Volume 23, Issue 2 (Jun _ Jul 2019)                   J Qazvin Univ Med Sci 2019, 23(2): 164-181 | Back to browse issues page

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Soltanian S. The Effect of Plant-Derived Compounds in Targeting Cancer Stem Cells. J Qazvin Univ Med Sci. 2019; 23 (2) :164-181
URL: http://journal.qums.ac.ir/article-1-2831-en.html
Department of Biology, Faculty of Science, Shahid Bahonar University of Kerman, Kerman, Iran. , sarasoltanian@gmail.com
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1. Introduction
ancer stem cells (CSCs) or tumor-initiating cells are a subpopulation of cancer cells. CSCs can self-renew (maintaining a population of CSCs) and differentiate into less tumorigenic non-CSCs [3]. Moreover, CSCs have a high resistance to chemo-radiotherapy through a variety of mechanisms. There is evidence of increased drug inactivation through the higher expression of detoxifying aldehyde dehydrogenases enzymes. These are a super-family of enzymes involved in oxidizing aldehydes to carboxylic acids, and increased activity of some isoforms is associated with detoxification capabilities of CSCs [30]. The platinum group of chemotherapeutic agents induces DNA damage. Cancer cells often have defective DNA repair pathways, and due to their rapid proliferation, these cells are often in S-phase, which is a vulnerable phase for DNA damage.
Therefore, DNA damage leads to cell cycle arrest or apoptosis. Data from many studies imply that CSCs have elevated levels of DNA repair. This is one explanation for the resistance of some tumors to platinum agents [34, 35]. CSCs increase expression of ATP-Binding Cassette (ABC) transport proteins of ABCB1, ABCC1, and ABCG2. These ABC transporters can efflux a wide array of chemotherapeutic drugs, and their expression is a major cause of multi-drug resistance in cancers [28, 29]. There is evidence to suggest that CSCs may be more quiescent or slower-cycling than their non-CSCs counterparts.
Quiescence and a slower progression through the cell cycle in CSCs would render these cells less susceptible to cell-cycle targeted therapies such as the antimitotic class of chemotherapeutics [34]. Three important signaling pathways contribute to both CSC maintenance and chemo-resistance; Wnt/β-catenin, Notch, and Hedgehog (Hh) pathways. 
In sum, CSCs have a role in all phases of tumorigenesis: initiation, progression, invasion, metastasis spreading, and tumor recurrence following chemotherapy [40, 41, 57, 51, 53]. Therefore, cancer therapeutic agents that selectively target CSCs, the root of cancer origin and recurrence, have been thought of as a promising approach to improve cancer survival rate or even to cure cancer. Today, numerous studies have shown that many plant-derived phytochemicals have antioxidant and anticancer effects. In addition, accumulating evidence has shown the anti-CSCs ability of many phytochemicals in many cancers [7].
This study aims to provide an overview of recently acquired scientific knowledge regarding some important phytochemicals, which have shown the capability to target and kill CSCs [63, 73, 82, 96, 100]
2. Materials and Methods 
Electronic databases of Google Scholar, PubMed, Scopus, and Science Direct were searched for valid published papers in prestigious international journals using the following keywords: “Cancer stem cell”, “phytochemical”, “cancer therapy”, “chemotherapy and radiotherapy” and “chemo-resistance”. Finally, 100 papers were selected for conducting the review. These 100 articles were related to the characterization of CSCs, mechanism of chemo-resistance, natural products, and phytochemicals that target CSCs.
3. Results
At first, properties of CSCs, mechanism of CSCs to overcome traditional cancer therapy, and important signaling pathways modulating their stem-like properties were explained. The core of the review was dedicated to introducing some important phytochemicals and their mechanism for targeting and inhibiting various types of CSCs. Plant-derived phytochemicals are defined as bioactive non-nutrient plant chemicals. It is predicted that more than 5000 particular phytochemicals have been recognized in grains, fruits, and vegetables, but a large percentage are still unknown and must be identified. Different biologically active phytochemicals have been identified as capable of controlling the carcinogenesis at different stages. Phytochemicals can impede initiation or repeal the promotion step of multistep carcinogenesis.
They can also stop or postpone the development of pre-cancerous cells into the malignant ones. Different mechanisms are involved in chemoprevention of different phytochemicals. For example, the antioxidant activity of phytochemicals leads to scavenge free radicals and reduce oxidative stress. Moreover, phytochemicals can inhibit cell proliferation, oncogene expression, cell adhesion, and invasion and induce tumor to suppress gene expression and cell cycle arrest. Unlike current chemotherapeutic agents and radiation therapy that largely target cells proliferation and differentiation, which form the bulk of the tumor (but not CSCs), in many reports, it was demonstrated that several phytochemicals have anti-CSCs effects. 
4. Conclusion
In this study, we provided a comprehensive review of some important dietary phytochemicals targeting CSCs. Moreover, the mechanism of natural products for targeting CSCs was discussed. Phytochemicals can sensitize CSCs to conventional treatment, induce cell death, and inhibit self-renewal in CSCs, induce CSCs to differentiate, prevent CSCs from entering a dormant and more resistant state. In addition, they target Wnt/ Notch/ Hedgehog signaling pathways, inhibit aldehyde dehydrogenase and ABC transporter, target cellular surface markers, and suppress EMT and migration ability of CSCs. In conclusion, dietary phytochemicals are suggested to possess anti-cancer properties with minimal or no side effects. Moreover, they have a significant impact on CSCs. Therefore, they may also improve the efficiency of chemo-radiotherapy and reduce recurrence or relapse of malignancy.

Ethical Considerations
Compliance with ethical guidelines

This article is a meta-analysis with no human or animal sample.
Research on anti-cancer effects of phytochemicals was supported by a grant from Vice Chancellor for Research and Technology, Shahid Bahonar University of Kerman.
Conflicts of interest
The author declares no conflict of interest.
The author thanks authorities of the Department of Biology, Faculty of Science, Shahid Bahonar University of Kerman.

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Type of Study: Review article | Subject: Pharmacology

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