Emodin and DHA potently increase arsenic trioxide interferon-α–induced cell death of HTLV-I–transformed cells by generation of reactive oxygen species and inhibition of Akt and AP-1

Abstract

Adult T-cell leukemia (ATL) is an aggressive lymphoproliferative disease of poor clinical prognosis associated with infection by the human T-cell leukemia virus type I (HTLV-I). The use of arsenic trioxide (As 2 O 3 ) has been shown to effectively treat acute promyelocytic leukemia (APL) with greater than 80% of patients achieving complete remission. The combination of arsenic and interferon has also shown promising results in the treatment of ATL.The requirement for slow dosage increases of arsenic and the time required to achieve a pharmacologic active dose in patients is a major obstacle because median survival of patients with ATL is about 6 months. In this study we report a potent synergistic effect of the combination of arsenic trioxide and interferon ␣ (As/IFN-␣) with emodin and DHA on cellcycle arrest and cell death of HTLV-Iinfected cells. Importantly, we found that clinically achievable doses of DHA and emodin allowed for reduced arsenic concentrations by 100-fold while still remaining highly toxic to tumor cells. Our data provide a rationale for combined use of As/IFN-␣ with emodin and DHA in patients with ATL refractory to conventional therapy. ( IntroductionAdult T-cell leukemia (ATL) is associated with a poor clinical prognosis, and treatment of patients using conventional chemotherapy has limited benefit given that HTLV-I cells are resistant to conventional anticancer, apoptosis-inducing agents. 1-3 Cyclophosphamide, adriamycin, vincristine, and prednisolone (CHOP) protocol has a reported 17% rate of remission but a predicted survival of less than 15% after 3 years. [4][5][6] Some success has been reported in treating ATL with a combination of zidovudine (AZT) and IFN-␣. [7][8][9][10] However, this success is fleeting as many patients relapse, because response to therapy requires the presence of a transcriptionally active p53 gene. 11 Other treatments include bone marrow transplantation, 12-14 topoisomerase inhibitors, 15,16 anti-Tac monoclonal antibody, 17 inhibitors of NF-kB 18,19 and proteasome inhibitors. 20 Arsenic trioxide in combination with IFN-␣ is very effective in treating APL [21][22][23] and showed promising results in the treatment of patients with ATL. [24][25][26][27][28][29] However, differences in sensitivity to arsenic, as well as the toxicity associated with its use, require a slow dose increase in vivo, and treatment may need to be discontinued in some patients with ATL. Thus, it is worthwhile to investigate the effectiveness of docosahexaenoic acid (DHA) a nontoxic -3 polyunsaturated fatty acid found in fish oil. HL-60, an acute myeloid leukemia cell line that is resistant to clinically relevant doses of arsenic, shows a 90% reduction in viability along with an increase in apoptosis, an increase in intracellular reactive oxygen species (ROSs) and lipid peroxidation, as well as an up-regulation of Bax when treated with a combination of arsenic and DHA. 30 Further, treatment with oleic acid, a monounsaturated fatty acid that is not susceptible to lipid peroxidation, did not en...

An anthraquinone derivative, emodin sensitizes hepatocellular carcinoma cells to TRAIL induced apoptosis through the induction of death receptors and downregulation of cell survival proteins

“…Emodin exerts its pleiotropic anti-cancer effects through diverse mechanisms including the activation of caspase-3 [23] and upregulation of p53 and p21 [26]. Moreover, emodin has been reported to inhibit the kinase activity/activation of p56lck, HER2/neu [21], casein kinase [27], NF-jB [28], activator protein 1 [29,30], AKT [30], matrix metalloproteinases [29,31], and the expression of chemokine receptor CXCR4 [32]. Our findings specifically in HCC cells clearly indicate that this quinone can enhance TRAIL-induced apoptosis through the downregulation of antiapoptotic proteins, upregulation of death receptors and the activation of C/EBP homologous protein (CHOP).…”

NK314 potentiates antitumor activity with adult T-cell leukemia-lymphoma cells by inhibition of dual targets on topoisomerase IIα and DNA-dependent protein kinase

“…Based on these studies, targeting therapies for various molecules, such as Tax, NF-B, Akt/PKB, mTOR, CD25, CD52, and chemokine receptor-4, have been developed under clinical or preclinical investigations using small molecules or monoclonal antibodies. [12][13][14][15][16][17][18][19][20][21][22][23] The DNA repair system is also a promising target for sensitization of cancer treatment. [24][25][26] Although genetic instability of proliferating cells is necessary for most cell types to become malignant, cells that are overly unstable genetically will die.…”

Emodin Has Cytotoxic and Protective Effects in Rat C6 Glioma Cells: Roles of Mdr1a and Nuclear Factor κB in Cell Survival

“…This compound also triggers mitochondrial dysfunction, Bcl-2 and Bax modulation, mitochondrial cytochrome c release, and caspase activation, leading to apoptosis (Su et al, 2005). Emodin induces apoptosis in human proximal tubular epithelial HK-2 cells through the caspase-3-dependent pathway (Wang et al, 2007a) and increases arsenic trioxide interferon-␥-induced cell death of HTLV-Itransformed cells by ROS generation and inhibition of AKT and AP-1 (Brown et al, 2007).…”