carcinoma (HNSCC) cell lines SCC25 and SCC104. Both TM-025 and TM-026 exert growth inhibitory effects on HNSCC cells by inhibiting cell proliferation. Interestingly, unlike their parent compound pactamycin, the analogs do not inhibit synthesis of nascent protein in a cell-based assay. Furthermore, they do not induce apoptosis or autophagy in a dose- or a time-dependent manner, but induce mild senescence in the tested cell lines. Cell cycle analysis demonstrated that both analogs significantly induce cell cycle arrest of the HNSCC cells at S-phase resulting in reduced accumulation of G2/M-phase cells. The pactamycin analogs induce expression of cell cycle regulatory proteins including master regulator p53, its downstream target p21Cip1/WAF1, p27kip21, p19, cyclin E, total and phospho Cdc2 (Tyr15) and Cdc25C. Besides, the analogs mildly reduce cyclin D1 expression without affecting expression of cyclin B, Cdk2 and Cdk4. Specific inhibition of p53 by pifithrin-α reduces the percentage of cells accumulated in S-phase, suggesting contribution of p53 to S-phase increase. Altogether, our results demonstrate that Pactamycin analogs TM-025 and TM-026 induce senescence and inhibit proliferation of HNSCC cells via accumulation in S-phase through possible contribution of p53. The two PCT analogs can be widely used as research tools for cell cycle inhibition studies in proliferating cancer cells with specific mechanisms of action.

A multi-targeted approach to suppress tumor-promoting inflammation.

Cancers harbor significant genetic heterogeneity and patterns of relapse following many therapies are due to evolved resistance to treatment. While efforts have been made to combine targeted therapies, significant levels of toxicity have stymied efforts to effectively treat cancer with multi-drug combinations using currently approved therapeutics. We discuss the relationship between tumor-promoting inflammation and cancer as part of a larger effort to develop a broad-spectrum therapeutic approach aimed at a wide range of targets to address this heterogeneity. Specifically, macrophage migration inhibitory factor, cyclooxygenase-2, transcription factor nuclear factor-κB, tumor necrosis factor alpha, inducible nitric oxide synthase, protein kinase B, and CXC chemokines are reviewed as important antiinflammatory targets while curcumin, resveratrol, epigallocatechin gallate, genistein, lycopene, and anthocyanins are reviewed as low-cost, low toxicity means by which these targets might all be reached simultaneously. Future translational work will need to assess the resulting synergies of rationally designed antiinflammatory mixtures (employing low-toxicity constituents), and then combine this with similar approaches targeting the most important pathways across the range of cancer hallmark phenotypes.

Broad targeting of resistance to apoptosis in cancer.

Apoptosis or programmed cell death is natural way of removing aged cells from the body. Most of the anti-cancer therapies trigger apoptosis induction and related cell death networks to eliminate malignant cells. However, in cancer, de-regulated apoptotic signaling, particularly the activation of an anti-apoptotic systems, allows cancer cells to escape this program leading to uncontrolled proliferation resulting in tumor survival, therapeutic resistance and recurrence of cancer. This resistance is a complicated phenomenon that emanates from the interactions of various molecules and signaling pathways. In this comprehensive review we discuss the various factors contributing to apoptosis resistance in cancers. The key resistance targets that are discussed include (1) Bcl-2 and Mcl-1 proteins; (2) autophagy processes; (3) necrosis and necroptosis; (4) heat shock protein signaling; (5) the proteasome pathway; (6) epigenetic mechanisms; and (7) aberrant nuclear export signaling. The shortcomings of current therapeutic modalities are highlighted and a broad spectrum strategy using approaches including (a) gossypol; (b) epigallocatechin-3-gallate; (c) UMI-77 (d) triptolide and (e) selinexor that can be used to overcome cell death resistance is presented. This review provides a roadmap for the design of successful anti-cancer strategies that overcome resistance to apoptosis for better therapeutic outcome in patients with cancer.

Therapeutic targeting of replicative immortality.

One of the hallmarks of malignant cell populations is the ability to undergo continuous proliferation. This property allows clonal lineages to acquire sequential aberrations that can fuel increasingly autonomous growth, invasiveness, and therapeutic resistance. Innate cellular mechanisms have evolved to regulate replicative potential as a hedge against malignant progression. When activated in the absence of normal terminal differentiation cues, these mechanisms can result in a state of persistent cytostasis. This state, termed "senescence," can be triggered by intrinsic cellular processes such as telomere dysfunction and oncogene expression, and by exogenous factors such as DNA damaging agents or oxidative environments. Despite differences in upstream signaling, senescence often involves convergent interdependent activation of tumor suppressors p53 and p16/pRB, but can be induced, albeit with reduced sensitivity, when these suppressors are compromised. Doses of conventional genotoxic drugs required to achieve cancer cell senescence are often much lower than doses required to achieve outright cell death. Additional therapies, such as those targeting cyclin dependent kinases or components of the PI3K signaling pathway, may induce senescence specifically in cancer cells by circumventing defects in tumor suppressor pathways or exploiting cancer cells' heightened requirements for telomerase. Such treatments sufficient to induce cancer cell senescence could provide increased patient survival with fewer and less severe side effects than conventional cytotoxic regimens. This positive aspect is countered by important caveats regarding senescence reversibility, genomic instability, and paracrine effects that may increase heterogeneity and adaptive resistance of surviving cancer cells. Nevertheless, agents that effectively disrupt replicative immortality will likely be valuable components of new combinatorial approaches to cancer therapy.

Genomic instability in human cancer: Molecular insights and opportunities for therapeutic attack and prevention through diet and nutrition.

Genomic instability can initiate cancer, augment progression, and influence the overall prognosis of the affected patient. Genomic instability arises from many different pathways, such as telomere damage, centrosome amplification, epigenetic modifications, and DNA damage from endogenous and exogenous sources, and can be perpetuating, or limiting, through the induction of mutations or aneuploidy, both enabling and catastrophic. Many cancer treatments induce DNA damage to impair cell division on a global scale but it is accepted that personalized treatments, those that are tailored to the particular patient and type of cancer, must also be developed. In this review, we detail the mechanisms from which genomic instability arises and can lead to cancer, as well as treatments and measures that prevent genomic instability or take advantage of the cellular defects caused by genomic instability. In particular, we identify and discuss five priority targets against genomic instability: (1) prevention of DNA damage; (2) enhancement of DNA repair; (3) targeting deficient DNA repair; (4) impairing centrosome clustering; and, (5) inhibition of telomerase activity. Moreover, we highlight vitamin D and B, selenium, carotenoids, PARP inhibitors, resveratrol, and isothiocyanates as priority approaches against genomic instability. The prioritized target sites and approaches were cross validated to identify potential synergistic effects on a number of important areas of cancer biology.

Sustained proliferation in cancer: Mechanisms and novel therapeutic targets.

Proliferation is an important part of cancer development and progression. This is manifest by altered expression and/or activity of cell cycle related proteins. Constitutive activation of many signal transduction pathways also stimulates cell growth. Early steps in tumor development are associated with a fibrogenic response and the development of a hypoxic environment which favors the survival and proliferation of cancer stem cells. Part of the survival strategy of cancer stem cells may manifested by alterations in cell metabolism. Once tumors appear, growth and metastasis may be supported by overproduction of appropriate hormones (in hormonally dependent cancers), by promoting angiogenesis, by undergoing epithelial to mesenchymal transition, by triggering autophagy, and by taking cues from surrounding stromal cells. A number of natural compounds (e.g., curcumin, resveratrol, indole-3-carbinol, brassinin, sulforaphane, epigallocatechin-3-gallate, genistein, ellagitannins, lycopene and quercetin) have been found to inhibit one or more pathways that contribute to proliferation (e.g., hypoxia inducible factor 1, nuclear factor kappa B, phosphoinositide 3 kinase/Akt, insulin-like growth factor receptor 1, Wnt, cell cycle associated proteins, as well as androgen and estrogen receptor signaling). These data, in combination with bioinformatics analyses, will be very important for identifying signaling pathways and molecular targets that may provide early diagnostic markers and/or critical targets for the development of new drugs or drug combinations that block tumor formation and progression.

Cancer prevention and therapy through the modulation of the tumor microenvironment.

Cancer arises in the context of an in vivo tumor microenvironment. This microenvironment is both a cause and consequence of tumorigenesis. Tumor and host cells co-evolve dynamically through indirect and direct cellular interactions, eliciting multiscale effects on many biological programs, including cellular proliferation, growth, and metabolism, as well as angiogenesis and hypoxia and innate and adaptive immunity. Here we highlight specific biological processes that could be exploited as targets for the prevention and therapy of cancer. Specifically, we describe how inhibition of targets such as cholesterol synthesis and metabolites, reactive oxygen species and hypoxia, macrophage activation and conversion, indoleamine 2,3-dioxygenase regulation of dendritic cells, vascular endothelial growth factor regulation of angiogenesis, fibrosis inhibition, endoglin, and Janus kinase signaling emerge as examples of important potential nexuses in the regulation of tumorigenesis and the tumor microenvironment that can be targeted. We have also identified therapeutic agents as approaches, in particular natural products such as berberine, resveratrol, onionin A, epigallocatechin gallate, genistein, curcumin, naringenin, desoxyrhapontigenin, piperine, and zerumbone, that may warrant further investigation to target the tumor microenvironment for the treatment and/or prevention of cancer.

Influence of Rituximab on Central Nervous System Relapse in Diffuse Large B-Cell Lymphoma and Role of Prophylaxis--A Systematic Review of Prospective Studies.

Despite the improvement in overall survival in patients with diffuse large B-cell lymphoma (DLBCL) in the rituximab era, the occurrence of central nervous system (CNS) relapse heralds a very poor prognosis. The evidence is conflicting on the incidence and pattern of CNS relapse in the rituximab era compared with before the rituximab era and on the role of CNS prophylaxis. We conducted a systematic analysis of the data from 7 prospective studies, studying the incidence and type of CNS relapse, the role of prophylaxis, and survival after CNS relapse, with and without rituximab-based chemotherapy. No statistically significant difference was found in the incidence of CNS relapse with the use of rituximab-based chemotherapy compared with CHOP (cyclophosphamide, doxorubicin, vincristine [Oncovin], prednisone) chemotherapy. Leptomeningeal disease was more common and the survival after CNS disease was better in the rituximab era. No difference was found in the incidence of isolated CNS relapse. Chemoprophylaxis significantly decreased the incidence of CNS recurrence. The use of rituximab has not influenced the incidence of CNS relapse compared with the use of CHOP. Chemoprophylaxis plays a significant role in high-risk patients with DLBCL in decreasing CNS recurrence. Large randomized clinical trials are warranted to differentiate between intrathecal and systemic chemoprophylaxis.

Immune evasion in cancer: Mechanistic basis and therapeutic strategies.

Cancer immune evasion is a major stumbling block in designing effective anticancer therapeutic strategies. Although considerable progress has been made in understanding how cancers evade destructive immunity, measures to counteract tumor escape have not kept pace. There are a number of factors that contribute to tumor persistence despite having a normal host immune system. Immune editing is one of the key aspects why tumors evade surveillance causing the tumors to lie dormant in patients for years through "equilibrium" and "senescence" before re-emerging. In addition, tumors exploit several immunological processes such as targeting the regulatory T cell function or their secretions, antigen presentation, modifying the production of immune suppressive mediators, tolerance and immune deviation. Besides these, tumor heterogeneity and metastasis also play a critical role in tumor growth. A number of potential targets like promoting Th1, NK cell, γδ T cell responses, inhibiting Treg functionality, induction of IL-12, use of drugs including phytochemicals have been designed to counter tumor progression with much success. Some natural agents and phytochemicals merit further study. For example, use of certain key polysaccharide components from mushrooms and plants have shown to possess therapeutic impact on tumor-imposed genetic instability, anti-growth signaling, replicative immortality, dysregulated metabolism etc. In this review, we will discuss the advances made toward understanding the basis of cancer immune evasion and summarize the efficacy of various therapeutic measures and targets that have been developed or are being investigated to enhance tumor rejection.

Broad targeting of angiogenesis for cancer prevention and therapy.

Deregulation of angiogenesis--the growth of new blood vessels from an existing vasculature--is a main driving force in many severe human diseases including cancer. As such, tumor angiogenesis is important for delivering oxygen and nutrients to growing tumors, and therefore considered an essential pathologic feature of cancer, while also playing a key role in enabling other aspects of tumor pathology such as metabolic deregulation and tumor dissemination/metastasis. Recently, inhibition of tumor angiogenesis has become a clinical anti-cancer strategy in line with chemotherapy, radiotherapy and surgery, which underscore the critical importance of the angiogenic switch during early tumor development. Unfortunately the clinically approved anti-angiogenic drugs in use today are only effective in a subset of the patients, and many who initially respond develop resistance over time. Also, some of the anti-angiogenic drugs are toxic and it would be of great importance to identify alternative compounds, which could overcome these drawbacks and limitations of the currently available therapy. Finding "the most important target" may, however, prove a very challenging approach as the tumor environment is highly diverse, consisting of many different cell types, all of which may contribute to tumor angiogenesis. Furthermore, the tumor cells themselves are genetically unstable, leading to a progressive increase in the number of different angiogenic factors produced as the cancer progresses to advanced stages. As an alternative approach to targeted therapy, options to broadly interfere with angiogenic signals by a mixture of non-toxic natural compound with pleiotropic actions were viewed by this team as an opportunity to develop a complementary anti-angiogenesis treatment option. As a part of the "Halifax Project" within the "Getting to know cancer" framework, we have here, based on a thorough review of the literature, identified 10 important aspects of tumor angiogenesis and the pathological tumor vasculature which would be well suited as targets for anti-angiogenic therapy: (1) endothelial cell migration/tip cell formation, (2) structural abnormalities of tumor vessels, (3) hypoxia, (4) lymphangiogenesis, (5) elevated interstitial fluid pressure, (6) poor perfusion, (7) disrupted circadian rhythms, (8) tumor promoting inflammation, (9) tumor promoting fibroblasts and (10) tumor cell metabolism/acidosis. Following this analysis, we scrutinized the available literature on broadly acting anti-angiogenic natural products, with a focus on finding qualitative information on phytochemicals which could inhibit these targets and came up with 10 prototypical phytochemical compounds: (1) oleanolic acid, (2) tripterine, (3) silibinin, (4) curcumin, (5) epigallocatechin-gallate, (6) kaempferol, (7) melatonin, (8) enterolactone, (9) withaferin A and (10) resveratrol. We suggest that these plant-derived compounds could be combined to constitute a broader acting and more effective inhibitory cocktail at doses that would not be likely to cause excessive toxicity. All the targets and phytochemical approaches were further cross-validated against their effects on other essential tumorigenic pathways (based on the "hallmarks" of cancer) in order to discover possible synergies or potentially harmful interactions, and were found to generally also have positive involvement in/effects on these other aspects of tumor biology. The aim is that this discussion could lead to the selection of combinations of such anti-angiogenic compounds which could be used in potent anti-tumor cocktails, for enhanced therapeutic efficacy, reduced toxicity and circumvention of single-agent anti-angiogenic resistance, as well as for possible use in primary or secondary cancer prevention strategies.

Comparing newer oral anti-platelets prasugrel and ticagrelor in reduction of ischemic events-evidence from a network meta-analysis.

The two newer antiplatelet drugs, prasugrel and ticagrelor have both been incorporated in various national guidelines and are both under consideration for approval or have already been approved by various drug regulatory authorities. Mortality benefits with clopidogrel were comparable to newer anti-platelets, and prasugrel had great anti-ischemic potency than ticagrelor. We searched PubMed, EMBASE and Cochrane Central Register of Controlled Trials' databases for randomized controlled trials conducted between 1990 and 2012 that assessed clinical outcomes with prasugrel or ticagrelor. The comparator was standard dosage of clopidogrel. Outcomes assessed were the risk of all causes mortality, TIMI non-CABG major bleeding, and a composite of stent thrombosis, recurrent ischemia and serious recurrent ischemia in the intervention groups versus the comparator groups. Event rates were compared using a forest plot of relative risk using a random effects model (Mantel-Haenszel); and Odd's ratio was calculated in the absence of significant heterogeneity. Prasugrel was indirectly compared with ticagrelor using network meta-analysis. Four studies (total N = 34,126) met the inclusion/exclusion criteria. Both drugs had improved mortality and greater risk of bleeding compared to clopidogrel; but outcomes were comparable for both (p = NS). However a composite of recurrent ischemic events, including rates of stent thrombosis (p = 0.045) was reduced to a modest degree with prasugrel compared with ticagrelor. This systematic review suggests greater clinical efficacy of both prasugrel and ticagrelor compared with clopidogrel and an indirect comparison indicates prasugrel may be more effective than ticagrelor for preventing stent thrombosis and recurrent ischemic events.