The Synthetic Triterpenoid 2-Cyano-3,12-dioxooleana-1,9-dien-28-oic Acid Induces Caspase-Dependent and -Independent Apoptosis in Acute Myelogenous Leukemia

Abstract

In acute myeloid leukemia (AML), resistance to chemotherapy is associated with defects in both the extrinsic and intrinsic pathways of apoptosis. Novel agents that activate endogenous apoptosis-inducing mechanisms directly may be potentially useful to overcome chemoresistance in AML. We examined the mechanisms of apoptosis induction by the novel synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) in AML cells. CDDO-induced apoptosis was associated with the loss of mitochondrial inner transmembrane potential, caspases activation, the translocation of apoptosis-inducing factor to the nucleus, and DNA fragmentation in AML cells. Apoptosis was equally evident in cells deficient in caspase-9 or caspase-8 after exposure to CDDO, suggesting caspaseindependent cell death. The use of small interfering RNA to reduce the expression of apoptosis-inducing factor partially inhibited CDDO-induced apoptosis in AML cells. Cells overexpressing Bcl-2 were markedly resistant to CDDO-induced apoptosis. Moreover, CDDO promoted the release of cytochrome c from isolated mitochondria, suggesting that CDDO targets the mitochondria directly to trigger the intrinsic pathway of cell death in intact cells. Together, these results suggest that CDDO functions by activating the intrinsic pathway of apoptosis and initiates caspase-dependent and independent cell death. The direct modulation of mitochondrialmediated, caspase-independent apoptosis by CDDO may be advantageous for overcoming chemoresistance in AML.

CDDO-imidazolide mediated inhibition of malignant cell growth in Waldenström macroglobulinemia

“…1 cells is caspase mediated, but not totally caspase dependent. Consistent with these results, in acute myelogenous leukemia,CDDO has been found to induce both caspase-dependent and caspase-independent apoptosis [16].…”

“…Studies have shown that CDDO-Im is more potent than its parent compound, CDDO, against murine melanoma and leukemic cells [7]. ST have been shown to provide effective control of cell growth of several tumor cell types [8] including breast cancer [9], lung cancer [10], ovarian cancer [11], melanoma [7], osteosarcoma [12], leukemia [13][14][15][16][17] and multiple myeloma cells [18,19]. Both CDDO and CDDO-Me are currently in Phase I clinical trials, with CDDO-Me being used in an oral form, highlighting the potential importance of these drugs as anti-cancer agents.…”

“…At the molecular level, ST have been shown to induce apoptosis of cancer cells by both caspasedependent and caspase-independent mechanisms [16]. They have also been shown to bind to and induce cell death through the nuclear receptor peroxisome proliferator activator receptorgamma (PPAR□) [20].…”

CDDO induces granulocytic differentiation of myeloid leukemic blasts through translational up-regulation of p42 CCAAT enhancer–binding protein alpha

“…CDDO induces apoptosis through both caspase-independent and -dependent mechanisms, the latter involving caspase-8 activation, Bid cleavage, cytochrome c release, and caspase-3 activation. [3][4][5][6] Furthermore, JNK, p38, and ERK pathways are involved in CDDO-induced apoptosis of tumor cell lines [7][8][9] mediated by disrupted intracellular redox balance and involving decreased glutathione and increased reactive oxygen species [9][10][11][12] CDDO-induced growth arrest of breast cancer cell lines correlates with transactivated PPARgamma and leads to up-regulation of p21 cip1waf1 , GADD153, CCAAT enhancer-binding proteins (CEBPs), and proteasome-regulatory factors, and to down-regulation of cyclin D1, PCNA, and IRS1. 13 CDDO and CDDO-Im activate the TGF␤ pathway through activation of Smad2/3, 14,15 which is required for the repression of inflammatory molecules by CDDO.…”

Targeted inhibition of tumor proliferation, survival, and metastasis by pentacyclic triterpenoids: Potential role in prevention and therapy of cancer

“…Synthetic OA derivatives modulated multiple signaling pathways and intracellular signaling molecules including NF-jB, AKT, STAT3, mTOR, caspases-3, -8, and -9, ICAM-1, VEGF, and PARP in a variety of cancer cells [14,[154][155][156]. In particular, synthetic OA derivatives induced apoptosis of acute myelogenous leukemia cells, upregulated c-Jun NH2 kinase mediated upregulation of DR5 in lung cancer cells and inhibited angiogenesis, invasion and metastasis of tumor cells [157][158][159]. The induction of phase-2 enzymes, such as hemeoxygenase 1 and NADPH-quinone oxidoreductase occurs by modulating Nrf2-Keap1 signaling pathway [160].…”