Natural Compounds Targeting Cancer Stem Cells: A Promising Resource for Chemotherapy

Background:Cancer Stem Cells (CSCs) are the subpopulation of cancer cells which are directly involved in drug resistance, metastases to distant organ and cancer recurrence.Methods:A systematic literature search was conducted through various electronic databases including, Pubmed, Scopus, Google scholar using the keywords "cancer stem cells" and "natural compounds" in the present study. Articles published between 1999 and 2019 were reviewed. All the expositions concerning CSCs associated cancer pathogenesis and therapy resistance, as well as targeting these properties of CSCs by natural compounds were selected for the current study.Results:Natural compounds have always been thought as a rich source of biologically active principles, which target aberrantly activated signaling pathways and other modalities of CSCs, while tethering painful side effects commonly involved in the first-line and second-line chemo-radiotherapies. In this review, we have described the key signaling pathways activated in CSCs to maintain their survival and highlighted how natural compounds interrupt these signaling pathways to minimize therapy resistance, pathogenesis and cancer recurrence properties of CSCs, thereby providing useful strategies to treat cancer or aid in cancer therapy improvement. Like normal stem cells, CSCs rely on different signaling pathways and other properties for their maintenance. Therefore, the success of cancer treatment depends on the development of proper anti-neoplastic drugs capable of intercepting those signaling pathways as well as other properties of CSCs in order to eradicate this evasive subpopulation of cancer cells.Conclusion:Compounds of natural origin might act as an outstanding source to design novel therapies against cancer stem cells.

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Novel Therapeutics Against Breast Cancer Stem Cells by Targeting Surface Markers and Signaling Pathways

Current Stem Cell Research & Therapy ◽

10.2174/1574888x14666190628104721 ◽

2019 ◽

Vol 14 (8) ◽

pp. 669-682 ◽

Cited By ~ 1

Author(s):

Plabon K. Das ◽

Md. A. Rakib ◽

Jahan A. Khanam ◽

Suja Pillai ◽

Farhadul Islam

Keyword(s):

Breast Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Signaling Pathways ◽

Cancer Recurrence ◽

Therapy Resistance ◽

Surface Markers ◽

Breast Cancer Stem Cells ◽

Novel Therapeutics ◽

Cancer Pathogenesis

Background: Breast cancer remains to be one of the deadliest forms of cancers, owing to the drug resistance and tumor relapse caused by breast cancer stem cells (BCSCs) despite notable advancements in radio-chemotherapies. Objective: To find out novel therapeutics against breast cancer stem cells by aiming surface markers and signaling pathways. Methods: A systematic literature search was conducted through various electronic databases including, Pubmed, Scopus, Google scholar using the keywords "BCSCs, surface markers, signaling pathways and therapeutic options against breast cancer stem cell. Articles selected for the purpose of this review were reviewed and extensively analyzed. Results: Novel therapeutic strategies include targeting BCSCs surface markers and aberrantly activated signaling pathways or targeting their components, which play critical roles in self-renewal and defense, have been shown to be significantly effective against breast cancer. In this review, we represent a number of ways against BCSCs surface markers and hyper-activated signaling pathways to target this highly malicious entity of breast cancer more effectively in order to make a feasible and useful strategy for successful breast cancer treatment. In addition, we discuss some characteristics of BCSCs in disease progression and therapy resistance. Conclusion: BCSCs involved in cancer pathogenesis, therapy resistance and cancer recurrence. Thus, it is suggested that a multi-dimensional therapeutic approach by targeting surface markers and aberrantly activated signaling pathways of BCSCs alone or in combination with each other could really be worthwhile in the treatment of breast cancer.

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Advances in Therapeutic Targeting of Cancer Stem Cells within the Tumor Microenvironment: An Updated Review

Cells ◽

10.3390/cells9081896 ◽

2020 ◽

Vol 9 (8) ◽

pp. 1896 ◽

Cited By ~ 3

Author(s):

Kevin Dzobo ◽

Dimakatso Alice Senthebane ◽

Chelene Ganz ◽

Nicholas Ekow Thomford ◽

Ambroise Wonkam ◽

...

Keyword(s):

Stem Cells ◽

Drug Resistance ◽

Tumor Microenvironment ◽

Cancer Stem Cells ◽

Cancer Cells ◽

Treatment Strategies ◽

Cancer Recurrence ◽

Therapy Resistance ◽

Microenvironmental Factors ◽

Novel Treatment Strategies

Despite great strides being achieved in improving cancer patients’ outcomes through better therapies and combinatorial treatment, several hurdles still remain due to therapy resistance, cancer recurrence and metastasis. Drug resistance culminating in relapse continues to be associated with fatal disease. The cancer stem cell theory posits that tumors are driven by specialized cancer cells called cancer stem cells (CSCs). CSCs are a subpopulation of cancer cells known to be resistant to therapy and cause metastasis. Whilst the debate on whether CSCs are the origins of the primary tumor rages on, CSCs have been further characterized in many cancers with data illustrating that CSCs display great abilities to self-renew, resist therapies due to enhanced epithelial to mesenchymal (EMT) properties, enhanced expression of ATP-binding cassette (ABC) membrane transporters, activation of several survival signaling pathways and increased immune evasion as well as DNA repair mechanisms. CSCs also display great heterogeneity with the consequential lack of specific CSC markers presenting a great challenge to their targeting. In this updated review we revisit CSCs within the tumor microenvironment (TME) and present novel treatment strategies targeting CSCs. These promising strategies include targeting CSCs-specific properties using small molecule inhibitors, immunotherapy, microRNA mediated inhibitors, epigenetic methods as well as targeting CSC niche-microenvironmental factors and differentiation. Lastly, we present recent clinical trials undertaken to try to turn the tide against cancer by targeting CSC-associated drug resistance and metastasis.

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Redox Regulation in Cancer Stem Cells

Oxidative Medicine and Cellular Longevity ◽

10.1155/2015/750798 ◽

2015 ◽

Vol 2015 ◽

pp. 1-11 ◽

Cited By ~ 51

Author(s):

Shijie Ding ◽

Chunbao Li ◽

Ninghui Cheng ◽

Xiaojiang Cui ◽

Xinglian Xu ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Cancer Stem Cells ◽

Cancer Cells ◽

Signaling Pathways ◽

Redox Regulation ◽

Cancer Recurrence ◽

Ros Generation ◽

Self Renewal ◽

Cellular Processes

Reactive oxygen species (ROS) and ROS-dependent (redox regulation) signaling pathways and transcriptional activities are thought to be critical in stem cell self-renewal and differentiation during growth and organogenesis. Aberrant ROS burst and dysregulation of those ROS-dependent cellular processes are strongly associated with human diseases including many cancers. ROS levels are elevated in cancer cells partially due to their higher metabolism rate. In the past 15 years, the concept of cancer stem cells (CSCs) has been gaining ground as the subpopulation of cancer cells with stem cell-like properties and characteristics have been identified in various cancers. CSCs possess low levels of ROS and are responsible for cancer recurrence after chemotherapy or radiotherapy. Unfortunately, how CSCs control ROS production and scavenging and how ROS-dependent signaling pathways contribute to CSCs function remain poorly understood. This review focuses on the role of redox balance, especially in ROS-dependent cellular processes in cancer stem cells (CSCs). We updated recent advances in our understanding of ROS generation and elimination in CSCs and their effects on CSC self-renewal and differentiation through modulating signaling pathways and transcriptional activities. The review concludes that targeting CSCs by manipulating ROS metabolism/dependent pathways may be an effective approach for improving cancer treatment.

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Mitotic quiescence in hepatic cancer stem cells: An incognito mode

Oncology Reviews ◽

10.4081/oncol.2020.452 ◽

2020 ◽

Vol 14 (1) ◽

Author(s):

Kandasamy Ashokachakkaravarthy ◽

Biju Pottakkat

Keyword(s):

Hepatocellular Carcinoma ◽

Stem Cells ◽

Cancer Stem Cells ◽

Cancer Cells ◽

Immune Evasion ◽

Immune Surveillance ◽

Cancer Recurrence ◽

Tumor Formation ◽

Proliferating Cells ◽

Recurrence Rates

Hepatocellular carcinoma represents one of the most aggressive cancers with high recurrence rates. The high recurrence is a major problem in the management of this disease. Cancer stem cells (CSCs) are often regarded as the basis of cancer recurrence. The anti-proliferative therapy kills the proliferating cells but induces mitotic quiescence in CSCs which remain as residual dormant CSCs. Later on, withdrawal of treatment reactivates the residual CSCs from dormancy to produce new cancer cells. The proliferation of these newly formed cancer cells initiates new tumor formation in the liver leading to tumor recurrence. HCC cells evade the immune surveillance via modulating the key immune cells by alpha feto-protein (AFP) secreted from CSCs or hepatic progenitor cells. This AFP mediated immune evasion assists in establishing new tumors by cancer cells in the liver. In this review, we will summarise the CSC mechanisms of recurrence, mitotic quiescence, dormancy and reactivation of CSCs, metastasis and immune evasion of hepatocellular carcinoma.

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Role of Exosomal miRNAs and the Tumor Microenvironment in Drug Resistance

Cells ◽

10.3390/cells9061450 ◽

2020 ◽

Vol 9 (6) ◽

pp. 1450 ◽

Cited By ~ 3

Author(s):

Patrick Santos ◽

Fausto Almeida

Keyword(s):

Stem Cells ◽

Drug Resistance ◽

Tumor Microenvironment ◽

Cancer Stem Cells ◽

Cancer Cells ◽

Extracellular Vesicles ◽

Therapy Resistance ◽

Chemotherapeutic Agents ◽

Exosomal Mirnas ◽

Key Factor

Tumor microenvironment (TME) is composed of different cellular populations, such as stromal, immune, endothelial, and cancer stem cells. TME represents a key factor for tumor heterogeneity maintenance, tumor progression, and drug resistance. The transport of molecules via extracellular vesicles emerged as a key messenger in intercellular communication in the TME. Exosomes are small double-layered lipid extracellular vesicles that can carry a variety of molecules, including proteins, lipids, and nucleic acids. Exosomal miRNA released by cancer cells can mediate phenotypical changes in the cells of TME to promote tumor growth and therapy resistance, for example, fibroblast- and macrophages-induced differentiation. Cancer stem cells can transfer and enhance drug resistance in neighboring sensitive cancer cells by releasing exosomal miRNAs that target antiapoptotic and immune-suppressive pathways. Exosomes induce drug resistance by carrying ABC transporters, which export chemotherapeutic agents out of the recipient cells, thereby reducing the drug concentration to suboptimal levels. Exosome biogenesis inhibitors represent a promising adjunct therapeutic approach in cancer therapy to avoid the acquisition of a resistant phenotype. In conclusion, exosomal miRNAs play a crucial role in the TME to confer drug resistance and survivability to tumor cells, and we also highlight the need for further investigations in this promising field.

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Chronic Oxidative Stress Promotes Molecular Changes Associated with Epithelial Mesenchymal Transition, NRF2, and Breast Cancer Stem Cell Phenotype

Antioxidants ◽

10.3390/antiox8120633 ◽

2019 ◽

Vol 8 (12) ◽

pp. 633 ◽

Cited By ~ 5

Author(s):

Ana Čipak Gašparović ◽

Lidija Milković ◽

Nadia Dandachi ◽

Stefanie Stanzer ◽

Iskra Pezdirc ◽

...

Keyword(s):

Breast Cancer ◽

Oxidative Stress ◽

Stem Cells ◽

Cancer Stem Cells ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Therapy Resistance ◽

Mesenchymal Transition ◽

Chronic Oxidative Stress ◽

Emt Markers

Oxidative stress plays a role in carcinogenesis, but it also contributes to the modulation of tumor cells and microenvironment caused by chemotherapeutics. One of the consequences of oxidative stress is lipid peroxidation, which can, through reactive aldehydes such as 4-hydroxy-2-nonenal (HNE), affect cell signaling pathways. On the other hand, cancer stem cells (CSC) are now recognized as a major factor of malignancy by causing metastasis, relapse, and therapy resistance. Here, we evaluated whether oxidative stress and HNE modulation of the microenvironment can influence CSC growth, modifications of the epithelial to mesenchymal transition (EMT) markers, the antioxidant system, and the frequency of breast cancer stem cells (BCSC). Our results showed that oxidative changes in the microenvironment of BCSC and particularly chronic oxidative stress caused changes in the proliferation and growth of breast cancer cells. In addition, changes associated with EMT, increase in glutathione (GSH) and Nuclear factor erythroid 2-related factor 2 (NRF2) were observed in breast cancer cells grown on HNE pretreated collagen and under chronic oxidative stress. Our results suggest that chronic oxidative stress can be a bidirectional modulator of BCSC fate. Low levels of HNE can increase differentiation markers in BCSC, while higher levels increased GSH and NRF2 as well as certain EMT markers, thereby increasing therapy resistance.

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Natural Products Targeting Cancer Stem Cells for Augmenting Cancer Therapeutics

International Journal of Molecular Sciences ◽

10.3390/ijms222313044 ◽

2021 ◽

Vol 22 (23) ◽

pp. 13044

Author(s):

Ari Meerson ◽

Soliman Khatib ◽

Jamal Mahajna

Keyword(s):

Stem Cells ◽

Natural Products ◽

Cancer Stem Cells ◽

Signaling Pathways ◽

Tumor Cells ◽

Cancer Therapeutics ◽

Chemotherapeutic Agents ◽

Biologically Active ◽

Approved Drugs ◽

Multiple Signaling

Cancer stem cells (CSC) have been identified in several types of solid tumors. In some cases, CSC may be the source of all the tumor cells, the cause of the tumor’s resistance to chemotherapeutic agents, and the source of metastatic cells. Thus, a combination therapy targeting non-CSC tumor cells as well as specifically targeting CSCs holds the potential to be highly effective. Natural products (NPs) have been a historically rich source of biologically active compounds and are known for their ability to influence multiple signaling pathways simultaneously with negligible side effects. In this review, we discuss the potential of NPs in targeting multiple signaling pathways in CSC and their potential to augment the efficacy of standard cancer therapy. Specifically, we focus on the anti-CSC activities of flavonoids, FDA-approved drugs originating from natural sources. Additionally, we emphasize the potential of NPs in targeting microRNA-mediated signaling, given the roles of microRNA in the maintenance of the CSC phenotype.

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Sulforaphane Inhibits Self-renewal of Lung Cancer Stem Cells Through the Modulation of Polyhomeotic Homolog 3 and Sonic Hedgehog Signaling Pathways

10.21203/rs.2.11459/v1 ◽

2019 ◽

Author(s):

FanPing Wang ◽

Jiateng Zhong ◽

Shanshan Wang ◽

Caijuan Qiao ◽

Xiangyang Li ◽

...

Keyword(s):

Lung Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Western Blot ◽

Cancer Cells ◽

Signaling Pathways ◽

Sonic Hedgehog ◽

Self Renewal ◽

Shh Signaling ◽

Lung Cancer Stem Cells

Abstract Background: Sulforaphane (SFN), an active compound in cruciferous vegetables has been characterized for its antiproliferative capacity. We investigated the role and molecular mechanism through which SFN regulates proliferation and self-renewal of lung cancer stem cells. Methods: Lung cancer stem cells (CD133-positive cells) were isolated by MACs and then measured by flow cytometry. The ability of cell proliferation was assessed by MTT assays and tumorsphere formation assays. The expressions of Sonic Hedgehog (Shh), Smoothened (Smo), Gli1 and Human Polyhomeotic Homolog 3 (PHC3) in cells were measured by quantitative reverse transcription polymerase chain reaction (qPCR) and western blot assays. The expression of transcription factor SOX2 in lung cancer stem cells was also determined by western blot assay. Shh was knocked down by siRNA to further study the role of SFN and Shh signaling pathways in lung cancer. Results: SFN inhibited the proliferation of lung cancer cells and lung cancer stem cells simultaneously. Meanwhile, we observed that Sonic Hedgehog (SHH) signaling pathway, SOX2 and Polyhomeotic Homolog 3 (PHC3) were highly activated in lung cancer stem cells. Knock-down of Shh led to reduced H460 and A549 cells proliferation. Furthermore, we observed that SFN inhibited the activity of PHC3 and SHH signaling pathways in the lung cancer stem cells. In addition, SFN combined with Knock-down of Shh gene showed a greater effect on the proliferation of lung cancer cells. Conclusion: SFN is an effective new drug which can inhibit proliferation of lung cancer stem cells through the modulation of PHC3 and SHH signaling pathways. It provides a novel target for improving therapeutic efficacy for lung cancer stem cells.

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Immunotherapy: Newer Therapeutic Armamentarium against Cancer Stem Cells

Journal of Oncology ◽

10.1155/2020/3963561 ◽

2020 ◽

Vol 2020 ◽

pp. 1-15 ◽

Cited By ~ 2

Author(s):

Saurabh Pratap Singh ◽

Richa Singh ◽

Om Prakash Gupta ◽

Shalini Gupta ◽

Madan Lal Brahma Bhatt

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Cancer Cells ◽

Effective Means ◽

Treatment Strategies ◽

Antigen Expression ◽

Therapy Resistance ◽

Treatment Modalities ◽

Self Renewal ◽

Primary Tumors

Mounting evidence from the literature suggests the existence of a subpopulation of cancer stem cells (CSCs) in almost all types of human cancers. These CSCs possessing a self-renewal capacity inhabit primary tumors and are more defiant to standard antimitotic and molecularly targeted therapies which are used for eliminating actively proliferating and differentiated cancer cells. Clinical relevance of CSCs emerges from the fact that they are the root cause of therapy resistance, relapse, and metastasis. Earlier, surgery, chemotherapy, and radiotherapy were established as cancer treatment modalities, but recently, immunotherapy is also gaining importance in the management of various cancer patients, mostly those of the advanced stage. This review abridges potential off-target effects of inhibiting CSC self-renewal pathways on immune cells and some recent immunological studies specifically targeting CSCs on the basis of their antigen expression profile, even though molecular markers or antigens that have been described till date as expressed by cancer stem cells are not specifically expressed by these cells which is a major limitation to target CSCs. We propose that owing to CSC stemness property to mediate immunotherapy response, we can apply a combination therapy approach by targeting CSCs and tumor microenvironment (TME) along with conventional treatment strategies as an effective means to eradicate cancer cells.

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Cancer Stem Cells and Nucleolin as Drivers of Carcinogenesis

Pharmaceuticals ◽

10.3390/ph14010060 ◽

2021 ◽

Vol 14 (1) ◽

pp. 60

Author(s):

Laura Sofia Carvalho ◽

Nélio Gonçalves ◽

Nuno André Fonseca ◽

João Nuno Moreira

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Cancer Cells ◽

Epithelial To Mesenchymal Transition ◽

Clonal Evolution ◽

Therapy Resistance ◽

Cellular Heterogeneity ◽

Multifunctional Protein ◽

Mesenchymal Transition ◽

Cancer Hallmarks

Cancer, one of the most mortal diseases worldwide, is characterized by the gain of specific features and cellular heterogeneity. Clonal evolution is an established theory to explain heterogeneity, but the discovery of cancer stem cells expanded the concept to include the hierarchical growth and plasticity of cancer cells. The activation of epithelial-to-mesenchymal transition and its molecular players are widely correlated with the presence of cancer stem cells in tumors. Moreover, the acquisition of certain oncological features may be partially attributed to alterations in the levels, location or function of nucleolin, a multifunctional protein involved in several cellular processes. This review aims at integrating the established hallmarks of cancer with the plasticity of cancer cells as an emerging hallmark; responsible for tumor heterogeneity; therapy resistance and relapse. The discussion will contextualize the involvement of nucleolin in the establishment of cancer hallmarks and its application as a marker protein for targeted anticancer therapies

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