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CSCs-activated signaling pathways: Schematic representation of the signaling pathway responsible for induction and maintenance of CSC state. The transcription factors, co-factors, main nodes reported are targetable by drugs. (Adapted from Pattabiraman and Weinberg, Nat Rev Drug Discovery, 2014 [44]).
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Resistance to therapy in patients with solid cancers represents a daunting challenge that must be addressed. Indeed, current strategies are still not effective in the majority of patients; which has resulted in the need for novel therapeutic approaches. Cancer stem cells (CSCs), a subset of tumor cells that possess self-renewal and multilineage dif...
Citations
... HDAC inhibitors have shown potential in overcoming drug resistance by reversing epigenetic changes that contribute to drug resistance mechanisms. For example, HDAC inhibitors can re-sensitize cancer cells to chemotherapy drugs by restoring the expression of tumor suppressor genes or inhibiting drug efflux pumps that expel chemotherapy drugs from cancer cells (Roca et al. 2019;Ramaiah et al. 2021). In addition to their effects on histones, HDAC inhibitors can also target non-histone proteins involved in cancer progression and drug resistance. ...
TNF-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily that is capable of apoptosis induction selectively in tumor cells. Although TRAIL has been harnessed in numerous clinical trials, resistance to TRAIL-induced apoptosis is a major challenge ahead of this therapy in various cancer models as well as in leukemia. Since histone deacetylases (HDACs) are known to affect drug resistance in malignant cells, the present study aimed to evaluate the potential of fisetin for sensitization of MOLT-4 and K-562 leukemic cells to TRAIL-induced apoptosis. The MOLT-4 and K-562 cells were treated with increasing concentrations of fisetin and its impact on the growth inhibition and apoptosis induction of TRAIL were evaluated by MTT and Annexin V/7-AAD assays. The impact of fisetin on the mRNA and protein expression levels of apoptosis regulatory genes such as BIRC2/c-IAP1, CFLAR/cFLIP, CASP3, CASP7, CASPP9, TNFRSF10A/DR4, TNFRSF10B/DR5, and BID were examined by PCR array, qRT-PCR, and flow cytometry. Pre-treatment of MOLT-4 and K-562 cells with fisetin reduced the IC50 of TRAIL in growth inhibition along with an improvement in apoptosis induction by TRAIL. The expression of the BIRC2 gene encoding antiapoptotic protein c-IAP1 downregulated in the fisetin-treated cells while the expressions of TNFRSF10A and TNFRSF10B encoding TRAIL death receptors increased. Fisetin demonstrated a potential for alleviating the TRAIL resistance by modulating the apoptosis regulatory factors and improving the expressions of TRAIL receptors that could facilitate the application of TRAIL in cancer therapies.
... Histone methylation is engaged in upregulation of ATPbinding cassette drug membrane (ABC) transporters in chemoresistant OCSCs (264). Disturbed function of histone deacetylases promotes tumor progression (265). Table 4 contains data on both the experimental and clinical trials of targeting OCSCs. ...
Ovarian cancer, especially high-grade serous type, is the most lethal gynecological malignancy. The lack of screening programs and the scarcity of symptomatology result in the late diagnosis in about 75% of affected women. Despite very demanding and aggressive surgical treatment, multiple-line chemotherapy regimens and both approved and clinically tested targeted therapies, the overall survival of patients is still unsatisfactory and disappointing. Research studies have recently brought some more understanding of the molecular diversity of the ovarian cancer, its unique intraperitoneal biology, the role of cancer stem cells, and the complexity of tumor microenvironment. There is a growing body of evidence that individualization of the treatment adjusted to the molecular and biochemical signature of the tumor as well as to the medical status of the patient should replace or supplement the foregoing therapy. In this review, we have proposed the principles of the novel regimen of the therapy that we called the “DEPHENCE” system, and we have extensively discussed the results of the studies focused on the ovarian cancer stem cells, other components of cancer metastatic niche, and, finally, clinical trials targeting these two environments. Through this, we have tried to present the evolving landscape of treatment options and put flesh on the experimental approach to attack the high-grade serous ovarian cancer multidirectionally, corresponding to the “DEPHENCE” system postulates.
... To efficiently deliver AS1411 to the nucleus and achieve a synergistic antitumor effect, Wang et al. designed a multifunctional peptide drug conjugate (PDC) comprising the cell penetration peptide RW9, 5-FU at the peptide's N-terminus, and an HDAC inhibitor (HDACi) warhead at the peptide's C-terminus. Many studies have suggested that HDAC is associated with cell differentiation and the expression of genes related to the cell cycle in CSCs [93,94]. For example, HDAC can reduce the tumor volume; however, CSCs can survive, resulting in tumor regrowth. ...
Cancer stem cells (CSCs) are believed to be the main cause of chemotherapy resistance and tumor relapse. Various therapeutic strategies to eliminate CSCs have been developed recently. Aptamers, also called "chemical antibodies", can specifically bind with their molecular targets through special tertiary structures. The advantages of aptamers, such as lower immunogenicity and smaller size, make them superior to conventional antibodies. Therefore, aptamers have been used widely as targeting ligands for CSC-targeted therapeutic strategies in different tumor types. To date, various therapeutic cargoes have been conjugated to aptamers to kill CSCs, such as chemotherapy drugs, small interfering RNAs, and microRNAs. Aptamer-based targeted therapies for CSCs have made great progress in recent years, especially the development of multifunctional aptamer-based therapeutic strategies. Besides, cell-systematic evolution of ligands by exponential enrichment has been applied to screen new aptamers that might have a higher binding ability for CSCs. In this review, we focus on recent advances and introduce some new modalities of aptamer-drug conjugates against CSCs. Some considerations of the advantages and limitations of different aptamer-based targeted therapies for CSCs are also discussed.
... Accumulating evidence suggests that epigenetic deregulation is a hallmark of cancer and has a major contribution to disease development, progression as well as resistance to antitumor treatment in several solid tumors, including pancreatic cancer. Histone deacetylase inhibitors (HDACi) are one of the most prominent classes of epigenetic drugs, we have been investigating as anticancer agents, both preclinically and clinically, for a long time [14]. Interestingly, it was reported that the antitumor effect of HDACi correlates with specific tumor epigenetic alterations, frequently associated with pancreatic cancer (i.e KDMA6 loss) [15]. ...
... Interestingly, it was reported that the antitumor effect of HDACi correlates with specific tumor epigenetic alterations, frequently associated with pancreatic cancer (i.e KDMA6 loss) [15]. Furthermore, HDACi have been demonstrated to target CSC subpopulation and to overcome drug resistance in several preclinical cancer models [14]. ...
... Interestingly, we and others have previously reported that one of the mechanisms of the antitumor effect exerted by HDACi is through the modulation of redox homeostasis [37]. We also recently highlighted the role of HDACi in targeting CSC compartment as a rationale for novel combinatorial approach with these agents to improve anticancer therapeutic efficacy and to revert drug resistance in solid tumors [14,38]. ...
Background
Pancreatic ductal adenocarcinoma (PDAC) represents an unmet clinical need due to the very poor prognosis and the lack of effective therapy. Here we investigated the potential of domatinostat (4SC-202), a new class I histone deacetylase (HDAC) inhibitor, currently in clinical development, to sensitize PDAC to first line standard gemcitabine (G)/taxol (T) doublet chemotherapy treatment.
Methods
Synergistic anti-tumor effect of the combined treatment was assessed in PANC1, ASPC1 and PANC28 PDAC cell lines in vitro as well as on tumor spheroids and microtissues, by evaluating combination index (CI), apoptosis, clonogenic capability. The data were confirmed in vivo xenograft models of PANC28 and PANC1 cells in athymic mice. Cancer stem cells (CSC) targeting was studied by mRNA and protein expression of CSC markers, by limiting dilution assay, and by flow cytometric and immunofluorescent evaluation of CSC mitochondrial and cellular oxidative stress. Mechanistic role of forkhead box M1 (FOXM1) and downstream targets was evaluated in FOXM1-overexpressing PDAC cells.
Results
We showed that domatinostat sensitized in vitro and in vivo models of PDAC to chemotherapeutics commonly used in PDAC patients management and particularly to GT doublet, by targeting CSC compartment through the induction of mitochondrial and cellular oxidative stress. Mechanistically, we showed that domatinostat hampers the expression and function of FOXM1, a transcription factor playing a crucial role in stemness, oxidative stress modulation and DNA repair. Domatinostat reduced FOXM1 protein levels by downregulating mRNA expression and inducing proteasome-mediated protein degradation thus preventing nuclear translocation correlated with a reduction of FOXM1 target genes. Furthermore, by overexpressing FOXM1 in PDAC cells we significantly reduced domatinostat-inducing oxidative mitochondrial and cellular stress and abolished GT sensitization, both in adherent and spheroid cells, confirming FOXM1 crucial role in the mechanisms described. Finally, we found a correlation of FOXM1 expression with poor progression free survival in PDAC chemotherapy-treated patients.
Conclusions
Overall, we suggest a novel therapeutic strategy based on domatinostat to improve efficacy and to overcome resistance of commonly used chemotherapeutics in PDAC that warrant further clinical evaluation.
... Hematological cancers tend to be especially responsive to HDAC inhibitors; nevertheless, a variety of new cancer types are now being studied to determine their susceptibility to HDAC inhibitor treatment [266]. The FDA has approved vorinostat (suberoylanilide hydroxamic acid; SAHA) as the first drug of HDAC inhibitors for the treatment of cutaneous T-cell lymphoma, which suppresses HDACs 1, 2, 3, and 6 [267]. In cancer cells, SAHA has been shown to induce apoptosis, growth arrest, and polyploidy, all of which are associated with its anticancer actions. ...
Despite conventional treatment options including chemoradiation, patients with the most aggressive primary brain tumor, glioblastoma multiforme (GBM), experience an average survival time of less than 15 months. Regarding the malignant nature of GBM, extensive research and discovery of novel treatments are urgently required to improve the patients’ prognosis. Autophagy, a crucial physiological pathway for the degradation and recycling of cell components, is one of the exciting targets of GBM studies. Interventions aimed at autophagy activation or inhibition have been explored as potential GBM therapeutics. This review, which delves into therapeutic techniques to block or activate autophagy in preclinical and clinical research, aims to expand our understanding of available therapies battling GBM.
... Panobinostat, trichostatin A, vorinostat, and belinostat are hydroxamates that block HDAC activity by binding to Zn 2+ at the HDAC binding site. Besides aliphatic acids, sodium butyrate and valproic acid (VPA) inhibit class I HDACs as well [65,66]. For example, this occurs with VPA, sodium butyrate, and TSA. ...
Human diseases such as cancer can be caused by aberrant epigenetic regulation. Polyphenols play a major role in mammalian epigenome regulation through mechanisms and proteins that remodel chromatin. In fruits, seeds, and vegetables, as well as food supplements, polyphenols are found. Compounds such as these ones are powerful anticancer agents and antioxidants. Gallic acid, kaempferol, curcumin, quercetin, and resveratrol, among others, have potent anti-tumor effects by helping reverse epigenetic changes associated with oncogene activation and tumor suppressor gene inactivation. The role dietary polyphenols plays in restoring epigenetic alterations in cancer cells with a particular focus on DNA methylation and histone modifications was summarized. We also discussed how these natural compounds modulate gene expression at the epigenetic level and described their molecular targets in cancer. It highlights the potential of polyphenols as an alternative therapeutic approach in cancer since they modulate epigenetic activity.
... Cancer populations are heterogeneous and acquire stemness properties for the increased potential of regenerating the tumor pool and migratory ability. HDACs are highly upregulated in cancer stem cells and upon their inhibition tumor cells lose these properties (Fig. 6) [120]. Class I HDACs are responsible for inducing and maintaining cancer stemness in cancer stem cells. ...
Genetic aberration including mutation in oncogenes and tumor suppressor genes transforms normal cells into tumor cells. Epigenetic modifications work concertedly with genetic factors in controlling cancer development. Histone acetyltransferases (HATs), histone deacetylases (HDACs), DNA methyltransferases (DNMTs) and chromatin structure modifier are prospective epigenetic regulators. Specifically, HDACs are histone modifiers regulating the expression of genes implicated in cell survival, growth, apoptosis, and metabolism. The majority of HDACs are highly upregulated in cancer, whereas some have a varied function and expression in cancer progression. Distinct HDACs have a positive and negative role in controlling cancer progression. HDACs are also significantly involved in tumor cells acquiring metastatic and angiogenic potential in order to withstand the anti-tumor microenvironment. HDACs’ role in modulating metabolic genes has also been associated with tumor development and survival. This review highlights and discusses the molecular mechanisms of HDACs by which they regulate cell survival, apoptosis, metastasis, invasion, stemness potential, angiogenesis, and epithelial to mesenchymal transitions (EMT) in tumor cells. HDACs are the potential target for anti-cancer drug development and various inhibitors have been developed and FDA approved for a variety of cancers. The primary HDAC inhibitors with proven anti-cancer efficacy have also been highlighted in this review.
... In addition to a robust DNA damage response, CSCs also undergo a persistent quiescence state which may contribute to therapy resistance. This is because some of the cytotoxic agents only target cancer cells that are highly proliferating [99][100][101][102]. Once treatment stops, these quiescent CSCs can re-enter the cell cycle and activate cell growth and proliferative signaling pathways, thus accelerating tumor regeneration [101]. ...
Cervical cancer (CC) is the fourth most common type of gynecological malignancy affecting females worldwide. Most CC cases are linked to infection with high-risk human papillomaviruses (HPV). There has been a significant decrease in the incidence and death rate of CC due to effective cervical Pap smear screening and administration of vaccines. However, this is not equally available throughout different societies. The prognosis of patients with advanced or recurrent CC is particularly poor, with a one-year relative survival rate of a maximum of 20%. Increasing evidence suggests that cancer stem cells (CSCs) may play an important role in CC tumorigenesis, metastasis, relapse, and chemo/radio-resistance, thus representing potential targets for a better therapeutic outcome. CSCs are a small subpopulation of tumor cells with self-renewing ability, which can differentiate into heterogeneous tumor cell types, thus creating a progeny of cells constituting the bulk of tumors. Since cervical CSCs (CCSC) are difficult to identify, this has led to the search for different markers (e.g., ABCG2, ITGA6 (CD49f), PROM1 (CD133), KRT17 (CK17), MSI1, POU5F1 (OCT4), and SOX2). Promising therapeutic strategies targeting CSC-signaling pathways and the CSC niche are currently under development. Here, we provide an overview of CC and CCSCs, describing the phenotypes of CCSCs and the potential of targeting CCSCs in the management of CC.
... Several of the KMT enzymes are over-expressed in multiple cancers [27]. Enhancer of Zeste-Homolog 2 (EZH2), Enhancer of Zeste-Homolog 3 (EZH3) and H3K27(lysine residue at position 27 of histone 3) KMTs were found at elevated levels in glioma, breast and leukemia CSCs, and are credited with maintaining their quiescent state [31]. ...
Tumor heterogeneity poses one of the greatest challenges to a successful treatment of cancer. Tumor cell populations consist of different subpopulations that have distinct phenotypic and genotypic profiles. Such variability poses a challenge in successfully targeting all tumor subpopulations at the same time. Relapse after treatment has been previously explained using the cancer stem cell model and the clonal evolution model. Cancer stem cells are an important subpopulation of tumor cells that regulate tumor plasticity and determine therapeutic resistance. Tumor plasticity is controlled by genetic and epigenetic changes of crucial genes involved in cancer cell survival, growth and metastasis. Targeting epigenetic modulators associated with cancer stem cell survival can unlock a promising therapeutic approach in completely eradicating cancer. Here, we review various factors governing epigenetic dysregulation of cancer stem cells ranging from the role of epigenetic mediators such as histone and DNA methyltransferases, histone deacetylases, histone methyltransferases to various signaling pathways associated with cancer stem cell regulation. We also discuss current treatment regimens targeting these factors and other promising inhibitors in clinical trials.
... Histone methylation is also responsible for the increased expression ABC of transmembrane transporters responsible for chemo-resistance of CSCs [326]. The dysregulated function of histone acetyltransferases (HAT) and deacetylases (HDAC) are also connected to cancer progression, and the over-activity of HDAC1 and HDAC7 enzymes promotes stemness in CSCs in ovarian cancer [344][345][346]. Hypomethylation is the next epigenetic regulator of OC behavior. ...
Ovarian cancer is the most lethal neoplasm of the female genital organs. Despite indisputable progress in the treatment of ovarian cancer, the problems of chemo-resistance and recurrent disease are the main obstacles for successful therapy. One of the main reasons for this is the presence of a specific cell population of cancer stem cells. The aim of this review is to show the most contemporary knowledge concerning the biology of ovarian cancer stem cells (OCSCs) and their impact on chemo-resistance and prognosis in ovarian cancer patients, as well as to present the treatment options targeted exclusively on the OCSCs. The review presents data concerning the role of cancer stem cells in general and then concentrates on OCSCs. The surface and intracellular OCSCs markers and their meaning both for cancer biology and clinical prognosis, signaling pathways specifically activated in OCSCs, the genetic and epigenetic regulation of OCSCs function including the recent studies on the non-coding RNA regulation, cooperation between OCSCs and the tumor microenvironment (ovarian cancer niche) including very specific environment such as ascites fluid, the role of shear stress, autophagy and metabolic changes for the function of OCSCs, and finally mechanisms of OCSCs escape from immune surveillance, are described and discussed extensively. The possibilities of anti-OCSCs therapy both in experimental settings and in clinical trials are presented, including the recent II phase clinical trials and immunotherapy. OCSCs are a unique population of cancer cells showing a great plasticity, self-renewal potential and resistance against anti-cancer treatment. They are responsible for the progression and recurrence of the tumor. Several completed and ongoing clinical trials have tested different anti-OCSCs drugs which, however, have shown unsatisfactory efficacy in most cases. We propose a novel approach to ovarian cancer diagnosis and therapy.
