An IκB kinase 2 inhibitor IMD‐0354 suppresses the survival of adult T‐cell leukemia cells

Abstract

Adult T-cell leukemia (ATL) is a fatal T-cell malignancy associated with human T-cell leukemia virus type I infection. The aberrant expression of nuclear factor-jB (NF-jB) is considered to contribute to the malignant phenotype and chemo-resistance of ATL cells. Because of the poor prognosis of ATL, the development of new therapeutic strategies is direly needed. In the present study, we show that an IjB kinase 2 (IKK2) inhibitor, IMD-0354, efficiently inhibits the survival of CD4 + CD25+ primary ATL cells and prevents the growth of or induces apoptosis of patient-derived ATL cell lines. Assays of transcription with integrated forms of reporter genes revealed that IMD-0354 suppresses NF-jB-dependent transcriptional activity. Moreover, the daily administration of IMD-0354 prevents the growth of tumors in mice inoculated with ATL cells. Our results suggest that targeting IKK2 with a small molecule inhibitor, such as IMD-0354, is an attractive strategy for the treatment of ATL. (Cancer Sci 2012; 103: 100-106) H uman T-cell leukemia virus type I (HTLV-I) is the etiological agent of adult T-cell leukemia (ATL) and is known to transform T lymphocytes.(1-3) While the majority of infected individuals remain asymptomatic during their lifetime, 2-5% of carriers develop an aggressive form of CD4-positive T-cell leukemia after a long latency period of 50-60 years, and another 0.25-3% of carriers develop a chronic neuro-inflammatory disorder termed HTLV-I-associated myelopathy ⁄ tropical spastic paraparesis.(4-7) At present, there are few established regimens for ATL treatment, mainly because of the intrinsic resistance to conventional drug therapies.(8) Thus, novel therapeutic interventions are urgently required. Although the viral oncoprotein Tax is believed to play a central role in HTLV-I-induced leukemogenesis, (9,10) the expression levels of Tax and other viral proteins are extremely low in leukemic cells freshly isolated from ATL patients and ATL-derived cell lines. (11,12) The tax gene is even mutated or truncated in some ATL cases. (13,14) Thus, Tax might not necessarily be required at later stages of disease progression, and Tax-independent mechanisms are likely to contribute to the proliferation and resistance to apoptosis of leukemic cells. The constitutive activation of nuclear factor-jB (NF-jB) was found in peripheral ATL cells and ATL-derived cell lines, (15) implying important prosurvival roles of NF-jB in ATL cells. Nuclear factor-jB activation has long been implicated in association with multiple processes of oncogenesis, including cell-cycle progression, control of apoptosis, migration, and metastasis.(16) Thus, the inhibition of NF-jB was suggested to be a potential means for cancer therapy in tumors highly expressing NF-jB. (17) We previously reported that a reduction of NF-jB activity by the forced expression of a dominantnegative form of IjBa strongly suppresses the survival of ATL cell lines, and that abrogation of NF-jB activity by a protease inhibitor, ritonavir, significantly prevented the growth ...

IKKβ Regulates VEGF Expression and Is a Potential Therapeutic Target for Ovarian Cancer as an Antiangiogenic Treatment

“…For these reasons, we assume that IMD-0354 would be an ideal candidate because it is feasible for combination with current chemotherapies. Several previous studies have reported the effect of IMD-0354 on adult T-cell leukemia cells (20), breast cancer cells (35) or chronic lymphocytic leukemia cells (36). In these studies, at higher concentrations (1-50 mmol/L), IMD-0354 induced apoptosis of cancer cells.…”

“…IMD-0354 is a synthesized low molecular weight compound that specifically inhibits IKKb, inducing the inhibition of NF-kB activation only in inflammatory conditions, and it was proven that this drug does not inhibit other kinases, proteases, or proteasome-related immune responses (34). No IKKb inhibitor is known to be in the process of clinical application at present, except for IMD-1041, a prodrug of IMD-0354; a phase I study with the IMD-0354 capsule confirmed sufficient safety (20). Since it appears obvious that the mere inhibition of NF-kB would be insufficient for a pronounced response unless combined with apoptosis-inducing drugs for ovarian cancer treatment, NF-kB inhibitors should be used as adjuvants along with cytotoxic chemotherapies in the clinical setting.…”

“…IMD-1041 is a prodrug of IMD-0354 for oral administration and on its way to clinical application at present. A phase I study was completed and up to 12 weeks of IMD-1041 administration proved to be sufficiently safe with very few adverse events ranked as mild (20). Therefore, we determined to elucidate the effect of this drug on ovarian cancer cells, focusing especially on VEGF expression.…”

A Novel IKK Inhibitor Prevents Progression of Restenosis After Arterial Injury in Mice

“…37) Several reports demonstrated that IMD-0354 induced apoptosis of cancer related cells, 38) therefore, this drug may have the same effects on VSMC. Further study will be needed to clarify the role of IMD-0354 on the apoptotic effects in the progression of vascular remodeling.…”

The Nf-κb Inhibitor Imd-0354 Targets Human Non-Small Cell Lung Cancer Stem Cells and Combined with Chemotherapy Reduces Multidrug Resistance

“…IMD-0354, an inhibitor of the NF-κB pathway, was initially developed to inhibit inflammation [51,52], but recently proven to have anticancer properties [24,53,54]. Here, we wanted to assess if IMD-0354 also affects CSCs, as indicated by prior screening.…”