Abstract

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.

Highlights

  • Over the past three decades, 1355 new drugs were approved for the treatment of malignancies [1,2].there are 18.1 million new cases of cancer, and 9.6 million mortalities due to cancer annually [3]

  • TQ possesses potential chemomodulatory effects to PTX when studied in breast cancer cells via enhancing PTX induced cell death including autophagy

  • Breast cancer stem cells (BCSCs) possess a remarkable ability to effectively persist after exposure to chemotherapy [7]

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Summary

Introduction

Over the past three decades, 1355 new drugs were approved for the treatment of malignancies [1,2]. There are 18.1 million new cases of cancer, and 9.6 million mortalities due to cancer annually [3]. Breast cancer has the highest incidence, causing the most female mortalities among other malignancies [4]. Breast cancer tissue is a heterogeneous tissue consisting of various cell types, which differ in terms of origin, function, genetic profile, morphology, and sensitivity to therapy [5,6]. Breast cancer stem cells (BCSCs) are a subclone of cancer cells that have gained great attention, Molecules 2020, 25, 426; doi:10.3390/molecules25020426 www.mdpi.com/journal/molecules. BCSCs possess a remarkable ability to effectively persist after exposure to chemotherapy [7]

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