stilbenes and HTLV-I-Infections

Adult T-cell leukemia (ATL) is an aggressive malignancy of peripheral T cells infected with human T-cell leukemia virus type 1 (HTLV-1). The prognosis of patients with aggressive ATL remains poor because ATL cells acquire resistance to conventional cytotoxic agents. Therefore, development of novel agents is urgently needed. We examined the effects of resveratrol, a well-known polyphenolic compound, on cell proliferation and survival of HTLV-1-infected T-cell lines, MT-2 and HUT-102. We found that resveratrol suppressed cell proliferation and induced cell death of MT-2 and HUT-102 cells. Immunoblot analysis showed inhibition of myeloid cell leukemia sequence (Mcl)-1 and cellular inhibitor of apoptosis protein (cIAP)-2 expression as well as signal transducers and activators of transcription (STAT) 3 phosphorylation at Tyr(705) and Ser(727) in resveratrol-treated cells. We also observed cleavage of caspase-3 and poly(ADP-ribose) polymerase in resveratrol-treated cells, indicating that resveratrol induces caspase-dependent apoptosis in MT-2 and HUT-102 cells. In addition, the STAT3 inhibitor S3I-201 not only induced cell growth arrest and cell death but also activated caspase-3 in MT-2 and HUT-102 cells, indicating that STAT3 may be a therapeutic target for ATL. These results suggest that resveratrol presents a potent anti-proliferative effect in part via the suppression of STAT3 phosphorylation and Mcl-1 and cIAP-2 expression in HTLV-1-infected T cells. Resveratrol merits further investigation as a potential chemotherapeutic agent for ATL.

Topics: Antimutagenic Agents; Baculoviral IAP Repeat-Containing 3 Protein; Cell Proliferation; Cells, Cultured; Drug Evaluation, Preclinical; Gene Expression Regulation; HTLV-I Infections; Human T-lymphotropic virus 1; Humans; Inhibitor of Apoptosis Proteins; Myeloid Cell Leukemia Sequence 1 Protein; Phosphorylation; Protein Kinases; Resveratrol; STAT3 Transcription Factor; Stilbenes; T-Lymphocytes; Ubiquitin-Protein Ligases

Resveratrol, a phytoalexin found in grapes and wine, has been shown to exhibit a wide range of pharmacological properties and is believed to play a role in the chemoprevention of human cancer. Resveratrol has also been shown to induce antiproliferation and apoptosis of several leukemia cell lines. In the present study, we investigated the effect of resveratrol in adult T cell leukemia. Our present observations showed that resveratrol induced growth inhibition in all five human T cell lymphotrophic virus-1-infected cell lines examined, with 50% effective dose of 10.4-85.6 mM. In the resveratrol-treated cells, induction of apoptosis was confirmed by annexin V-based analyses and morphological changes. The most surprising observation was that resveratrol treatment resulted in a gradual decrease in the expression of survivin, an antiapoptotic protein, during cell apoptosis. These findings indicate that resveratrol inhibits the growth of human T cell lymphotrophic virus-1-infected cell lines, at least in part, by inducing apoptosis mediated by downregulation in survivin expression. In view of the accumulating evidence that survivin may be an important determinant of a clinical response in adult T cell leukemia, our present findings have led to the suggestion that resveratrol, a common constituent of the human diet, merits further investigation as a potential therapeutic agent for this incurable disease.

Topics: Adult; Annexin A5; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Cell Line; Cysteine Proteinase Inhibitors; Down-Regulation; Flow Cytometry; Gene Expression; HTLV-I Infections; Humans; Inhibitor of Apoptosis Proteins; Leukemia-Lymphoma, Adult T-Cell; Microtubule-Associated Proteins; Neoplasm Proteins; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; Stilbenes; Survivin