The Mevalonate Pathway, a Metabolic Target in Cancer Therapy.

A hallmark of cancer cells includes a metabolic reprograming that provides energy, the essential building blocks, and signaling required to maintain survival, rapid growth, metastasis, and drug resistance of many cancers. The influence of tumor microenviroment on cancer cells also results an essential driving force for cancer progression and drug resistance. Lipid-related enzymes, lipid-derived metabolites and/or signaling pathways linked to critical regulators of lipid metabolism can influence gene expression and chromatin remodeling, cellular differentiation, stress response pathways, or tumor microenviroment, and, collectively, drive tumor development. Reprograming of lipid metabolism includes a deregulated activity of mevalonate (MVA)/cholesterol biosynthetic pathway in specific cancer cells which, in comparison with normal cell counterparts, are dependent of the continuous availability of MVA/cholesterol-derived metabolites (i.e., sterols and non-sterol intermediates) for tumor development. Accordingly, there are increasing amount of data, from preclinical and epidemiological studies, that support an inverse association between the use of statins, potent inhibitors of MVA biosynthetic pathway, and mortality rate in specific cancers (e.g., colon, prostate, liver, breast, hematological malignances). In contrast, despite the tolerance and therapeutic efficacy shown by statins in cardiovascular disease, cancer treatment demands the use of relatively high doses of single statins for a prolonged period, thereby limiting this therapeutic strategy due to adverse effects. Clinically relevant, synergistic effects of tolerable doses of statins with conventional chemotherapy might enhance efficacy with lower doses of each drug and, probably, reduce adverse effects and resistance. In spite of that, clinical trials to identify combinatory therapies that improve therapeutic window are still a challenge. In the present review, we revisit molecular evidences showing that deregulated activity of MVA biosynthetic pathway has an essential role in oncogenesis and drug resistance, and the potential use of MVA pathway inhibitors to improve therapeutic window in cancer.

Signal transducer and activator of transcription (STAT)-5: an opportunity for drug development in oncohematology.

The signal transducer and activator of transcription (STAT) are transcription factors that work via JAK/STAT pathway regulating the expression of genes involved in cell survival, proliferation, differentiation, development, immune response, and, among other essential biological functions, hematopoiesis. JAK/STAT signaling is strictly regulated under normal physiological conditions. However, a large group of diverse diseases has been associated to an aberrant regulation of STAT factors. Erroneous modulation of the pathway leads to constitutive STAT activation, thereby driving proliferation, inflammation, and an uncontrolled immune response. Deregulated STAT5 activation has been found in the development of many hematopoietic tumors, including chronic and acute leukemias, polycythemia vera, and lymphoma. Mutations in the kinases that phosphorylate STAT5, and/or overexpression of the upstream receptor-associated tyrosine kinases have been suggested as the main drivers of constitutive STAT5 activation. Hyper-activated STAT5 leads to the aberrant expression of its target genes including antiapoptotic, proliferative, and pro-inflammatory genes, favouring tumorigenesis. In this review, we intent to discuss the biology of JAK/STAT pathway, with particular focus on STAT5 and its crucial role in the development and progression of hematologic malignancies. Furthermore, we provide a synopsis of potential therapeutic strategies based on STAT5 activity inhibition that may represent an excellent opportunity for drug development in oncohematology.

Histopathologic and Radiologic Assessment of Chemotherapeutic Response in Ewing's Sarcoma: A Review.

Ewing's sarcoma is a highly malignant tumor that metastasizes rapidly and is thus associated with a low survival rate. The intensification of chemotherapy has been shown to improve the overall survival of patients with Ewing's sarcoma. However, intensified chemotherapy can lead to increased toxicity or even the development of secondary malignancies. The stratification of patients with Ewing's sarcoma into "good" and "poor" responders may help guide the administration of progressively more intensified chemotherapy. Thus, an accurate assessment of the chemotherapeutic response, as well as the extent of chemotherapy-induced tumor necrosis, is critical for avoiding potential treatment-related complications in these patients. This paper reviews the methods currently used to evaluate chemotherapeutic response in Ewing's sarcoma, focusing specifically on histopathologic and imaging analyses, and discusses novel therapies and imaging methods that may help improve the overall survival of these patients.

Searching for novel molecular targets of chronic rejection in an orthotopic experimental lung transplantation model.

BACKGROUND: Chronic rejection (CR) is the main reason for the limited survival rates among lung transplant (LT) recipients. There remains no effective treatment for CR. The aim of this study was to identify new molecular mechanisms involved in CR by using DNA microarray analysis. METHODS: We performed 10 left LTs using the microsurgical cuff technique in inbred Sprague-Dawley rats. Lung isograft samples were obtained 3 months after surgery. We analyzed histologic, apoptotic and gene expression changes by DNA microarray and quantitative PCR analysis. RESULTS: Histologic analyses confirmed signs of CR in all lungs and positive labeling for apoptotic and anti-apoptotic markers. A total of 702 genes were regulated in the CR lungs: 317 genes were upregulated and 385 were downregulated. Significant changes for about 30 biologic processes, including regulation of the cytoskeleton, and 15 signaling pathways, such as adherens junctions, were observed. We found significantly increased mRNA expression of the Cldn5, Epas1, Tgfb1, Vegf, Selp1, Hsp27 and Igf1 genes. CONCLUSIONS: This is the first experimental study performed in an orthotopic model of LT using DNA microarray analysis. The individual genes, biologic process and pathways identified may represent novel targets that could be manipulated and contribute to the development of treatments capable of providing protection from CR.

Nonleukemic myeloid dendritic cells obtained from autologous stem cell products elicit antileukemia responses in patients with acute myeloid leukemia.

BACKGROUND: Dendritic cell (DC)-based immunotherapeutic protocols are being developed to treat acute myeloid leukemia (AML). So far, DCs for clinical use are obtained from leukemic blasts or from monocytes, after 6 to 10 days of ex vivo culture. However, DC precursors are easily driven to DCs in short-term culture. We tested if DC precursors contained in peripheral blood stem cell (PBSC) products obtained from AML patients can be used to induce antileukemia responses. STUDY DESIGN AND METHODS: PBSCs obtained from 30 consecutive AML patients were tested. Myeloid DCs (MDCs) were purified by immunomagnetic selection and screened for cytogenetic and/or molecular abnormalities by fluorescence in situ hybridization (FISH) or polymerase chain reaction (PCR) assays. MDCs were matured and pulsed with autologous blast lysates and tested for stimulatory capability against AML cells. RESULTS: A median of 0.62 × 10(6) MDCs (range, 0.04-3.25)/mL were quantified in PBSC products. Isolated MDC expressed Class I and II HLA but CD86, CD54, and CCR5 partially. By FISH or PCR assay, these MDCs lacked cytogenetic or molecular abnormalities detected in leukemia cells at diagnosis. MDCs achieved a maturated stage (mature-MDCs) after 24-hour ex vivo culture with tumor necrosis factor-α and autologous blast lysates. These mature-MDCs were capable of stimulating autologous peripheral blood effectors to exert cytotoxicity against autologous leukemia cells and HL-60 cell line. CONCLUSION: We conclude that PBSCs obtained for autologous stem cell transplantation can constitute a novel source of MDCs to design feasible vaccination trials.

Pulsed ultrasounds accelerate healing of rib fractures in an experimental animal model: an effective new thoracic therapy?

OBJECTIVES: Rib fractures are a frequent traumatic injury associated with a relatively high morbidity. Currently, the treatment of rib fractures is symptomatic. Since it has been reported that pulsed ultrasounds accelerates repair of limb fractures, we hypothesized that the application of pulsed ultrasounds will modify the course of healing in an animal model of rib fracture. METHODS: We studied 136 male Sprague-Dawley rats. Animals were randomly assigned to different groups of doses (none, 50, 100, and 250 mW/cm(2) of intensity for 3 minutes per day) and durations (2, 10, 20, and 28 days) of treatment with pulsed ultrasounds. In every subgroup, we analyzed radiologic and histologic changes in the bone callus. In addition, we examined changes in gene expression of relevant genes involved in wound repair in both control and treated animals. RESULTS: Histologic and radiologic consolidation was significantly increased by pulsed ultrasound treatment when applied for more than 10 days. The application of 50 mW/cm(2) was the most effective dose. Only the 100 and 250 mW/cm(2) doses were able to significantly increase messenger RNA expression of insulin-like growth factor 1, suppressor of cytokine signaling-2 and -3, and vascular endothelial growth factor and decrease monocyte chemoattractant protein-1 and collagen type II-alpha 1. CONCLUSIONS: Our findings indicate that pulsed ultrasound accelerates the consolidation of rib fractures. This study is the first to show that pulsed ultrasound promotes the healing of rib fractures. From a translational point of view, this easy, cheap technique could serve as an effective new therapeutic modality in patients with rib fractures.

Synthesis and pharmacophore modeling of naphthoquinone derivatives with cytotoxic activity in human promyelocytic leukemia HL-60 cell line.

Catalyst/HypoGen pharmacophore modeling approach and three-dimensional quantitative structure-activity relationship (3D-QSAR)/comparative molecular similarity indices analysis (CoMSIA) methods have been successfully applied to explain the cytotoxic activity of a set of 51 natural and synthesized naphthoquinone derivatives tested in human promyelocytic leukemia HL-60 cell line. The computational models have facilitated the identification of structural elements of the ligands that are key for antitumoral properties. The four most salient features of the highly active beta-cycled-pyran-1,2-naphthoquinones [0.1 microM < IC50 < 0.6 microM] are the hydrogen-bond interactions of the carbonyl groups at C-1 (HBA1) and C-2 (HBA2), the hydrogen-bond interaction of the oxygen atom of the pyran ring (HBA3), and the interaction of methyl groups (HYD) at the pyran ring with a hydrophobic area at the receptor. The moderately active 1,4-naphthoquinone derivatives accurately fulfill only three of these features. The results of our study provide a valuable tool in designing new and more potent cytotoxic analogues.

Methylthioadenosine phosphorylase gene deletions are common in osteosarcoma.

PURPOSE: Methylthioadenosine phosphorylase (MTAP) is an enzyme essential in the salvage of cellular adenine and methionine synthesis. The MTAP gene is located in the 9p21 chromosomal region and its loss is frequently associated with deletion of the tumor suppressor genes p15(INK4b) and p16(INK4a). The aim of this study was to investigate the frequency of molecular alterations in MTAP in osteosarcoma. EXPERIMENTAL DESIGN: Samples from patients with high-grade osteosarcoma (n = 96) and three osteosarcoma cell lines (HOS, SaOS-2, and U2OS) were analyzed. Genomic DNA was analyzed for MTAP gene deletions by PCR, RNA expression was measured by semiquantitative reverse transcription-PCR, and the protein levels were measured by immunohistochemistry. RESULT: Deletion of at least one MTAP exon was found in 36 of 96 (37.5%) osteosarcoma patient samples and in one of the three cell lines (HOS). In all cases in which an MTAP gene deletion was observed, there was absence of detectable mRNA and protein. Furthermore, in four osteosarcoma patients, an MTAP deletion which was not evident at diagnosis was detected in subsequent tumor samples. CONCLUSIONS: The MTAP gene is commonly deleted in osteosarcoma patient samples, leading to an absence of mRNA and protein expression; these results indicate that inhibitors of de novo purine synthesis or methionine depletion may be effective as treatments for osteosarcoma patients whose tumors fail to express MTAP.