Targeting Cancer Stem Cells Research Articles

4-Hydroxynonenal Promotes Colorectal Cancer Progression Through Regulating Cancer Stem Cell Fate.

Aims: Tumor microenvironment (TME) plays a crucial role in sustaining cancer stem cells (CSCs). 4-hydroxynonenal (4-HNE) is abundantly present in the TME of colorectal cancer (CRC). However, the contribution of 4-HNE to CSCs and cancer progression remains unclear. This study aimed to investigate the impact of 4-HNE on the regulation of CSC fate and tumor progression. Methods: Human CRC cells were exposed to 4-HNE, and CSC signaling was analyzed using quantitative real-time polymerase chain reaction, immunofluorescent staining, fluorescence-activated cell sorting, and bioinformatic analysis. The tumor-promoting role of 4-HNE was confirmed using a xenograft model. Results: Exposure of CRC cells to 4-HNE activated noncanonical hedgehog (HH) signaling and homologous recombination repair (HRR) pathways in LGR5+ CSCs. Furthermore, blocking HH signaling led to a significant increase in the expression of γH2AX, indicating that 4-HNE induces double-stranded DNA breaks (DSBs) and simultaneously activates HH signaling to protect CSCs from 4-HNE-induced damage via the HRR pathway. In addition, 4-HNE treatment increased the population of LGR5+ CSCs and promoted asymmetric division in these cells, leading to enhanced self-renewal and differentiation. Notably, 4-HNE also promoted xenograft tumor growth and activated CSC signaling invivo. Innovation and Conclusion: These findings demonstrate that 4-HNE, as a signaling inducer in the TME, activates the noncanonical HH pathway to shield CSCs from oxidative damage, enhances the proliferation and asymmetric division of LGR5+ CSCs, and thereby facilitates tumor growth. These novel insights shed light on the regulation of CSC fate within the oxidative TME, offering potential implications for understanding and targeting CSCs for CRC therapy.

A select thiosemicarbazone copper(II) complex induces apoptosis in gastric cancer and targets cancer stem cells reducing pluripotency markers

Copper(II)-based complexes are promising candidates as anti-cancer agents due to their ability to target cancer cells. Here we describe the synthesis and characterization of two copper(II) thiosemicarbazone complexes with the ligands 4-(dimethylamino)benzaldehyde N4-methylthiosemicarbazone (HL1) and 4-(dimethylamino)benzaldehyde N4-(4-(dimethylamino)phenylthiosemicarbazone (HL2) and general formula [Cu(L)2]. The complexes show stability in aqueous solution with 1 % of DMSO that allows to stablish its solution profile in biological buffers. Compound [Cu(L1)₂] lipophilicity was lower than [Cu(L2)₂], however, its solubility in biological buffer was not only better but also its DLS and ζ-potential data. In vitro studies demonstrate a higher cytotoxic effect of [Cu(L1)₂] on gastric cancer cells. The proposed mechanism of action consists in the generation of free radicals that induce DNA lesions, oxidative stress and ultimately autophagy deregulation and apoptosis. Additionally, [Cu(L1)₂] is equally active on gastric cancer stem cells and tumor cells resistant to cisplatin. More importantly, stem cells treated with [Cu(L1)₂] show a downregulation of pluripotency markers such as TWIST, NANOG and OCT4. Overall, our results with [Cu(L1)₂] prompt a significant advancement in the development of rational-designed pharmaceuticals for combating cancer.

Characterization of stem cell landscape and assessing the stemness degree to aid clinical therapeutics in hematologic malignancies

Hematological malignancies are a group of cancers that affect the blood, bone marrow, and lymphatic system. Cancer stem cells (CSCs) are believed to be responsible for the initiation, progression, and relapse of hematological malignancies. However, identifying and targeting CSCs presents many challenges. We aimed to develop a stemness index (HSCsi) to identify and guide the therapy targeting CSCs in hematological malignancies. We developed a novel one-class logistic regression (OCLR) algorithm to identify transcriptomic feature sets related to stemness in hematologic malignancies. We used the HSCsi to measure the stemness degree of leukemia stem cells (LSCs) and correlate it with clinical outcomes.We analyze the correlation of HSCsi with genes and pathways involved in drug resistance and immune microenvironment of acute myeloid leukemia (AML). HSCsi revealed stemness-related biological mechanisms in hematologic malignancies and effectively identify LSCs. The index also predicted survival and relapse rates of various hematologic malignancies. We also identified potential drugs and interventions targeting cancer stem cells (CSCs) of hematologic malignancies by the index. Moreover, we found a correlation between stemness and bone marrow immune microenvironment in AML. Our study provides a novel method and tool to assess the stemness degree of hematologic malignancies and its implications for clinical outcomes and therapeutic strategies. Our HSC stemness index can facilitate the precise stratification of hematologic malignancies, suggest possible targeted and immunotherapy options, and guide the selection of patients.

The Potential of Epigallocatechin Gallate in Targeting Cancer Stem Cells: A Comprehensive Review.

The dreadful scenario of cancer prevails due to the presence of cancer stem cells (CSCs), which contribute to tumor growth, metastasis, invasion, resistance to chemo- and radiotherapy, and recurrence. CSCs are a small subpopulation of cells within the tumor that are characterized by self-renewal capability and have the potential to manifest heterogeneous lineages of cancer cells that constitute the tumor. The major bioactive green tea polyphenol (-)-epigallocatechin gallate (EGCG) has been fruitful in downgrading cancer stemness signaling and CSC biomarkers in cancer progression. EGCG has been evidenced to maneuver extrinsic and intrinsic apoptotic pathways in order to decrease the viability of CSCs. Cancer stemness is intricately related to epithelial-mesenchymal transition (EMT), metastasis and therapy resistance, and EGCG has been evidenced to regress all these CSC-related effects. By inhibiting CSC characteristics EGCG has also been evidenced to sensitize the tumor cells to radiotherapy and chemotherapy. However, the use of EGCG in in vitro and in vivo cancer models raises concern about its bioavailability, stability and efficacy against spheroids raised from parental cells. Therefore, novel nano formulations of EGCG and adjuvant therapy of EGCG with other phytochemicals or drugs or small molecules may have a better prospect in targeting CSCs. However, extensive clinical research is still awaited to elucidate a full proof impact of EGCG in cancer therapy.

Everything you ever wanted to know about cancer stem cells in neuroendocrine neoplasms but were afraid to ask

While the role of cancer stem cells (CSCs) in tumorigenesis, chemoresistance, metastasis and relapse has been extensively studied in solid tumors, such as adenocarcinomas or sarcomas, the same cannot be said for neuroendocrine neoplasms (NENs). While lagging, CSCs have been described in numerous NENs including gastrointestinal and pancreatic neuroendocrine neoplasms (PanNENs), and they have been found to play critical roles in tumor initiation, progression, and treatment resistance. However, it seems there is still skepticism regarding the role of CSCs in NENs, even in light of studies that support the CSC model in these tumors and the therapeutic benefit of targeting them. For example, in lung neuroendocrine carcinoids, a high percentage of CSCs have been found in atypical carcinoids, suggesting the presence of CSCs in these cancers. In PanNENs, CSCs marked by aldehyde dehydrogenases or CD90 have been identified, and targeting CSCs with inhibitors of molecular pathways has shown therapeutic potential. Overall, while evidence exists for the presence of CSCs in NENs, either the CSC field has neglected NENs or the NEN field has not fully embraced the CSC model. Both might apply and/or may be a consequence of the fact that NENs are a relatively rare and heterogeneous tumor entity, with confusing histology and nomenclature to match. Regardless, this review intends to summarize our current knowledge of CSCs in NENs and highlight the importance of understanding the role of CSCs in the biology of these rare tumors, with a special focus on developing targeted therapies to improve patients' outcomes.

Meta-Analysis of Prognostic Significance of Cancer Stem Cell Markers in Oral Squamous Cell Carcinoma.

Researchers have shown significant interest in cancer stem cells in recent years. CD44, CD24, CD133, and ALDH serve as indicators of cancer stem cell-like cells in Oral Squamous Cell Carcinoma. However, the prognostic significance of these Cancer Stem Cell markers in Squamous Cell Carcinoma is still debated. This study employed meta-analysis to evaluate the prognostic significance of cancer stem cells about Oral Squamous Cell Carcinoma. CD44, CD133, CD24, and ALDH markers were analyzed in 19 retrospective studies to determine their relationship with prognosis and clinicopathological parameters. Risk ratios (RRs) and odds ratios (ORs) were calculated for 3-years survival rates and clinicopathological parameters, respectively, using a fixed-effects model. The finding of our study based on extracted survival rates showed that cancer stem cell markers, CD133 expression was related with the poor prognosis (RR= 1.62 ,95% CI = 1.08-2.44, P= 0.02). ALDH expression significantly correlated with lymph node metastasis (OR= 4.13, 95% Cl= 1.88-9.10, P<0.001) and clinical staging (OR= 2.26, 95% CI= 1.05-4.88, P= 0.04). The findings indicate that CSC markers could be used to predict oral cancer prognosis. Our study contributes to the literature on survival outcomes of Oral Squamous Cell Carcinoma. These findings offer a structure for the advancement of cancer treatments that specifically target cancer stem cells. Conducting additional studies with a broader group of patients will help confirm the role of cancer stem cells as dependable predictors of prognosis.

Targeting Cervical Cancer Stem Cells by Phytochemicals.

Cervical cancer (CaCx) poses a significant global health challenge, ranking as the fourth most common cancer among women worldwide. Despite the emergence of advanced treatment strategies, recurrence remains a bottleneck in favorable treatment outcomes and contributes to poor prognosis. The chemo- or radio-therapy resistance coupled with frequent relapse of more aggressive tumors are some key components that contribute to CaCx-related mortality. The onset of therapy resistance and relapse are attributed to a small subset of, slow-proliferating Cancer Stem Cells (CSC). These CSCs possess the properties of tumorigenesis, self-renewal, and multi-lineage differentiation potential. Because of slow cycling, these cells maintain themselves in a semi-quiescent stage and protect themselves from different anti-proliferative anti-cancer drugs. Keeping in view recent advances in their phenotypic and functional characterization, the feasibility of targeting CSC and associated stem cell signaling bears a strong translational value. The presence of CSC has been reported in CaCx (CCSC) which remains a forefront area of research. However, we have yet to identify clinically useful leads that can target CCSC. There is compelling evidence that phytochemicals, because of their advantages over synthetic anticancer drugs, could emerge as potential therapeutic leads to target these CCSCs. The present article examined the potential of phytochemicals with reported anti-CSC properties and evaluated their future in preclinical and clinical applications against CaCx.

Genotoxic and Anti-Migratory Effects of Camptothecin Combined with Celastrol or Resveratrol in Metastatic and Stem-like Cells of Colon Cancer.

Background: Colorectal cancer is one of the leading and most lethal neoplasms. Standard chemotherapy is ineffective, especially in metastatic cancer, and does not target cancer stem cells. A promising approach to improve cancer treatment is the combination therapy of standard cytostatic drugs with natural compounds. Several plant-derived compounds have been proven to possess anticancer properties, including the induction of apoptosis and inhibition of cancer invasion. This study was focused on investigating in vitro the combination of camptothecin (CPT) with celastrol (CEL) or resveratrol (RSV) as a potential strategy to target metastatic (LOVO) and stem-like (LOVO/DX) colon cancer cells. Methods: The genotoxic effects that drive cancer cells into death-inducing pathways and the ability to inhibit the migratory properties of cancer cells were evaluated. The γH2AX+ assay and Fast-Halo Assay (FHA) were used to evaluate genotoxic effects, the annexin-V apoptosis assay to rate the level of apoptosis, and the scratch test to assess antimigratory capacity. Results: The results showed that both combinations CPT-CEL and CPT-RSV improve general genotoxicity of CPT alone on metastatic cells and CSCs. However, the assessment of specific double-stranded breaks (DSBs) indicated a better efficacy of the CPT-CEL combination on LOVO cells and CPT-RSV in LOVO/DX cells. Interestingly, the combinations CPT-CEL and CPT-RSV did not improve the pro-apoptotic effect of CPT alone, with both LOVO and LOVO/DX cells suggesting activation of different cell death mechanisms. Furthermore, it was found that the combinations of CPT-CEL and CPT-RSV improve the inhibitory effect of camptothecin on cell migration. Conclusions: These findings suggest the potential utility of combining camptothecin with celastrol or resveratrol in the treatment of colon cancer, including more aggressive forms of the disease. So far, no studies evaluating the effects of combinations of these compounds have been published in the available medical databases.

Advancing Cancer Stem Cell-Targeted Therapeutic Applications

Cancer stem cells (CSCs), first identified in blood cancers, are increasingly recognized as significant biomarkers and targets in tumor therapy due to their metastatic potential and role in cancer recurrence. Recent research has demonstrated the dedication of scientists in targeting CSCs to explore novel therapeutic strategies. Many types of cancer exhibit metastasis, heterogeneity, and resistance to treatment, all of which are influenced by CSCs. These cells utilize various transcription factors and signaling pathways to carry out these functions. By identifying and understanding these pathways, new therapeutic breakthroughs can be achieved. Thus, targeting cancer stem cells holds great potential and importance in cancer treatment. Moreover, CSCs offer promising avenues for treating otherwise incurable diseases. However, targeting CSCs presents challenges such as immunological rejection and disease recurrence. Advancing research into CSCs may reveal new insights in the fight against cancer and ultimately improve human health. This review explores the roles of CSCs in cancer development and treatment, aiming to uncover new therapeutic approaches.

Effective Synthesis of C20-epi-Isothiocyanato-Salinomycin and Its Thiourea Derivatives as Potential Anticancer Agents.

Salinomycin, a naturally occurring polyether ionophore antibiotic isolated from Streptomyces albus, has been demonstrated potent cytotoxic activity against a variety of cancer cell lines. In particular, it exhibits selective targeting of cancer stem cells. However, systemic toxicity, drug resistance and low bioavailability of the drug significantly limit its potential applications. In this study, the C20-epi-isothiocyanate of salinomycin was designed and synthesized, and then reacted with amines as a versatile synthon to assemble a series of salinomycin thiourea derivatives, which improved the druggability of salinomycin. The antiproliferative activities of the compounds were evaluated in vitro against A549, HepG2, Hela, 4T1, and MCF-7 cancer cell lines using the CCK-8 assay. The pharmacological results showed that some salinomycin thiourea derivatives exhibited excellent inhibitory activity against at least one of the tested tumor cells and high selectivity. Further mechanistic studies showed that compound 9f, containing a 3,5-difluorobenzyl moiety, could directly induce apoptosis, probably by increasing caspase-9 protein expression and cell cycle arrest in G1 phase in a concentration dependent manner.

Psoralidin: emerging biological activities of therapeutic benefits and its potential utility in cervical cancer

Cervical cancer (CaCx) is the fourth most prevalent cancer in women contributing to 341,831 annual deaths globally in 2020. Owing to its high mortality rate, the identification of novel inhibitors preventing CaCx progression is of utmost importance. Recent studies have emphasized the use of phytochemicals for cancer prevention due to their low toxicity. Psoralidin, a bioactive compound extracted from the seeds of the medicinal plant Psoralea corylifolia, showcases the potential for promoting health benefits. A range of studies showing anti-inflammatory, anti-oxidant, estrogenic, neuroprotective, anti-diabetic, anti-depressant, antimicrobial, and anti-tumor activities substantiate its promising biological effects. The anti-tumor potential of psoralidin has been well-documented. Its capacity to effectively target cancer stem cells (CSCs) in general adds to its therapeutic potential. Psoralidin carries out its anti-cancer activity by inducing oxidative stress, autophagy, and apoptosis. This unique characteristic suggests its potential to be used as an adjunct molecule in combination with existing treatment to enhance the efficacy of chemo/radiotherapy for treating CaCx. However, low bioavailability and intestinal efflux limit the use of psoralidin in clinical applications. Therefore, further investigation is needed in area of drug delivery and mechanism of action to fully harness the beneficial effects of psoralidin. The present study examines the current understanding of the molecular properties of this coumestan, as well as its various molecular targets with a particular emphasis on its anti-cancer activity. The study will help in designing effective and novel therapeutic interventions for targeting signaling pathways and other regulators involved in mediating CaCx progression, which will eventually help in effective management of CaCx.

To Elucidate the Effective Role of Small Molecule Regulated lncRNAs in the Tumour Microenvironment in Immunotherapy.

The tumour microenvironment is a complex ecosystem comprising tumour cells, and cancer stem cells, and support cells that facilitate cancer growth and escape from treatment. Cancer immunotherapy focuses on immunological pathways such as PD-1/PD-L1 and CTLA-4 to target cancer stem cells via immune cells. Small molecules, immune checkpoint inhibitors, are employed to impede tumour growth by targeting cellular mediators in the cell cycle and tumour microenvironment. Long non-coding RNAs (lncRNAs) affect the growth, development, motility, and differentiation of cancer cells by regulating gene expression and are therefore considered important biomarkers. Small molecules demonstrate their effects on gene expression and behaviour of cancer cells by inducing lncRNAs. This relationship between lncRNAs and small molecules is of great importance in terms of their impact on cancer and the tumour microenvironment. The evaluation of this communication in clinical trials is of critical importance for the development of therapeutic strategies. This review provides a detailed description of the role of lncRNAs and small molecules in the tumour microenvironment and their relationship with cancer stem cells. Thus, the potential of controlling lncRNAs and using anti-cancer small molecules in TME to improve the efficacy of cancer therapy was evaluated.

Stat3 Inhibitors TTI-101 and SH5-07 Suppress Bladder Cancer Cell Survival in 3D Tumor Models.

Bladder cancer (BCa) is one of the most lethal genitourinary malignancies owing to its propensity for recurrence and poor survival. The biochemical pathway, signal transducer and activator of transcription 3 (STAT3), has gained significance as a molecular pathway that promotes proliferation, invasion, and chemoresistance. In this study, we explored the targeting of STAT3 with TTI-101 and SH5-07 in BCa and elucidated the mechanisms in three-dimensional (3D) spheroid and organoid models. We optimized the growth of spheroids from human, rat, and mouse BCa cell lines (J82, NBT-II, and MB49 respectively) and organoids from BBN (N-butyl-N-(4-hydroxybutyl)-nitrosamine)-induced rat bladder tumors. Cell viability was assessed using MTT and trypan blue assays. Intracellular ATP production, ROS production, and calcium AM (CA)/EtBr staining were used to measure the spheroid and organoid inhibition and mitochondrial function. Western blot analysis was performed to evaluate the pharmacodynamic markers involved in cell proliferation, apoptosis, cancer stem cells (CSCs), and STAT3 signaling in BCa. We found that targeting STAT3 (using TTI-101 and SH5-07) significantly reduced the proliferation of BCa spheroids and organoids, which was accompanied by decreased expression of pSTAT3, Cyclin D1, and PCNA. Our data also demonstrated that treatment with STAT3 inhibitors induced ROS production and cell death in BCa spheroids and organoids. STAT3 inhibition-induced cell death was associated with the activation of caspase 3/7 and PARP cleavage. Moreover, TTI-101 and SH5-07 target cancer stem cells by downregulating the expression of CD44 and CD133 in 3D models. This study provides the first evidence for the prevention of BCa with small-molecule inhibitors TTI-101 and SH5-07 via suppression of CSCs and STAT3 signaling.

Construction of a pathomics model for predicting mRNAsi in lung adenocarcinoma and exploration of biological mechanism

ObjectiveThis study aimed to predict the level of stemness index (mRNAsi) and survival prognosis of lung adenocarcinoma (LUAD) using pathomics model. MethodsFrom The Cancer Genome Atlas (TCGA) database, 327 LUAD patients were randomly assigned to a training set (n = 229) and a validation set (n = 98) for pathomics model development and evaluation. PyRadiomics was used to extract pathomics features, followed by feature selection using the mRMR-RFE algorithm. In the training set, Gradient Boosting Machine (GBM) was utilized to establish a model for predicting mRNAsi in LUAD. The model's predictive performance was evaluated using ROC curves, calibration curves, and decision curve analysis (DCA). Prognostic analysis was conducted using Kaplan-Meier curves and cox regression. Additionally, gene enrichment analysis, tumor microenvironment analysis, and tumor mutational burden (TMB) analysis were performed to explore the biological mechanisms underlying the pathomics prediction model. ResultsMultivariable cox analysis (HR = 1.488, 95 % CI 1.012–2.187, P = 0.043) identified mRNAsi as a prognostic risk factor for LUAD. A total of 465 pathomics features were extracted from TCGA-LUAD histopathological images, and ultimately, the most representative 8 features were selected to construct the predictive model. ROC curves demonstrated the significant predictive value of the model for mRNAsi in both the training set (AUC = 0.769) and the validation set (AUC = 0.757). Calibration curves and Hosmer-Lemeshow goodness-of-fit test showed good consistency between the model's prediction of mRNAsi levels and the actual values. DCA indicated a good net benefit of the model. The prediction of mRNAsi levels by the pathomics model is represented using the pathomics score (PS). PS was strongly associated with the prognosis of LUAD (HR = 1.496, 95 % CI 1.008–2.222, P = 0.046). Signaling pathways related to DNA replication and damage repair were significantly enriched in the high PS group. Prediction of immune therapy response indicated significantly reduced Dysfunction in the high PS group (P < 0.001). The high PS group exhibited higher TMB values (P < 0.001). ConclusionsThe predictive model constructed based on pathomics features can forecast the mRNAsi and survival risk of LUAD. This model holds promise to aid clinical practitioners in identifying high-risk patients and devising more optimized treatment plans for patients by jointly employing therapeutic strategies targeting cancer stem cells (CSCs).

Exploring potential roles of long non-coding RNAs in cancer immunotherapy: a comprehensive review.

Cancer treatment has long been fraught with challenges, including drug resistance, metastasis, and recurrence, making it one of the most difficult diseases to treat effectively. Traditional therapeutic approaches often fall short due to their inability to target cancer stem cells and the complex genetic and epigenetic landscape of tumors. In recent years, cancer immunotherapy has revolutionized the field, offering new hope and viable alternatives to conventional treatments. A particularly promising area of research focuses on non-coding RNAs (ncRNAs), especially long non-coding RNAs (lncRNAs), and their role in cancer resistance and the modulation of signaling pathways. To address these challenges, we performed a comprehensive review of recent studies on lncRNAs and their impact on cancer immunotherapy. Our review highlights the crucial roles that lncRNAs play in affecting both innate and adaptive immunity, thereby influencing the outcomes of cancer treatments. Key observations from our review indicate that lncRNAs can modify the tumor immune microenvironment, enhance immune cell infiltration, and regulate cytokine production, all of which contribute to tumor growth and resistance to therapies. These insights suggest that lncRNAs could serve as potential targets for precision medicine, opening up new avenues for developing more effective cancer immunotherapies. By compiling recent research on lncRNAs across various cancers, this review aims to shed light on their mechanisms within the tumor immune microenvironment.

Jiedu Xiaozheng Yin extract targets cancer stem cells by Wnt signaling pathway in colorectal cancer

Ethnopharmacological relevanceThe clinical application of the traditional Chinese medicinal formula Jiedu Xiaozheng Yin (JXY) for gastrointestinal tumors, particularly colorectal cancer (CRC), is well-established, yet the precise biological mechanism underlying its efficacy in CRC treatment remains elusive. Aims of the studyThis study endeavors to unravel the intricate mechanism through which JXY modulates colorectal cancer stem cells, thus elucidating the pathways by which it exerts its potent anti-tumor effects. Materials and methodsIn this study, the regulatory impact of JXY on the signaling pathway and function of CRC cells was analyzed through Network pharmacology. The ethyl acetate extract of JXY was detected the major compounds using HPLC and then treated the HCT-116 cells for RNA-Sequencing (RNA-Seq). Protein expression and stemness of HCT-15 and HCT-116 cells following JXY extract treatment were assessed using Western blot analysis and matrigel spheroid assays. Additionally, the β-catenin transcriptional activity was evaluated using a TOPflash reporter assay with or without Lithium chloride (LiCl) stimulation. Patient-derived organoids of CRC (CRC PDOs) were cultured using a stemness maintenance medium, and their viability was measured using ATP assays after treatment of JXY extract. Furthermore, the anti-tumor efficacy of JXY extract was assessed using a xenograft mice model derived from HCT-15 cells. ResultsNetwork pharmacology emphasized the influence of JXY on cancer stem cells and the Wnt signaling pathway. HPLC analysis confirmed that the JXY extract contained the three most prevalent pharmaceutical compounds among the four herbs documented in the Chinese Pharmacopoeia (rosmarinic acid, quercetin, and kaempferol). RNA-Seq results further elucidated the effect of JXY extract, particularly targeting cancer stem cells and the Wnt signaling pathway. Furthermore, JXY extract inhibited spheroid formation in CRC cells and downregulated CRC CSC markers (CD133, DCLK1, and C-MYC). Additionally, JXY extract suppressed the β-catenin expression and transcriptional activity as well as the Wnt pathway target proteins, including C-MYC and Cyclin D1. Consistent with findings from cell lines, JXY extract suppressed the growth of CRC PDOs exhibiting stemness characteristics. And JXY extract demonstrated a significant inhibitory effect on tumor growth, C-MYC, and β-catenin protein levels in xenograft tumors. ConclusionsThese results highlight the novel function of JXY extract in targeting CRC CSCs by regulating Wnt signaling pathway, underscoring its potential as a therapeutic agent for treating CRC.

Revolution of blood cancer treatment in the oral cavity: Breakthroughs in nanotherapy

This comprehensive review explores the potential of nanotherapy in the treatment of blood cancers, specifically leukemia, lymphoma, and myeloma, in the oral cavity. Nanoparticles (NPs) made from organic and inorganic materials have shown promise in delivering therapeutic substances to cancer cells, enhancing their pharmacological efficacy, and reducing their systemic toxicity. Different types of nanoparticles, such as liposomes, extracellular vehicles, and polymeric nanoparticles, have been studied for their effectiveness in targeting cancer cells. Nanotherapy has also been investigated for overcoming drug resistance, targeting cancer stem cells, bypassing efflux pumps, and gene silencing. Clinical trials and research findings have demonstrated the potential of nanotherapy for improving outcomes in patients with acute myeloid leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, and multiple myeloma. However, challenges exist in addressing the heterogeneity of blood cancers in the oral cavity, navigating the tumor microenvironment, overcoming drug resistance, and modulating immune evasion. Future directions include individualized treatment plans, multifunctional nanoparticles, combination therapies, and improved nanoparticle design. The translation of these breakthroughs into clinical practice requires collaboration among researchers, physicians, and industry stakeholders. Overall, nanotherapy holds promise for more effective and less invasive treatments for blood cancer in the oral cavity.

Peroxiredoxin 1 modulates oxidative stress resistance and cell apoptosis through stemness in liver cancer under non-thermal plasma treatment

The role of peroxiredoxin 1 (PRDX1), a crucial enzyme that reduces reactive oxygen and nitrogen species levels in HepG2 human hepatocellular carcinoma (HCC) cells, in the regulation of HCC cell stemness under oxidative stress and the underlying mechanisms remain largely unexplored. Here, we investigated the therapeutic potential of non-thermal plasma in targeting cancer stem cells (CSCs) in HCC, focusing on the mechanisms of resistance to oxidative stress and the role of PRDX1. By simulating oxidative stress conditions using the plasma-activated medium, we found that a reduction in PRDX1 levels resulted in a considerable increase in HepG2 cell apoptosis, suggesting that PRDX1 plays a key role in oxidative stress defense mechanisms in CSCs. Furthermore, we found that HepG2 cells had higher spheroid formation capability and increased levels of stem cell markers (CD133, c-Myc, and OCT-4), indicating strong stemness. Interestingly, PRDX1 expression was notably higher in HepG2 cells than in other HCC cell types such as Hep3B and Huh7 cells, whereas the expression levels of other PRDX family proteins (PRDX 2–6) were relatively consistent. The inhibition of PRDX1 expression and peroxidase activity by conoidin A resulted in markedly reduced stemness traits and increased cell death rate. Furthermore, in a xenograft mouse model, PRDX1 downregulation considerably inhibited the formation of solid tumors after plasma-activated medium (PAM) treatment. These findings underscore the critical role of PRDX 1 in regulating stemness and apoptosis in HCC cells under oxidative stress, highlighting PRDX1 as a promising therapeutic target for NTP-based treatment in HCC.

Neem Leaf Glycoprotein Disrupts Exhausted CD8+ T-Cell-Mediated Cancer Stem Cell Aggression.

Targeting exhausted CD8+ T-cell (TEX)-induced aggravated cancer stem cells (CSC) holds immense therapeutic potential. In this regard, immunomodulation via Neem Leaf Glycoprotein (NLGP), a plant-derived glycoprotein immunomodulator is explored. Since former reports have proven immune dependent-tumor restriction of NLGP across multiple tumor models, we hypothesized that NLGP might reprogram and rectify TEX to target CSCs successfully. In this study, we report that NLGP's therapeutic administration significantly reduced TEX-associated CSC virulence in in vivo B16-F10 melanoma tumor model. A similar trend was observed in in vitro generated TEX and B16-F10/MCF7 coculture setups. NLGP rewired CSCs by downregulating clonogenicity, multidrug resistance phenotypes and PDL1, OCT4, and SOX2 expression. Cell cycle analysis revealed that NLGP educated-TEX efficiently pushed CSCs out of quiescent phase (G0G1) into synthesis phase (S), supported by hyper-phosphorylation of G0G1-S transitory cyclins and Rb proteins. This rendered quiescent CSCs susceptible to S-phase-targeting chemotherapeutic drugs like 5-fluorouracil (5FU). Consequently, combinatorial treatment of NLGP and 5FU brought optimal CSC-targeting efficiency with an increase in apoptotic bodies and proapoptotic BID expression. Notably a strong nephron-protective effect of NLGP was also observed, which prevented 5FU-associated toxicity. Furthermore, Dectin-1-mediated NLGP uptake and subsequent alteration of Notch1 and mTOR axis were deciphered as the involved signaling network. This observation unveiled Dectin-1 as a potent immunotherapeutic drug target to counter T-cell exhaustion. Cumulatively, NLGP immunotherapy alleviated exhausted CD8+ T-cell-induced CSC aggravation. Implications: Our study recommends that NLGP immunotherapy can be utilized to counter ramifications of T-cell exhaustion and to target therapy elusive aggressive CSCs without evoking toxicity.

Resveratrol: Targeting Cancer Stem Cells and ncRNAs to Overcome Cancer Drug Resistance.

A major challenge in treating cancer is the development of drug resistance, which can result in treatment failure and tumor recurrence. Targeting cancer stem cells (CSCs) and non-coding RNAs (ncRNAs) with a polyphenolic substance called resveratrol has the ability to combat this problem by lowering cancer resistance to drugs and opening up new therapeutic options. Resveratrol alters the expression of genes related to self-renewal, modulating important signaling pathways involved in cancer initiation and CSC control. Additionally, resveratrol affects non-coding RNAs (ncRNAs), including Micro-RNAs (miRNAs) and long non-coding RNAs (lncRNAs which are essential for stemness, drug resistance, and other cancer-related activities. Numerous studies have shown that resveratrol has the potential to be an effective anticancer drug when used in combination therapy, but issues with absorption and pharmacokinetics still need to be resolved before it can be used in clinical applications. Reducing chemotherapy resistance by better understanding the intricate mechanisms by which resveratrol affects cancer cells and CSCs, as well as its impact on ncRNA expression, could eventually contribute to more effective cancer treatments. To completely understand these pathways and optimize the utilization of resveratrol in combination treatments, additional study is necessary.