title: Thymoquinone Promotes Pancreatic Cancer Cell Death and Reduction of Tumor Size through Combined Inhibition of Histone Deacetylation and Induction of Histone Acetylation.
abstract: Pancreatic ductal adenocarcinoma (PDAC) is virtually therapy-resistant. As noninvasive lesions progress to malignancy, the precursor period provides a window for cancer therapies that can interfere with neoplastic progression. Thymoquinone (Tq), a major bioactive component of essential oil fromNigella sativa's seeds, has demonstrated antineoplastic activities in multiple cancers. In this study, we investigated antineoplastic potential of Tq in human PDAC cell lines, AsPC-1 and MiaPaCa-2. Tq (10-50μM) inhibited cell viability and proliferation and caused partial G2 cycle arrest in dose-dependent manner in both cell lines. Cells accumulated in subG0/G1 phase, indicating apoptosis. This was associated with upregulation of p53 and downregulation of Bcl-2. Independently of p53, Tq increased p21 mRNA expression 12-fold. Tq also induced H4 acetylation (lysine 12) and downregulated HDACs activity, reducing expression of HDACs 1, 2, and 3 by 40-60%. In vivo, Tq significantly reduced tumor size in 67% of established tumor xenografts (P< 0.05), along with increased H4 acetylation and reduced HDACs expression. Our results showed that Tq mediated posttranslational modification of histone acetylation, inhibited HDACs expression, and induced proapoptotic signaling pathways. These molecular targets demonstrate rationale for using Tq as a promising antineoplastic agent to prevent postoperative cancer recurrence and to prolong survival of PDAC patients after surgical resection.
authors.affiliation: Departments of Surgery, Jefferson Pancreatic, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Relles
authors.affiliation: Department of Biomedical Sciences, University of New England, Biddeford, ME, USA.
authors.forename: Galina I
authors.identifier: 0000-0002-2397-3230
authors.initials: GI
authors.lastname: Chipitsyna
authors.affiliation: Departments of Surgery, Jefferson Pancreatic, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Qiaoke
authors.initials: Q
authors.lastname: Gong
authors.affiliation: Departments of Surgery, Jefferson Pancreatic, Biliary and Related Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Charles J
authors.identifier: 0000-0001-8097-0071
authors.initials: CJ
authors.lastname: Yeo
authors.affiliation: Department of Biomedical Sciences, University of New England, Biddeford, ME, USA.
authors.forename: Hwyda A
authors.identifier: 0000-0003-3400-7705
authors.initials: HA
authors.lastname: Arafat