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Biochemical Pharmacology (v.85, #5)

Editorial Board (pp. iii).

Dysfunctional cell signaling dynamics in oncology: Diagnostic, prognostic and treatment opportunities by Khosrow Kashfi (pp. 595-596).

The diverse roles of nonsteroidal anti-inflammatory drug activated gene (NAG-1/GDF15) in cancer by Xingya Wang; Seung Joon Baek; Thomas E. Eling (pp. 597-606).

Nonsteroidal anti-inflammatory drug (NSAID) activated gene-1, NAG-1, is a divergent member of the transforming growth factor-beta (TGF-β) superfamily that plays a complex but poorly understood role in several human diseases including cancer. NAG-1 expression is substantially increased during cancer development and progression especially in gastrointestinal, prostate, pancreatic, colorectal, breast, melanoma, and glioblastoma brain tumors. Aberrant increases in the serum levels of secreted NAG-1 correlate with poor prognosis and patient survival rates in some cancers. In contrast, the expression of NAG-1 is up-regulated by several tumor suppressor pathways including p53, GSK-3β, and EGR-1. NAG-1 expression is also induced by many drugs and dietary compounds which are documented to prevent the development and progression of cancer in mouse models. Studies with transgenic mice expressing human NAG-1 demonstrated that the expression of NAG-1 inhibits the development of intestinal tumors and prostate tumors in animal models. Laboratory and clinical evidence suggest that NAG-1, like other TGF-β family members, may have different or pleiotropic functions in the early and late stages of carcinogenesis. Upon understanding the molecular mechanism and function of NAG-1 during carcinogenesis, NAG-1 may serve as a potential biomarker for the diagnosis and prognosis of cancer and a therapeutic target for the inhibition and treatment of cancer development and progression.

Keywords: NAG-1; GDF15; Cancer; Tumor suppressor

Targeting peroxisome proliferator-activated receptor-β/δ in colon cancer: How to aim? by Min Xu; Xiangsheng Zuo; Imad Shureiqi (pp. 607-611).

Peroxisome proliferator-activated receptor-β/δ (PPARδ) is a ubiquitously expressed, ligand-activated transcriptional factor that performs diverse critical functions in normal cells ( e.g., fatty acid metabolism, obesity, apoptosis, and inflammation). Various studies in humans have found that PPARδ is upregulated in primary colorectal cancers; however, these findings have been challenged by those of other reports. Similarly, various in vitro and in vivo mechanistic pre-clinical models have yielded data demonstrating that PPARδ promotes colonic tumorigenesis, but other models have yielded data that contradicts this notion. Definitive studies are therefore needed to establish the exact role of PPARδ in human colorectal tumorigenesis and to provide a theoretical basis for PPARδ therapeutic targeting.

Keywords: Peroxisome proliferator-activated receptor-delta; Colonic tumorigenesis

Glioblastoma cancer stem cells: Role of the microenvironment and therapeutic targeting by Luca Persano; Elena Rampazzo; Giuseppe Basso; Giampietro Viola (pp. 612-622).

It has been recently suggested that many types of cancer, including glioblastoma (GBM), contain functionally subsets of cells with stem-like properties named “cancer stem cells” (CSCs). These are characterized by chemotherapy resistance and considered one of the key determinants driving tumor relapse. Many studies demonstrated that Glioma stem cells (GSCs) reside in particular tumor niches, that are necessary to support their behavior. A hypoxic microenvironment has been reported to play a crucial role in controlling GSC molecular and phenotypic profile and in promoting the recruitment of vascular and stromal cells in order to sustain tumor growth.Recent advances in the field allow researches to generate models able to recapitulate, at least in part, the extreme heterogeneity found within GBM tumors. These models try to account for the presence of GSCs and more differentiated cells, the influence of different microenvironments enclosed within the mass, heterotypic interactions between GBM and stromal cells and genetic aberrations. Understanding the mechanism of action of the microenvironmental signals and the interplay between different cell types within the tumor mass, open new questions on how GSCs modulate GBM aggressiveness and response to therapy. The definition of these tumor features will allow to setup innovative multimodal therapies able to target GBM cells at multiple levels. Here, we will discuss the major advances in the study of GSC role in GBM and the therapeutic implications resulting from them, thus reporting the latest strategies applied to counteract and overcome GBM intrinsic resistance to therapy for a better management of patients.

Keywords: Glioblastoma multiforme; Hypoxia; Cancer stem cells; Molecular targeting

Control of stem cells and cancer stem cells by Hedgehog signaling: Pharmacologic clues from pathway dissection by Sonia Coni; Paola Infante; Alberto Gulino (pp. 623-628).

Hedgehog is a key morphogen regulating embryonic development and tissue repair. Remarkably, when misregulated, it leads to tumorigenesis. Hedgehog signaling is triggered by binding of ligands with transmembrane receptor Ptch and is subsequently mediated by transcriptional effectors belonging to the Gli family, whose functions is tuned by a number of molecular interactions and post-synthetic modifications. The complex of these regulatory circuitries provides a tight control of developmental processes, mainly involving the modulation of genes determining the fate of stem cells. Similarly, Hedgehog regulates cancer stem cells fostering tumorigenesis. To this regard, these processes represent promising targets for novel therapeutic strategies aiming at the control of stemness reactivation and maintenance in cancer.

Keywords: Abbreviations; Bcl2; B-cell CLL/lymphoma 2; β-TrCP; β-transducin repeat containing E3 ubiquitin protein ligase; Bmi1; B lymphoma Mo-MLV insertion region 1 homolog; CKI; casein kinase I; Elk1; ETS-like gene 1; FoxM1; forkhead box M1; FoxA2; forkhead box A2; FoxF1; forkhead box F1; GCP; granule cell progenitors; Gli; glioma-associated oncogene; Gli2A/Gli3A; Gli activator; Gli2R/Gli3R; Gli repressor; GSK3β; glycogen synthase kinase 3β; Hh; Hedgehog; HES1; hairy and enhancer of split 1; IGFBP3; insulin-like growth factor binding protein 3; IGF2; insulin-like growth factor 2; Msx2; homeobox msh-like 2; Myf5; myogenic factor 5; Nanog; Tìr na nOg [early embryo specific expression NK-type homeobox protein]; N-Myc; myelocytomatosis viral oncogene homolog; Nkx2.2; NK2 transcription factor related locus 2; PDGFR; platelet-derived growth factor receptor; PKA; protein kinase A; Ptch; Patched; Sip1; survival of motor neuron protein interacting protein 1; Smo; smoothened; Snail1; snail homolog 1; SUFU; suppressor of fused; VEGF; vascular endothelial growth factor; Wnt; wingless-related integration siteHedgehog; Gli; Cancer; Stem cell; Smo-antagonists; Gli-antagonists

Pim kinases in cancer: Diagnostic, prognostic and treatment opportunities by Carmen Blanco-Aparicio; Amancio Carnero (pp. 629-643).

PIM proteins belong to a family of ser/thr kinases composed of 3 members, PIM1, PIM2 and PIM3, with greatly overlapping functions. PIM kinases are mainly responsible for cell cycle regulation, antiapoptotic activity and the homing and migration of receptor tyrosine kinases mediated via the JAK/STAT pathway. PIM kinases have been found to be upregulated in many hematological malignancies and solid tumors. Although these kinases have been described as weak oncogenes, they are heavily targeted for anticancer drug discovery. The present review summarizes the discoveries made to date regarding PIM kinases as driving oncogenes in the process of tumorigenesis and their validation as drug targets.

Keywords: Abbreviations; 3-MC; 3-methylcholanthrene; 4E-BP1; eukaryotic translation initiation factor 4E-binding protein 1; AKT; V-AKT murine thymoma viral oncogene homolog; AML; acute myeloid leukemia; AMP; adenosine-monophosphate; AMPK; AMP-dependent kinase; API5; apoptosis inhibitor 5; AR; androgen receptor; ara C; arabinosilcitosina, citarabina; ASK1; apoptosis signal-regulating kinase 1; ATP; adenosine-5′-triphosphate; Bad; BCL2 antagonist of cell death; Bcl2; B-cell CLL/lymphoma 2; BCR; breakpoint cluster region; BCR/ABL; breakpoint cluster region fused to Abelson gene; CBX3; chromobox homolog 3; Cdc25; cell division cycle 25; CDK2; cyclin dependent kinase 2; CK2; casein kinase 2; CLK; CDC-like kinase 1; CLL; chronic lymphocytic leukemia; c-MYB; avian myeloblastosis viral oncogene homolog; DLBLC; diffuse large B-cell lymphoma; DYRK1A; dual-specificity tyrosine phosphorylation-regulated kinase 1A; EBNA2; Epstein–Barr virus (EBV) nuclear antigen-2; E-box; enhancer box; EGFR; epidermal growth factor receptor; eIF-4E; eukaryotic translation initiation factor 4E; ERK; extracellular signal-regulated kinase; ETK; EPH-like tyrosine kinase 1; FasL; tumor necrosis factor ligand superfamily, member 6, TNFSF6, Fas ligand; FL; follicular lymphoma; FLT3; FMS-related tyrosine kinase 3; FoxO; forkhead box O; Frat1; frequently rearranged in advanced T-cell lymphomas; G1; Gap 1 phase; GAS; gastrin; GCSF; granulocyte colony-stimulating factor; GFI1; growth factor-independent 1; GI50, IC50; growth inhibition 50%; GM-CSF; granulocyte-macrophage colony-stimulating factor; GSK3β; glycogen synthase kinase-3 beta; H3; histone 3; hERG; human ether-a-go-go-related gene; Hif1a; hypoxia induced factor 1a; HIPK; homeodomain-interacting protein kinase; HoxA9; HOMEOBOX A9; HP1; heterochromatin protein-1; HSP70; heat shock protein 70; kDa; HSP90; heat shock protein 90; kDa; IFN; interferon; IL-6; interleukin 6; JAK; janus kinase; kDa; kiloDalton; KFL5; Krüppel-like factor 5; Kid1; PIM3; Kip1; cyclin-dependent kinase inhibitor 1B; Kit; mast cell growth factor receptor; KSHV; Kaposi sarcoma-associated herpes virus; L/h/kg; liter/hour/kilogram; LANA; latency-associated nuclear antigen; MAX; MYC-associated factor X; MCL; mantle cell lymphoma; MCL-1; myeloid cell leukemia sequence 1; Mdm2; murine double minutes 2; MEFs; mouse embryo fibroblasts; MEK; MAP/ERK kinase; mg/kg; milligrams per kilogram; MLL/AF9; myeloid/lymphoid or mixed lineage leukemia gene fusion with AF9 gene; MLL/ENL; myeloid/lymphoid or mixed lineage leukemia gene fusion with ENL gene; MLL-X; myeloid/lymphoid or mixed lineage leukemia gene X; MMLV; moloney murine leukemia virus; mRNA; messenger RNA; MTD; maximum tolerated dose; mTOR; mammalian target of rapamycin; myc; avian myelocytomatosis viral oncogene homolog; MZL-MALT; marginal zone lymphoma-MALT type; NFAT; nuclear factor of activated T cells; NFATc1; NFAT transcription complex, cytosolic component 1; NF-κB; nuclear factor of kappa light chain gene enhancer in B cells; NMZL; nodal marginal zone lymphoma; NUMA; nuclear mitotic apparatus; p100; EBNA2 coactivator; p70S6K; S6 kinase of 70; kDa; PBX1; pre-b-cell leukemia transcription factor 1 ;; PD; pharmacodynamics; PDGF; Platelet derived growth factor; PDGFR1; platelet derived growth factor receptor 1; PGP; phosphoglycolate phosphatase; PI3K; phosphatidyl-inositol 3 kinase; PK; pharmacokinetics; PO; orally; PP2A; protein phosphatase 2A; PRAS40; proline-rich AKT substrate, 40-kDa; PSA; prostate-specific antigen; PTEN; phosphatase and tensin homolog; PTPRO; protein-tyrosine phosphatase, receptor-type, O; QDx5; everyday during 5 days a week; RCC; renal cell carcinoma; RelA; NFKB, p65 subunit; RP9; ribosomal protein 9; RPS6KA1; ribosomal protein S6 kinase A1; RuNX; runt-related transcription factor; S6RP; ribosomal protein S6; SAHA; hydroxamic acid; SCID; severe combined immunodeficiency; ser/thr; serine/threonine; shRNA; short hairpin RNA; siRNA; small interference RNA; SND1; p100, staphylococcal nuclease domain-containing protein 1; SNX6; sorting nexin 6; SOCS; suppressor of cytokine signaling; STAT; signal transducer and activator of transcription; Tak1; transforming growth factor-beta-activated kinase 1; Tiam1; T-cell lymphoma invasion and metastasis 1; UTR; untranslated region; waf1; wildtype p53-activated fragment 1; WT; wild typePim kinases; Cancer targets; Therapeutics; PIM inhibitors; Oncogenes

Targeting FOXM1 in cancer by Marianna Halasi; Andrei L. Gartel (pp. 644-652).

Oncogenic transcription factor FOXM1 is overexpressed in the majority of human cancers. In addition, FOXM1 has been implicated in cell migration, invasion, angiogenesis and metastasis. The important role of FOXM1 in cancer affirms its significance for therapeutic intervention. Current data suggest that targeting FOXM1 in mono- or combination therapy may have promising therapeutic benefits for the treatment of cancer. However, challenges with the delivery of anti-FOXM1 siRNA to tumors and the absence of small molecules, which specifically inhibit FOXM1, are delaying the development of FOXM1 inhibitors as feasible anticancer drugs. In this review, we describe and summarize the efforts that have been made to target FOXM1 in cancer and the consequences of FOXM1 suppression in human cancer cells.

Keywords: FOXM1; RNAi; Proteasome inhibitors; NPM; ARF; Apoptosis

Pharmacological targeting of endoplasmic reticulum stress signaling in cancer by Axel H. Schönthal (pp. 653-666).

The endoplasmic reticulum (ER) stress response constitutes a cellular process that can be triggered by a great variety of conditions that cause imbalances in intracellular homeostasis and threaten proper cell functioning. In response, the ER stress response activates an adaptive effort aimed at neutralizing these threats and reestablishing homeostasis. However, if these countermeasures are unsuccessful and severe imbalances persist, the ER stress response may abandon its pro-survival efforts and instead may initiate a pro-apoptotic program to eliminate the faulty cell for the benefit of the organism as a whole. Because vigorous growth of malignant tumors may create stressful conditions, such as hypoglycemia, hypoxia, or accumulation of misfolded proteins during revved up protein synthesis, the adaptive, pro-survival components of the ER stress response system (e.g., GRP78/BiP) are frequently found chronically activated in tumor cells. This differential to non-stressed normal cells has been proposed to represent an Achilles’ heel of tumor cells that may be exploitable by therapeutic intervention. In this model, the goal would be to further aggravate the pre-existing stress conditions in tumor cells with appropriate pharmacological agents, so that the already engaged pro-survival mechanism would be overwhelmed and the ER stress response forced to switch to its pro-apoptotic mode (e.g., CHOP/GADD153). This review will discuss the principle of pharmacological ER stress aggravation, and will present preclinical models with promise for cancer therapeutic applications.

Keywords: Abbreviations; ATF; activating transcription factor; CHOP; CCAAT/enhancer binding protein homologous protein (also called GADD153); JNK; c-jun N-terminal kinase; 2-DG; 2-deoxy-; d; -glucose; DMC; 2,5-dimethyl-celecoxib; DR5; death receptor 5; ER; endoplasmic reticulum; ERAD; endoplasmic reticulum-associated degradation; ERSA; endoplasmic reticulum stress aggravator; GRP78; glucose regulated protein of molecular weight 78 (also called BiP); IRE1; inositol-requiring enzyme; NF-κB; nuclear factor kappa B; PERK; protein kinase activated by double-stranded RNA (PKR)-like ER kinase (also called pancreatic ER kinase); SERCA; sarcoplasmic/endoplasmic reticulum calcium ATPase; TRAIL; tumor necrosis factor-related apoptosis-inducing ligandAutophagy; Chemoresistance; GRP78 inhibitors; Yin–Yang principle

Modulation of signaling pathways in prostate cancer by green tea polyphenols by Naghma Khan; Hasan Mukhtar (pp. 667-672).

Prostate cancer (PCa) is the most common malignancy found in American men and the risk factors for PCa include age, family history, ethnicity, hormonal status, diet and lifestyle. For the successful development of cancer-preventive/therapeutic approaches, consumption of dietary agents capable of inhibiting or delaying the growth and proliferation of cancer cells without significantly affecting normal cells could be an effective strategy. Polyphenols derived from green tea, termed as green tea polyphenols (GTP) have received great attention in recent years for their beneficial effects, in particular, their significant involvement in cancer chemoprevention and chemotherapy. Several studies have reported beneficial effects of GTP using in vitro and in vivo approaches and in human clinical trials. Among green tea catechins, epigallocatechin-3-gallate (EGCG) is best studied for its cancer preventive properties. In this review article, we present available scientific literature about the effects of GTP and EGCG on signaling pathways in PCa.

Keywords: Cancer; EGCG; Green tea; Signaling pathways

Emerging targets in lipid-based therapy by Stephanie C. Tucker; Kenneth V. Honn (pp. 673-688).

The use of prostaglandins and NSAIDS in the clinic has proven that lipid mediators and their associated pathways make attractive therapeutic targets. When contemplating therapies involving lipid pathways, several basic agents come to mind. There are the enzymes and accessory proteins that lead to the metabolism of lipid substrates, provided through diet or through actions of lipases, the subsequent lipid products, and finally the lipid sensors or receptors. There is abundant evidence that molecules along this lipid continuum can serve as prognostic and diagnostic indicators and are in fact viable therapeutic targets. Furthermore, lipids themselves can be used as therapeutics. Despite this, the vernacular dialog pertaining to “biomarkers” does not routinely include mention of lipids, though this is rapidly changing. Collectively these agents are becoming more appreciated for their respective roles in diverse disease processes from cancer to preterm labor and are receiving their due appreciation after decades of ground work in the lipid field. By relating examples of disease processes that result from dysfunction along the lipid continuum, as well as examples of lipid therapies and emerging technologies, this review is meant to inspire further reading and discovery.

Keywords: Cancer; Bioactive lipids; Raman; Therapeutics; Biomarkers; Drug synergism

Biology and therapeutic potential of hydrogen sulfide and hydrogen sulfide-releasing chimeras by Khosrow Kashfi; Kenneth R. Olson (pp. 689-703).

Mechanisms of action of H₂S-releasing NSAIDs.Hydrogen sulfide, H₂S, is a colorless gas with a strong odor that until recently was only considered to be a toxic environmental pollutant with little or no physiological significance. However, the past few years have demonstrated its role in many biological systems and it is becoming increasingly clear that H₂S is likely to join nitric oxide (NO) and carbon monoxide (CO) as a major player in mammalian biology. In this review, we have provided an overview of the chemistry and biology of H₂S and have summarized the chemistry and biological activity of some natural and synthetic H₂S-donating compounds. The naturally occurring compounds discussed include, garlic, sulforaphane, erucin, and iberin. The synthetic H₂S donors reviewed include, GYY4137; cysteine analogs; S-propyl cysteine, S-allyl cysteine, S-propargyl cysteine, and N-acetyl cysteine. Dithiolethione and its NSAID and other chimeras such as, L-DOPA, sildenafil, aspirin, diclofenac, naproxen, ibuprofen, indomethacin, and mesalamine have also been reviewed in detail. The newly reported NOSH-aspirin that releases both NO and H₂S has also been discussed.

Keywords: Hydrogen sulfide; NSAIDs; Cancer prevention; Inflammation; Cardiovascular

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Biochemical Pharmacology (v.85, #5)

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Biochemical Pharmacology (v.85, #5)