Therapeutic potential of thymoquinone in combination therapy against cancer and cancer stem cells

Abstract

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.

Metformin and thymoquinone co‐treatment enhance 5‐fluorouracil cytotoxicity by suppressing the PI3K/mTOR/HIF1α pathway and increasing oxidative stress in colon cancer cells

“…Our findings agree with many prior studies that have shown anti-cancer activities for TQ [24][25][26][27][28][29]42,43 and Met [17][18][19][20][21][22][23] against CRC by inducing cell cycle arrest and apoptosis, modulating the PI3K/mTOR/HIF1α pathway, promoting glucose oxidation, and increasing ROS production. Our data also correlate and support the findings of earlier studies that reported enhanced anti-cancer effects by adding Met 23,33 or TQ 28,32 with 5-FU for the treatment of CRC, as well as by combining both agents for treating other malignancies.…”

“…17,18,20 Similarly, TQ halted cancer progression by inhibiting cell survival (e.g., survivin) and increasing pro-apoptotic (e.g., BAX, caspases) molecules in many malignancies, including CRC. 28,42,43 Furthermore, TQ induced apoptosis in cancer cells by promoting glucose oxidative phosphorylation following inhibition of LDHA enzyme, enhancing ROS production with declines in antioxidants, and downregulating the PI3K/mTOR/HIF1α network. [24][25][26][27][28][29] Further studies have also reported that combining 5-FU with TQ 28,32 or Met 23,33 resulted in boosted in vitro and in vivo anti-cancer actions against CRC.…”

Thymoquinone, piperine, and sorafenib combinations attenuate liver and breast cancers progression: epigenetic and molecular docking approaches

“…Many recent reports, including the current study, indicated promising chemo-modulatory actions of TQ when combined with other chemotherapeutic agents used against various cancers [ 42 , 43 ]. In 2020, it was reported that TQ enhanced docetaxel efficiency in MDA-MB-231 and MCF-7 cells by reducing its effective dose [ 44 ].…”

Thymoquinone Radiosensitizes Human Colorectal Cancer Cells in 2D and 3D Culture Models

“…Studies investigating the effect of TQ on CSCs are very few. Recent studies have shown that combining TQ with chemotherapeutic agents or natural compounds enhances inhibition of CSCs [55][56][57]. The combined treatment of TQ and emodin enhanced eradication of CD44+/CD24− CSCS population, when compared to either treatment alone.…”