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. 2023 Jul 4;11(7):1891.
doi: 10.3390/biomedicines11071891.

Enhancing the Anti-Leukemic Potential of Thymoquinone/Sulfobutylether-β-cyclodextrin (SBE-β-CD) Inclusion Complexes

Eltayeb E M Eid  1 , Salah Abdalrazak Alshehade  2 , Amer A Almaiman  3 , Sareh Kamran  2 , Vannajan Sanghiran Lee  4 , Mohammed Abdullah Alshawsh  2
Affiliations

Enhancing the Anti-Leukemic Potential of Thymoquinone/Sulfobutylether-β-cyclodextrin (SBE-β-CD) Inclusion Complexes

Eltayeb E M Eid et al. Biomedicines. .

Abstract

Leukemia, a condition characterized by the abnormal proliferation of blood cells, poses significant challenges in cancer treatment. Thymoquinone (TQ), a bioactive compound derived from black seed, has demonstrated anticancer properties, including telomerase inhibition and the induction of apoptosis. However, TQ's poor solubility and limited bioavailability hinder its clinical application. This study explored the use of Sulfobutylether-β-cyclodextrin (SBE-β-CD), a cyclodextrin derivative, to enhance the solubility and stability of TQ for leukemia treatment. SBE-β-CD offers low hemolytic activity and has been successfully employed in controlled drug release systems. The study investigated the formation of inclusion complexes between TQ and SBE-β-CD and evaluated their effects on leukemia cell growth and telomerase activity. The results indicated that the TQ/SBE-β-CD complex exhibited improved solubility and enhanced cytotoxic effects against K-562 leukemia cells compared to TQ alone, suggesting the potential of SBE-β-CD as a drug delivery system for TQ. The annexin V-FITC assay demonstrated increased apoptosis, while the qPCR quantification assay revealed reduced telomerase activity in leukemia cells treated with TQ/SBE-β-CD, supporting its anti-leukemic potential. The molecular docking analysis indicated a strong binding affinity between TQ and telomerase. However, further research is needed to optimize the apoptotic effects and minimize necrosis induction. In conclusion, TQ/SBE-β-CD shows promise as a novel strategy for leukemia treatment by inhibiting telomerase and enhancing the cytotoxic effects of TQ, offering a potential solution to overcome the limitations of TQ's poor solubility and bioavailability.

Keywords: SBE-β-CD; apoptosis; drug delivery system; leukemia; telomerase inhibition; thymoquinone.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
(A–D) Cytotoxicity results of leukaemia cells (K-562) after 24, 48, 72, and 96 h of the treatment. The control group was untreated cells. Data are presented as mean ± SD. * p < 0.05, ** p < 0.01, *** p < 0.001 indicate significant differences between TQ and TQ/SBE-ß-CDs for the same concentration level.
Figure 2
Figure 2
(A) Flow cytometry graphs and result quantification in leukaemia cells after 96 h of treatment. (B) The control group remained untreated. Data are presented as mean ± SD; * p < 0.05, *** p< 0.001 indicate significant differences compared to control; ### p < 0.001 indicates significant differences between TQ- and TQ/SBE-ß-CDs-treated groups.
Figure 3
Figure 3
(A) Caspase 3/7, (B) Caspase 8, and (C) Caspase 9 activities induced by TQ, SBE-ß-CDs, and TQ/SBE-ß-CDs therapy in leukemia cells. Estimation was carried out using luminescence analysis at 96 h treatment. Data are presented as mean ± SD. * p < 0.05, ** p< 0.01, *** p < 0.001 indicates a significant difference compared to the control cells (untreated).
Figure 4
Figure 4
Quantitative PCR results of telomerase activity. Numbers represent the average fold reduction compared to the untreated cells. ** p < 0.01, *** p < 0.001.
Figure 5
Figure 5
Molecular docking modeling of thymoquinone with SBE-ß-CDs. (A) interaction geometry of TQ with SBE-β-CD; (B) interaction geometry of TQ with SBE-β-CD; (C) the interaction geometry of TQ with SBE-β-CD; (D) Thymoquinone.
Figure 5
Figure 5
Molecular docking modeling of thymoquinone with SBE-ß-CDs. (A) interaction geometry of TQ with SBE-β-CD; (B) interaction geometry of TQ with SBE-β-CD; (C) the interaction geometry of TQ with SBE-β-CD; (D) Thymoquinone.
Figure 6
Figure 6
Molecular docking modeling of thymoquinone with telomerase. (A) telomerase; (B) telomerase; (C) Thymoquinone; (D) the geometric interaction of thymoquinone with telomerase.
Figure 7
Figure 7
Molecular dynamic simulation results. (A) Root mean square deviation (RMSD) values for α-carbon atoms (blue curves) of telomerase and TQ (red curves); (B) H-bond number formed over the simulation time; (C) root mean square fluctuation (RMSF) results; (D) radius of gyration, plotted with respect to 100 ns MD simulation time.
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