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Article

Thymoquinone Enhances Paclitaxel Anti-Breast Cancer Activity via Inhibiting Tumor-Associated Stem Cells Despite Apparent Mathematical Antagonism

1
Department of Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia
2
Department of Medical Biochemistry, Medical Division, National Research Centre, Giza 12622, Egypt
3
Department of Pharmaceutical Sciences, College of Pharmacy, Gulf Medical University, Ajman 4184, UAE
4
Department of Pharmacology, Medical Division, National Research Centre, Giza 12622, Egypt
*
Author to whom correspondence should be addressed.
Academic Editor: Marian Brestic
Molecules 2020, 25(2), 426; https://doi.org/10.3390/molecules25020426
Received: 4 December 2019 / Revised: 10 January 2020 / Accepted: 17 January 2020 / Published: 20 January 2020
Thymoquinone (TQ) has shown substantial evidence for its anticancer effects. Using human breast cancer cells, we evaluated the chemomodulatory effect of TQ on paclitaxel (PTX). TQ showed weak cytotoxic properties against MCF-7 and T47D breast cancer cells with IC50 values of 64.93 ± 14 µM and 165 ± 2 µM, respectively. Combining TQ with PTX showed apparent antagonism, increasing the IC50 values of PTX from 0.2 ± 0.07 µM to 0.7 ± 0.01 µM and from 0.1 ± 0.01 µM to 0.15 ± 0.02 µM in MCF-7 and T47D cells, respectively. Combination index analysis showed antagonism in both cell lines with CI values of 4.6 and 1.6, respectively. However, resistance fractions to PTX within MCF-7 and T47D cells (42.3 ± 1.4% and 41.9 ± 1.1%, respectively) were completely depleted by combination with TQ. TQ minimally affected the cell cycle, with moderate accumulation of cells in the S-phase. However, a significant increase in Pre-G phase cells was observed due to PTX alone and PTX combination with TQ. To dissect this increase in the Pre-G phase, apoptosis, necrosis, and autophagy were assessed by flowcytometry. TQ significantly increased the percent of apoptotic/necrotic cell death in T47D cells after combination with paclitaxel. On the other hand, TQ significantly induced autophagy in MCF-7 cells. Furthermore, TQ was found to significantly decrease breast cancer-associated stem cell clone (CD44+/CD24-cell) in both MCF-7 and T47D cells. This was mirrored by the downregulation of TWIST-1 gene and overexpression of SNAIL-1 and SNAIL-2 genes. TQ therefore possesses potential chemomodulatory effects to PTX when studied in breast cancer cells via enhancing PTX induced cell death including autophagy. In addition, TQ depletes breast cancer-associated stem cells and sensitizes breast cancer cells to PTX killing effects. View Full-Text
Keywords: paclitaxel; thymoquinone; apoptosis; autophagy; tumor-associated stem cells paclitaxel; thymoquinone; apoptosis; autophagy; tumor-associated stem cells
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MDPI and ACS Style

Bashmail, H.A.; Alamoudi, A.A.; Noorwali, A.; Hegazy, G.A.; Ajabnoor, G.M.; Al-Abd, A.M. Thymoquinone Enhances Paclitaxel Anti-Breast Cancer Activity via Inhibiting Tumor-Associated Stem Cells Despite Apparent Mathematical Antagonism. Molecules 2020, 25, 426. https://doi.org/10.3390/molecules25020426

AMA Style

Bashmail HA, Alamoudi AA, Noorwali A, Hegazy GA, Ajabnoor GM, Al-Abd AM. Thymoquinone Enhances Paclitaxel Anti-Breast Cancer Activity via Inhibiting Tumor-Associated Stem Cells Despite Apparent Mathematical Antagonism. Molecules. 2020; 25(2):426. https://doi.org/10.3390/molecules25020426

Chicago/Turabian Style

Bashmail, Hanan A., Aliaa A. Alamoudi, Abdulwahab Noorwali, Gehan A. Hegazy, Ghada M. Ajabnoor, and Ahmed M. Al-Abd 2020. "Thymoquinone Enhances Paclitaxel Anti-Breast Cancer Activity via Inhibiting Tumor-Associated Stem Cells Despite Apparent Mathematical Antagonism" Molecules 25, no. 2: 426. https://doi.org/10.3390/molecules25020426

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