Targeting cancer stem cells by nutraceuticals for cancer therapy
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.
References (238)
- et al.
Emerging mechanisms by which EMT programs control stemness
Trends Cancer
(2020) - et al.
Implications of cancer stem cell theory for cancer chemoprevention by natural dietary compounds
J. Nutr. Biochem.
(2011) - et al.
Resveratrol, cancer and cancer stem cells: a review on past to future
Curr. Res. Food Sci.
(2020) - et al.
Targeting molecular pathways in cancer stem cells by natural bioactive compounds
Pharmacol. Res.
(2018) - et al.
Targeting cancer stem cells and signaling pathways by phytochemicals: novel approach for breast cancer therapy
Semin. Cancer Biol.
(2016) - et al.
HER2 overexpression triggers the IL-8 to promote arsenic-induced EMT and stem cell-like phenotypes in human bladder epithelial cells
Ecotoxicol. Environ. Saf.
(2021) - et al.
Genistein inhibits the stemness properties of prostate cancer cells through targeting Hedgehog-Gli1 pathway
Cancer Lett.
(2012) - et al.
Anti-metastasis activity of curcumin against breast cancer via the inhibition of stem cell-like properties and EMT
Phytomed.: Int. J. Phytother. Phytopharmacol.
(2019) - et al.
Curcumin inhibits the side population (SP) phenotype of the rat C6 glioma cell line: towards targeting of cancer stem cells with phytochemicals
Cancer Lett.
(2010) - et al.
Synergistic anti-cancer mechanisms of curcumin and paclitaxel for growth inhibition of human brain tumor stem cells and LN18 and U138MG cells
Neurochem. Int.
(2012)
Targeting human brain cancer stem cells by curcumin-loaded nanoparticles grafted with anti-aldehyde dehydrogenase and sialic acid: colocalization of ALDH and CD44
Mater. Sci. Eng. C Mater. Biol. Appl.
Curcumin inhibits cancer stem cell phenotypes in ex vivo models of colorectal liver metastases, and is clinically safe and tolerable in combination with FOLFOX chemotherapy
Cancer Lett.
Curcumin suppresses proliferation and in vitro invasion of human prostate cancer stem cells by ceRNA effect of miR-145 and lncRNA-ROR
Gene
Resveratrol, a potential radiation sensitizer for glioma stem cells both in vitro and in vivo
J. Pharmacol. Sci.
Resveratrol suppresses migration, invasion and stemness of human breast cancer cells by interfering with tumor-stromal cross-talk
Arch. Biochem. Biophys.
Resveratrol-induced apoptosis and increased radiosensitivity in CD133-positive cells derived from atypical teratoid/rhabdoid tumor
Int. J. Radiat. Oncol. Biol. Phys.
Generation of novel thyroid cancer stem-Like cell clones: effects of resveratrol and valproic acid
Am. J. Pathol.
Targeting cancer stem cell pathways for cancer therapy
Signal Transduct. Target. Ther.
Advancements in cancer stem cell isolation and characterization
Stem Cell Rev. Rep.
Epithelial cell polarity, stem cells and cancer
Nat. Rev. Cancer
Cancer stem cells in solid tumours: accumulating evidence and unresolved questions
Nat. Rev. Cancer
Identification of pancreatic cancer stem cells
Cancer Res.
EMT, CSCs, and drug resistance: the mechanistic link and clinical implications
Nat. Rev. Clin. Oncol.
Linking EMT programmes to normal and neoplastic epithelial stem cells
Nat. Rev. Cancer
lncRNA involvement in cancer stem cell function and epithelial-mesenchymal transitions
Semin. Cancer Biol.
Signaling pathways involved in nutrient sensing control in cancer stem cells: an overview
Front. Endocrinol.
Signaling pathways essential for triple-negative breast cancer stem-like cells
Stem Cells
Targeting stemness of cancer stem cells to fight colorectal cancers
Semin. Cancer Biol.
Natural products targeting cancer stem cells: a revisit
Curr. Med. Chem.
In silico ranking of phenolics for therapeutic effectiveness on cancer stem cells
BMC Bioinform.
Soy isoflavones in integrative oncology: increased efficacy and decreased toxicity of cancer therapy
Integr. Cancer Ther.
Antioxidant function of isoflavone and 3,3’-diindolylmethane: are they important for cancer prevention and therapy?
Antioxid. Redox Signal.
Repression of mammosphere formation of human breast cancer cells by soy isoflavone genistein and blueberry polyphenolic acids suggests diet-mediated targeting of cancer stem-like/progenitor cells
Carcinogenesis
Genistein decreases the breast cancer stem-like cell population through Hedgehog pathway
Stem Cell Res. Ther.
Genistein-induced differentiation of breast cancer stem/progenitor cells through a paracrine mechanism
Int. J. Oncol.
Genistein attenuates cancer stem cell characteristics in gastric cancer through the downregulation of Gli1
Oncol. Rep.
Genistein-inhibited cancer stem cell-like properties and reduced chemoresistance of gastric cancer
Int. J. Mol. Sci.
Genistein inhibits stemness of SKOV3 cells induced by macrophages co-cultured with ovarian cancer stem-like cells through IL-8/STAT3 axis
J. Exp. Clin. Cancer Res.
7-Difluoromethoxyl-5,4’-di-n-octyl genistein inhibits the stem-like characteristics of gastric cancer stem-like cells and reverses the phenotype of epithelial-mesenchymal transition in gastric cancer cells
Oncol. Rep.
Disruption of crosstalk between LX-2 and liver cancer stem-like cells from MHCC97H cells by DFOG via inhibiting FOXM1
Acta Biochim. Biophys. Sin.
FOXO3a-mediated suppression of the self-renewal capacity of sphere-forming cells derived from the ovarian cancer SKOV3 cell line by 7-difluoromethoxyl-5,4’-di-n-octyl genistein
Mol. Med. Rep.
7-difluoromethoxyl-5,4’-di-n-octyl genistein inhibits ovarian cancer stem cell characteristics through the downregulation of FOXM1
Oncol. Lett.
Genistein inhibits lung cancer cell stem-like characteristics by modulating MnSOD and FoxM1 expression
Oncol. Lett.
Genistein protects hematopoietic stem cells against G-CSF-induced DNA damage
Cancer Prev. Res.
Metformin and soybean-derived bioactive molecules attenuate the expansion of stem cell-like epithelial subpopulation and confer apoptotic sensitivity in human colon cancer cells
Genes Nutr.
Genistein regulates tumor microenvironment and exhibits anticancer effect in dimethyl hydrazine-induced experimental colon carcinogenesis
BioFactors
Genistein suppression of matrix metalloproteinase 2 (MMP-2) and vascular endothelial growth factor (VEGF) expression in mesenchymal stem cell like cells isolated from high and low grade gliomas
Asian Pac. J. Cancer Prev. APJCP
Activation of JNK and p38 MAPK mediated by ZDHHC17 drives glioblastoma multiforme development and malignant progression
Theranostics
Soy isoflavone genistein impedes cancer stemness and mesenchymal transition in head and neck cancer through activating miR-34a/RTCB Axis
Nutrients
Genistein inhibits nasopharyngeal cancer stem cells through sonic hedgehog signaling
Phytother. Res.: PTR
Cited by (15)
Circulating tumor cells in lung cancer: Integrating stemness and heterogeneity to improve clinical utility
2024, International Review of Cell and Molecular BiologyTherapeutic potential and limitations of curcumin as antimetastatic agent
2023, Biomedicine and PharmacotherapyTargeting cancer stem cells and signalling pathways through phytochemicals: A promising approach against colorectal cancer
2023, PhytomedicineCitation Excerpt :Resveratrol is a healthy natural polyphenolic compound widely found in plants such as Vitis vinifera Linnaeus (L.) and Polygonum cuspidatum and is known for its anti-cancer, antioxidant, anti-inflammatory, neuroprotective, and cardioprotective properties, as reported in clinical trials (Singh et al., 2019). Interestingly, resveratrol is also able to eliminate CSCs from different types of cancer, such as breast, pancreatic, and glioma (Chu et al., 2021). Interactions between the tumour and the TME are critical for malignant tumour progression, and blocking the intercellular crosstalk in the TME is an effective approach for treating CRC.
Focus on immune checkpoint PD-1/PD-L1 pathway: New advances of polyphenol phytochemicals in tumor immunotherapy
2022, Biomedicine and PharmacotherapyCitation Excerpt :Additionally, polyphenols can regulate multiple signaling pathways involved in different types of cancer to counteract oncogenic drivers [25,71,72] and inhibit the chronic local inflammation that maintains and supports tumor growth [73]. Notably, the use of polyphenols as a primary chemopreventive agent significantly reduces the risk of cancer in the population [74,75]. The activity of tumor-infiltrating lymphocytes (TILs) is a major determinant of immunosurveillance success.
Applications of lipid-engineered nanoplatforms in the delivery of various cancer therapeutics to surmount breast cancer
2022, Journal of Controlled ReleaseCitation Excerpt :There are several evidences depicting the role of cancer stem cells in tumor proliferation development of drug resistance in BC. Nutraceuticals are naturally occurring, non-toxic compounds, widely present in several dietary items, and have been reported to exert antitumor activity by targeting these cancer stem cells [121,122]. There have also been several reports depicting the importance of natural compounds such as Organo-sulphur compounds having potential ability to reduce risks of several chronic diseases including BC.
The role of oncolytic virotherapy and viral oncogenes in the cancer stem cells: a review of virus in cancer stem cells
2023, Cancer Cell International
- 1
These authors contributed equally to this work.