Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Oncol. Jul 24, 2021; 12(7): 522-543
Published online Jul 24, 2021. doi: 10.5306/wjco.v12.i7.522
Therapeutic potential of thymoquinone in combination therapy against cancer and cancer stem cells
Zaynab Fatfat, Maamoun Fatfat, Hala Gali-Muhtasib
Zaynab Fatfat, Maamoun Fatfat, Hala Gali-Muhtasib, Department of Biology, American University of Beirut, Beirut 1107 2020, Lebanon
Hala Gali-Muhtasib, Center for Drug Discovery, American University of Beirut, Beirut 1107 2020, Lebanon
Author contributions: Fatfat Z and Fatfat M reviewed the literature and drafted the manuscript; Gali-Muhtasib H initiated the idea and revised the manuscript; all authors have read and approved the final manuscript.
Conflict-of-interest statement: The authors declare that they have no conflicts of interest.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Hala Gali-Muhtasib, PhD, Professor, Department of Biology, and Center for Drug Discovery, American University of Beirut, Bliss Street, Beirut 1107 2020, Lebanon.
Received: February 27, 2021
Peer-review started: February 27, 2021
First decision: March 31, 2021
Revised: April 11, 2021
Accepted: June 18, 2021
Article in press: June 18, 2021
Published online: July 24, 2021

The long-term success of standard anticancer monotherapeutic strategies has been hampered by intolerable side effects, resistance to treatment and cancer relapse. These monotherapeutic strategies shrink the tumor bulk but do not effectively eliminate the population of self-renewing cancer stem cells (CSCs) that are normally present within the tumor. These surviving CSCs develop mechanisms of resistance to treatment and refuel the tumor, thus causing cancer relapse. To ensure durable tumor control, research has moved away from adopting the monotreatment paradigm towards developing and using combination therapy. Combining different therapeutic modalities has demonstrated significant therapeutic outcomes by strengthening the anti-tumor potential of monotreatment against cancer and cancer stem cells, mitigating their toxic adverse effects, and ultimately overcoming resistance. Recently, there has been growing interest in combining natural products from different sources or with clinically used chemotherapeutics to further improve treatment efficacy and tolerability. Thymoquinone (TQ), the main bioactive constituent of Nigella sativa, has gained great attention in combination therapy research after demonstrating its low toxicity to normal cells and remarkable anticancer efficacy in extensive preclinical studies in addition to its ability to target chemoresistant CSCs. Here, we provide an overview of the therapeutic responses resulting from combining TQ with conventional therapeutic agents such as alkylating agents, antimetabolites and antimicrotubules as well as with topoisomerase inhibitors and non-coding RNA. We also review data on anticancer effects of TQ when combined with ionizing radiation and several natural products such as vitamin D3, melatonin and other compounds derived from Chinese medicinal plants. The focus of this review is on two outcomes of TQ combination therapy, namely eradicating CSCs and treating various types of cancers. In conclusion, the ability of TQ to potentiate the anticancer activity of many chemotherapeutic agents and sensitize cancer cells to radiotherapy makes it a promising molecule that could be used in combination therapy to overcome resistance to standard chemotherapeutic agents and reduce their associated toxicities.

Keywords: Thymoquinone, Combination therapy, Cancer cells, Cancer stem cells, Conventional cancer therapy, Natural products

Core Tip: There has been great interest in integrating thymoquinone (TQ) in combination therapy particularly to target cancer stem cells, which are known to be responsible for resistance to treatment and cancer recurrence. The combination of TQ with standard chemotherapeutics and other natural products has exhibited promising anticancer responses. TQ was also shown to sensitize cancer cells to radiotherapy and help in overcoming major limitations that restrict the potency of chemotherapy, which are chemoresistance and treatment associated toxic effects.