Effects of the proteasome inhibitor PS-341 on tumor growth in HTLV-1 Tax transgenic mice and Tax tumor transplants

Abstract

IntroductionHuman T-cell leukemia/lymphotropic virus type 1 (HTLV-1) infection is present in 10 to 20 million people worldwide. 1,2 HTLV-1 infection results in 2 different diseases: adult T-cell leukemia/lymphoma (ATLL or ATL) and the neurologic disorder tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/ HAM). 3,4 Although the epidemiology and clinical characteristics of HTLV-1 infection are defined, the molecular mechanisms used by the virus to establish persistent infection and subsequently promote lymphocyte proliferation and the host immune evasion remain poorly understood. Thus, the quest for appropriate antiviral therapy and a vaccine are difficult, but important. The vast majority of patients with ATL present with resistance to chemotherapy, limiting survival to less than a year. 5,6 Recent investigation of the molecular events associated with HTLV progression has identified a number of molecular targets within the virus and the host that could represent excellent targets for therapeutic intervention. The 40-kDa transactivator protein, Tax, mediates the transition from latency to virion production by interacting with specific host proteins associated with cellular transcriptional pathways such as nuclear factorB (NF-B), cyclic adenosine monophosphate response element-binding-activating transcription factor (CREB/ATF), serum response factor (SRF), stimulatory protein 1 (SP1), and early growth response protein 1 (EGR-1). Through interaction with cellular transcription factors, Tax potently activates transcription from the viral promoter and enhancer elements of many cellular genes involved in host cell proliferation. 7,8 The oncogenic potential of Tax has been demonstrated in animal models, 9-12 and activation of NF-B has been implicated as a critical feature of transformation. 13,14 Tax may be responsible for many of the required events necessary for HTLV-1-mediated lymphocyte immortalization and transformation.The NF-B family of transcription factors participates in regulation of diverse biologic processes, including immune responses, cell growth, and apoptosis. [15][16][17][18][19] Mammalian cells express 5 NF-B members, RelA, RelB, c-Rel, p50, and p52, which function as various homodimers and heterodimers. 20 The NF-B factors are normally sequestered in the cytoplasm through physical interaction with ankyrin repeat-containing inhibitors, including IB␣ and related proteins. 21 A well-characterized pathway leading to NF-B activation is through phosphorylation and subsequent degradation of IB␣. 22,23 This canonical NF-B signaling pathway depends on a multisubunit IB kinase (IKK), which responds to various stimuli, such as the inflammatory cytokine tumor necrosis factor ␣ (TNF-␣), the mitogen phorbol 12-myristate 13-acetate (PMA), and certain viral proteins. 15,24,25 IKK is composed of 2 catalytic subunits, IKK␣ and IKK␤, and a regulatory subunit, IKK␥ (also named NEMO, IKKAP1,. 26 Another level of NF-B regulation is via processing of the NF-B1 and NF-B2 precursor proteins p105 and p100, a prot...

Animal models for human T-lymphotropic virus type 1 (HTLV-1) infection and transformation

“…The proteasome inhibitor, borteozomib, inhibits the degradation of the inhibitor of NF-kB, IkBa. It was shown to inhibit NF-kB activation in ATL cells and Tax transgenic tumor cells in culture and in mouse transplantation studies (Tan and Waldmann, 2002;Satou et al, 2004;Mitra-Kaushik et al, 2004b). In several of these studies, the majority of the cell death was found to be due to apoptosis.…”

Human T-Cell Lymphotropic Virus (HTLV-1) and Adult T-Cell Leukemia

“…One of its mechanisms is suppression of the NF-κB pathway by inhibiting the proteasomal degradation of IκB protein. Several groups have shown that Bortezomib is effective against ATL cells both in vitro and in vivo (Mitra-Kaushik et al 2004). The sensitivity to Bortezomib is well correlated with the extent of NF-κB activation.…”

Pathogenesis and Treatment of Human T-Cell Leukemia Virus Infection

“…Inhibitors of NF-κB activation, including sodium salicylate and cyclopentenone prostaglandins, blocked tumor cell proliferation in culture and sensitized the cells to γ irradiation. A proteasome inhibitor, PS-341 or bortezomib (Velcade), which blocks degradation of the inhibitor of NF-κB, also inhibited tumor cell proliferation in culture and sensitized cells to γ irradiation-induced apoptosis (29). Moreover, PS-341 inhibited tumor cell proliferation in vivo in transgenic mice and mice transplanted with Tax transgenic tumor cells.…”