Interaction of human telomeric G-quadruplex DNA with thymoquinone: A possible mechanism for thymoquinone anticancer effect

Alaa A. Salem, Ismail A. El Haty, Ibrahim M. Abdou, Yuguang Mu

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)

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 × 105 and 1.12 × 107 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.

Conclusion 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. General significance Our results represent a change in the paradigms reported for structural features of G-quadruplex's stabilizers and anticancer mechanisms of TQ.

Original languageEnglish
Pages (from-to)329-342
Number of pages14
JournalBiochimica et Biophysica Acta - General Subjects
Volume1850
Issue number2
DOIs
Publication statusPublished - Feb 2015

Keywords

  • Anticancer
  • Calf thymus DNA
  • DNA G-quadruplex
  • Human telomere
  • Thymoquinone

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology

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