title: Spiruchostatin A and B, novel histone deacetylase inhibitors, induce apoptosis through reactive oxygen species-mitochondria pathway in human lymphoma U937 cells.
abstract: Spiruchostatin A (SP-A) and spiruchostatin B (SP-B) are the potent histone deacetylase inhibitors (HDACi), that has the potential for chemotherapy of leukemia but the exact mechanism of these compounds remains unclear. In the present study, the role of reactive oxygen species (ROS) production and the mechanism involved in the apoptosis was investigated in human lymphoma U937 cell. When the U937 cells were treated with SP-A and SP-B for 24h at different concentrations, evidence of apoptotic features, including increase in DNA fragmentation and changes in nuclear morphology, were obtained. SP-B showed maximum potency to induce apoptosis, while SP-A was less potent. Apoptosis was also determined by increase in the fraction of sub-G1 cells and Annexin V-FITC staining cells. SP-A and SP-B induced apoptosis was accompanied by significant increase in the formation of intracellular reactive oxygen species (ROS). Pre-treatment with N-acetyl-l-cysteine (NAC), significantly inhibited the SP-A and SP-B mediated apoptosis, suggesting a vital role of ROS involved in the lethality of both agents. Moreover, SP-A and SP-B treatment resulted in the loss of mitochondrial membrane potential (MMP), and Fas, caspase-8 and caspase-3 activation. In addition Bid activation and the release of cytochrome-c to the cytosol was also observed. In this study, we suggest that a marked induction of intracellular ROS mediated mitochondrial pathway and the Fas plays a role in the SP-A and SP-B induced apoptosis. Taken together, our data provides further insights of the mechanism of action of SP-A and SP-B and their potential application as novel chemotherapeutic agents.
authors: Department of Dermatology, Graduate School of Medicine and Pharmaceutical Science, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
authors: Mati Ur
authors: MU
authors: Rehman
authors: Department of Radiological Sciences, Graduate School of Medicine and Pharmaceutical Science, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
authors: Paras
authors: P
authors: Jawaid
authors: Department of Dermatology, Graduate School of Medicine and Pharmaceutical Science, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
authors: Yoko
authors: Y
authors: Yoshihisa
authors: Department of Radiological Sciences, Graduate School of Medicine and Pharmaceutical Science, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
authors: Peng
authors: P
authors: Li
authors: Department of Radiological Sciences, Graduate School of Medicine and Pharmaceutical Science, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
authors: Qing Li
authors: QL
authors: Zhao
authors: Laboratory of Synthetic and Medicinal Chemistry, Faculty of Chemical Pharmaceutical Science, Tohoku Pharmaceutical University, Aoba-ku, Sendai 981-8558, Japan.
authors: Koichi
authors: K
authors: Narita
authors: Laboratory of Synthetic and Medicinal Chemistry, Faculty of Chemical Pharmaceutical Science, Tohoku Pharmaceutical University, Aoba-ku, Sendai 981-8558, Japan.
authors: Tadashi
authors: T
authors: Katoh
authors: Department of Radiological Sciences, Graduate School of Medicine and Pharmaceutical Science, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan. Electronic address: kondot@med.u-toyama.ac.jp.
authors: Takashi
authors: T
authors: Kondo
authors: Department of Dermatology, Graduate School of Medicine and Pharmaceutical Science, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
authors: Tadamichi
authors: T
authors: Shimizu
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D047630:Depsipeptides / Q000737:chemistry / Q000494:pharmacology*; D005434:Flow Cytometry; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000032:analysis / Q000378:metabolism*; D020298:U937 Cells
chemical_list: D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D010456:Peptides, Cyclic; D017382:Reactive Oxygen Species; C529984:spiruchostatin B; C485419:spiruchostatin A
keywords: Apoptosis; HDAC inhibitors; ROS; Spiruchostatin A; Spiruchostatin B