It has been shown that the novel synthetic triterpenoid CDDO inhibits proliferation and induces differentiation and apoptosis in myeloid leukemia cells. In the current study the effects of the C-28 methyl ester of CDDO, CDDO-Me, were analyzed on cell growth and apoptosis of leukemic cell lines and primary acute myelogenous leukemia (AML) . IntroductionAcute myelogenous leukemia (AML) remains incurable in most patients, largely because of its resistance to chemotherapy. The therapeutic regimens used have not changed in the past 3 decades and usually include cytosine arabinoside (ara-C) and anthracycline analogs. 1,2 Recently, topoisomerase inhibitors, cytokines, and multidrug resistant (MDR)-1 blockers have been evaluated, but they failed to have major impact on patient survival. [3][4][5][6][7] Most chemotherapy agents used in the treatment of hematologic malignancies eliminate cells by inducing apoptosis, and many factors that inhibit chemotherapy-induced apoptosis have been identified. The initiation of a cascade of cysteine proteases of the ICE/ced3 family (caspases) plays a pivotal role in apoptosis. 8 The extrinsic death receptor pathway, triggered by members of the tumor necrosis factor family, is activated when the proximal regulator caspase-8 is recruited into the death receptor complex. The Bcl-2 family of proteins, on the other hand, seems to play a central role in the regulation of the mitochondrial (intrinsic) apoptotic pathway. In particular, Bcl-2 and Bcl-X L overexpression prevent the mitochondrial release of cytochrome c, caspase activation, and apoptosis (for review, see [9][10][11] ). Bax is a pro-apoptotic member of the Bcl-2 family that dimerizes with itself or with Bcl-2/Bcl-X L , and an increase in the levels of free Bax, or Bax homodimers, promotes apoptosis. 12,13 Bcl-2 has been the subject of intense study as a mechanism of chemoresistance because of its ability to suppress chemotherapy-induced apoptosis. 12,14,15 Recent studies have demonstrated that phosphorylation of Bcl-2 at the serine 70 site is required to inhibit apoptosis. 16,17 Protein kinase (PKC)-␣ and the mitogen-activated protein (MAP) kinases ERK1 (p44) and ERK2 (p42) were identified as physiologic Bcl-2 kinases, 18,19 and PKC-␣ expression was observed to modulate the prognostic impact of Bcl-2 in AML. 20 These collective results strongly suggest that Bcl-2 phosphorylation plays a role in the resistance of cells to chemotherapy-induced apoptosis.Triterpenoids The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 U.S.C. section 1734. For personal use only. on April 27, 2019. by guest www.bloodjournal.org From are both derived from squalene and have definite, though weak, anti-inflammatory and anticarcinogenic properties. 22,23 2-Cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) is a novel synthetic triterpenoid that is more than 10 000-fold more potent than its parent compound, ole...

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Secreted proteins such as growth factors, cytokines and chemokines play important roles in tumor development. Through expression microarray and bioinformatic analysis, we discovered a novel secreted protein, neuroblastoma derived secretory protein (NDSP). The NDSP gene is found on chromosome 1q25.2 and encodes a 167 amino acid protein with a putative signal peptide. Using real-time PCR and immunoblotting we find that NDSP is specifically overexpressed in neuroblastoma at much higher levels than other adult and pediatric malignancies and normal tissues. NDSP is an 18 kDa protein that can be secreted by NDSP-transfected HEK-293T cells, as well as, neuroblastoma cell lines endogenously expressing NDSP. Inhibiting NDSP expression in neuroblastoma cell lines with retrovirally transduced NDSP small hairpin interfering RNA (shRNA), sh-NDSP, results in decreased cellular proliferation and colony formation. We also find inhibited ERK1/2 phosphorylation in the sh-NDSP cell line. Treating the parental cell line with MEK1/2 inhibitors which diminish ERK1/2 phosphorylation results in decreased cell proliferation. Culturing these transduced cells with recombinant NDSP, reintroducing NDSP overexpression in the knockdown cell line, or inducing Ras oncogene overexpression for constitutive ERK1/2 activation results in a reversal of the growth inhibited phenotype and proliferation rates similar to the control cells. In addition, reintroduction of NDSP overexpression in the sh-NDSP cell line results in ERK1/2 phosphorylation similar to control. We conclude that NDSP is specifically overexpressed in neuroblastoma and actively secreted from tumor cells. Furthermore, NDSP serves as a growth factor for neuroblastoma tumor cells through activation of the ERK-mediated proliferation pathway.

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Corresponding Author: (Same for reprint requests), Oluyinka Olutoye, MB, ChB, PhD, Division of Pediatric Surgery, Baylor College of Medicine, 6621 Fannin St, CC650.00, Houston, TX 77030-2399, Tel: (832) Fax: (832) 825-3141, oolutoye@bcm.tmc.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.Presented at the 39 th Annual Meeting of the Canadian Association of Pediatric Surgeons. Winner of the best basic science paper presentation (ANG). NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptIntroduction-GCSF is commonly employed for the treatment of chemotherapy-induced neutropenia. Despite high-dose intensive chemotherapy for advanced stage neuroblastoma, the survival rate remains poor. GCSF therapy is quite common in these children, thus we questioned its effect on neuroblastoma cells. We hypothesized that exogenous GCSF stimulates the proliferation and invasive character of neuroblastoma cells.

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