High expression of the longevity gene product SIRT1 and apoptosis induction by sirtinol in adult T‐cell leukemia cells

Abstract

Adult T-cell leukemia-lymphoma (ATL) is an aggressive peripheral T-cell neoplasm that develops after long-term infection with human T-cell leukemia virus (HTLV-1). SIRT1, a nicotinamide adenine dinucleotide 1 -dependent histone/protein deacetylase, plays a crucial role in various physiological processes, such as aging, metabolism, neurogenesis and apoptosis, owing to its ability to deacetylate numerous substrates, such as histone and NF-jB, which is implicated as an exacerbation factor in ATL.Here, we assessed how SIRT1 is regulated in primary ATL cells and leukemic cell lines. SIRT1 expression in ATL patients was significantly higher than that in healthy controls, especially in the acute type. Sirtinol, a SIRT1 inhibitor, induced significant growth inhibition or apoptosis in cells from ATL patients and leukemic cell lines, especially HTLV-1-related cell lines. Sirtinolinduced apoptosis was mediated by activation of the caspase family and degradation of SIRT1 in the nucleus. Furthermore, SIRT1 knockdown by SIRT1-specific small interfering RNA caused apoptosis via activation of caspase-3 and PARP in MT-2 cells, HTLV-1-related cell line. These results suggest that SIRT1 is a crucial antiapoptotic molecule in ATL cells and that SIRT1 inhibitors may be useful therapeutic agents for leukemia, especially in patients with ATL.

Sirtuin Inhibition Induces Apoptosis-like Changes in Platelets and Thrombocytopenia

“…Sirtuin Inhibition Induces Apoptosis-like Signaling in Human Platelets in Vitro-Sirtinol is known to possess antitumor activity and to induce apoptosis in several cancer cell lines (7)(8)(9). To examine the effect of sirtuin inhibitors on platelets, we studied ⌬ m , an indicator of intrinsic cell death, in both sirtinol-as well as EX-527-treated platelets.…”

“…Sirtinol is a cell-permeable six-membered lactone ring derived from naphthol and is a dual Sirt1/Sirt2 inhibitor of low potency (6). Sirtinol has been reported to induce senescence-like growth arrest in human breast cancer cells as well as in H1299 and leukemic cells (7)(8)(9). EX-527 is a potent and selective Sirt1 inhibitor (10).…”

“…Inhibition of sirtuins with sirtinol attenuated the activation phenotype of platelets, which included agonist-induced platelet aggregation, a rise in intracellular Ca 2ϩ , and the generation of thromboxane B2 (6). However, it is not yet clear whether sirtuins have any role in platelet survival, as demonstrated for other cells (7)(8)(9). Earlier studies, including ours, have shown that delimitation of platelet life span involves balancing interactions between Bcl-X L , Bax/Bak, and the proteasome system (14,15).…”

The Investigation of the Apoptose Structural Effects and Mechanism in Leukemic Cells of Sirt1 Inhibitor Sirtinol

“…Caspase 3 is an important mediator of apoptosis. It has been shown in previous studies that Sirtinol apoptosed Jurkat and that Caspase3 was involved in this process [6]. However, the effect on Bax and Bcl2 was not studied.…”

“…Sirtrin has been shown to induce apoptosis in adult T-cell leukemia cells [6]. However, no study investigating the apoptotic effect and mechanism of Sirtinol in Chronic Myeloid Leukemia (CML) cells has been found.…”