Elsevier

Seminars in Cancer Biology

Volume 85, October 2022, Pages 234-245
Seminars in Cancer Biology

Targeting cancer stem cells by nutraceuticals for cancer therapy

https://doi.org/10.1016/j.semcancer.2021.07.008Get rights and content

Abstract

Accumulating evidence has demonstrated that cancer stem cells (CSCs) play an essential role in tumor progression and reoccurrence and drug resistance. Multiple signaling pathways have been revealed to be critically participated in CSC development and maintenance. Emerging evidence indicates that numerous chemopreventive compounds, also known as nutraceuticals, could eliminate CSCs in part via regulating several signaling pathways. Therefore, in this review, we will describe the some natural chemopreventive agents that target CSCs in a variety of human malignancies, including soy isoflavone, curcumin, resveratrol, tea polyphenols, sulforaphane, quercetin, indole-3-carbinol, 3,3′-diindolylmethane, withaferin A, apigenin, etc. Moreover, we discuss that eliminating CSCs by nutraceuticals might be a promising strategy for treating human cancer via overcoming drug resistance and reducing tumor reoccurrence.

Introduction

Cancer stem cells (CSCs) have been validated in various types of human cancers, including breast cancer, colon cancer, hematopoietic cancer, liver cancer, leukemia, lung cancer, pancreatic cancer, prostate cancer, ovarian cancer, etc [1,2]. CSCs possess the self-renewal capacity, metastasis and differentiation ability [3]. It is well accepted that CSCs often have stem cell markers, including CD24, CD34, CD44, CD133, ALDH1, and ESA. It is important to mention that various types of tumors have different CSC markers for the isolation and validation [4]. For example, pancreatic CSCs exhibit CD24, CD44, CD133, ESA, ALDH1, and c-Met cell surface markers [5]. CSCs are often associated with EMT and drug resistance in human cancer [[6], [7], [8]]. Evidence has suggested that noncoding RNAs could target CSCs via regulating their downstream targets [9]. It has been documented that signaling pathways are critically involved in CSC development [1,10,11]. Thus, targeting these key signaling pathways is useful to eliminate CSCs, including Notch, hedgehog, Wnt/β-catenin, PI3K/Akt, NF-κB, MEK/ERK, MAPK, mTOR, and JAK/STAT3 pathways. Because chemotherapy and radiotherapy cannot effectively remove CSCs, it is necessary to find new therapeutic agents to eradicate CSCs for suppression of metastasis and reversal of drug resistance.

Specific chemical inhibitors have been shown to target CSCs in human cancer cells. Although chemical inhibitors are easily administrated and have a high oral bioavailability, they also have side-effects, such as the cytotoxicity in vivo. Importantly, one chemical inhibitor often target one molecule in single signaling pathway. To overcome these limitations, natural agents, non-toxic compounds derived from edible sources, also called nutraceuticals, have been found to exert antitumor activity in part via targeting CSCs by regulating several signaling pathways [[12], [13], [14], [15], [16], [17]]. Therefore, in this review, we will summarize the natural chemopreventive compounds, such as soy isoflavone, curcumin, resveratrol, tea polyphenols, sulforaphane, quercetin, indole-3-carbinol (I3C), 3,3′-diindolylmethane (DIM), withaferin A, and apigenin, that target CSCs in a variety of human cancers. Furthermore, we describe the molecular mechanisms by which nutraceuticals eliminate CSCs in plenty of human cancers. Moreover, we discuss that eliminating CSCs by these nutraceuticals might be a promising therapeutic strategy via overcoming drug resistance and reducing tumor reoccurrence.

Section snippets

Targeting CSCs by nutraceuticals

Evidence has demonstrated that nutraceuticals could eliminate CSCs in a broad range of cancer types. For instance, one study screened 21 phenolics for detecting the interaction of 1118 CSC genes obtained from the publicly available databases [18]. This investigation validated that top five compounds are resveratrol, curcumin, quercetin, epigallocatechin gallate (EGCG) and genistein, which were further measured for their oral bioavailability and drug likeness and interacting network with CSC

Combination of natural compounds for targeting CSCs

Target CSCs by a natural compound alone or combinations might be helpful for treating cancer. Curcumin and EGCG combination attenuated the CD44+ cell population via inhibition of pSTAT3 and retaining the crosstalk between STAT3 and NF-κB in breast cancer cells [233]. Curcumin and piperine attenuated self-renewal of breast stem cells via targeting lipid metabolism [234]. Combination of curcumin and quinacrine promoted cell death of breast CSCs via repressing ABCG2 and blocking DNA damage repair

Conclusions and perspectives

In conclusion, nutraceuticals could eliminate CSCs via targeting cellular signaling pathways in human cancers, which could contribute to overcoming drug resistance and inhibiting tumor metastasis (Fig. 1, Fig. 2). Although CSCs might be intriguing targets for cancer therapy, eliminating CSCs has some challenges. For instance, specific CSC biomarkers for different cancer types are necessary to identify CSCs. In addition, common signaling pathways are required for maintenance of normal cells and

Declaration of Competing Interest

The authors report no declarations of interest.

Acknowledgements

The authors apologize to those authors whose work was not cited due to space limitation.

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    These authors contributed equally to this work.

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