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...
