title: Interaction of human telomeric G-quadruplex DNA with thymoquinone: a possible mechanism for thymoquinone anticancer effect.
abstract: BACKGROUND
  Thymoquinone (TQ) has been documented to possess chemo-preventive and chemotherapeutic antitumor effects. Studies reported that TQ inhibits the growth of cancer cells in animal models, culture and xenografted tumors. Molecular mechanisms underlying these anticancer effects were attributed to inductions of cell cycle arrest, apoptosis, oxidative damage of cellular macromolecules, blockade of tumor angiogenesis and inhibitions in migration, invasion and metastasis of cancer cells. On the other hand, human telomere DNA plays a role in regulating genes' transcriptions. It folds up into G-quadruplex structures that inhibit telomerase enzyme over-expressed in cancerous cells. Molecules that selectively stabilize G-quadruplex are potential anticancer agents. Therefore, this work aimed to explore the interaction of TQ with G-quadruplex DNA as a possible underlying mechanism for the anticancer effect of TQ.
  
  
  METHODS
  Interactions of TQ with telomeric G-quadruplex (5'-AGGG(TTAGGG)3-3') and duplex DNAs were studied using UV-vis, fluorescence, circular dichroism, liquid and solid NMR (1H and 13C), melting temperature and docking simulation.
  
  
  RESULTS
  Changes in UV-vis, CD, fluorescence, 1H NMR and 13C NMR, spectra as well as melting temperatures and docking simulations provided evidences for TQ's interactions with G-quadruplex. TQ was found to interact with G-quadruplex on two binding sites adjacent to the TTA loop with binding constants 1.80×10(5) and 1.12×10(7) M(-1). Melting temperatures indicated that TQ stabilized G-quadruplex by 5.6 °C and destabilized ct-DNA by 5.1 °C. Selectivity experiment indicated that TQ is preferentially binding to G-quadruplex over duplex with selectivity coefficients of 2.80-3.33×10(-3). Results suggested an intercalation binding mode based on π-π stacking.
  
  
  CONCLUSIONS
  Our results propose that TQ can possibly act as a G-quadruplex DNA stabilizer and subsequently contribute to the inhibition of telomerase enzyme and cancer's proliferation.
  
  
  CONCLUSIONS
  Our results represent a change in the paradigms reported for structural features of G-quadruplex's stabilizers and anticancer mechanisms of TQ.
authors.affiliation: Department of Chemistry, College of Science, United Arab Emirates University, P.O. Box 15551, Al Ain, United Arab Emirates. Electronic address: asalem@uaeu.ac.ae.
authors.forename: Alaa A
authors.initials: AA
authors.lastname: Salem
authors.affiliation: Department of Chemistry, College of Science, United Arab Emirates University, P.O. Box 15551, Al Ain, United Arab Emirates.
authors.forename: Ismail A
authors.initials: IA
authors.lastname: El Haty
authors.affiliation: Department of Chemistry, College of Science, United Arab Emirates University, P.O. Box 15551, Al Ain, United Arab Emirates.
authors.forename: Ibrahim M
authors.initials: IM
authors.lastname: Abdou
authors.affiliation: School of Biological Sciences, College of Science, Nanyang Technological University, Singapore 637551, Singapore.
authors.forename: Yuguang
authors.initials: Y
authors.lastname: Mu
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D016227:Benzoquinones / Q000737:chemistry*; D004273:DNA, Neoplasm / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008956:Models, Chemical; D009690:Nucleic Acid Conformation; D016615:Telomere / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D004273:DNA, Neoplasm; C003466:thymoquinone
keywords: Anticancer; Calf thymus DNA; DNA; G-quadruplex; Human telomere; Thymoquinone