Search

Ciclesonide is an FDA-approved glucocorticoid used to treat asthma and allergic rhinitis. However, whether it has anticancer and anti-cancer stem cell (CSC) effects is unknown. This study focused on investigating the effect of ciclesonide on breast cancer and CSCs and determining its underlying mechanism. Here, we showed that ciclesonide inhibits breast cancer and CSC formation. Similar glucocorticoids&mdash, dexamethasone and prednisone&mdash, did not inhibit CSC formation. Ciclesonide-induced glucocorticoid receptor (GR) degradation was dependent on ubiquitination. We showed via GR small interfering RNA (siRNA) that GR plays an important role in CSC formation. We showed via western blot and immunofluorescence assays that ciclesonide reduces the nuclear level of GR. The GR antagonist RU-486 also inhibited CSC formation. Ciclesonide reduced the protein level of the Hippo transducer Yes-associated protein (YAP). GR siRNA induced a decrease in YAP protein expression and inhibited mammosphere formation. The YAP inhibitor verteporfin inhibited CSC formation and transcription of the connective tissue growth factor and cysteine-rich protein 61 genes. The GR/YAP1 pathway regulated breast CSC formation. We showed that the GR/YAP signaling pathway regulates breast CSC formation and revealed a new approach for targeting GR and YAP to inhibit CSC formation.

Cancer stem cells have certain characteristics, such as self-renewal, differentiation, and drug resistance, which are related to tumor progression, maintenance, recurrence, and metastasis. In our study, we targeted breast cancer stem cells (BCSCs) using a natural compound, coriolic acid, from Salicornia herbacea L. This compound was isolated by mammosphere formation inhibition bioassay-guided fractionation and identified by using NMR spectroscopy and electrospray ionization mass spectrometry. Coriolic acid inhibited the formation of mammospheres and induced BCSC apoptosis. It also decreased the subpopulation of CD44high/CD24low cells, a cancer stem cell (CSC) phenotype, and specific genes related to CSCs, such as Nanog, Oct4, and CD44. Coriolic acid decreased the transcriptional and translational levels of the c-Myc gene, which is a CSC survival factor. These results indicated that coriolic acid could be a novel compound to target BCSCs via regulation of c-Myc.

The presence of breast cancer stem cells (BCSCs) induces the aggressive progression and recurrence of breast cancer. These cells are drug resistant, have the capacity to self-renew and differentiate and are involved in recurrence and metastasis, suggesting that targeting BCSCs may improve treatment efficacy. In this report, methanol extracts of carrot root were purified by means of silica gel, Sephadex LH-20, and preparative high-performance liquid chromatography to isolate a compound targeting mammosphere formation. We isolated the compound 6-methoxymellein, which inhibits the proliferation and migration of breast cancer cells, reduces mammosphere growth, decreases the proportion of CD44+/CD24&minus, cells in breast cancer cells and decreases the expression of stemness-associated proteins c-Myc, Sox-2 and Oct4. 6-Methoxymellein reduces the nuclear localization of nuclear factor-&kappa, B (NF-&kappa, B) subunit p65 and p50. Subsequently, 6-methoxymellein decreases the mRNA transcription and secretion of IL-6 and IL-8. Our data suggest that 6-methoxymellein may be an anticancer agent that inhibits BCSCs via NF-&kappa, B/IL-6 and IL-8 regulation.

Breast cancer is a major health problem that affects lives worldwide. Breast cancer stem cells (BCSCs) are small subpopulations of cells with capacities for drug resistance, self-renewal, recurrence, metastasis, and differentiation. Herein, powder extracts of beetroot were subjected to silica gel, gel filtration, thin layer chromatography (TLC), and preparatory high-pressure liquid chromatography (HPLC) for isolation of one compound, based on activity-guided purification using tumorsphere formation assays. The purified compound was identified as betavulgarin, using nuclear magnetic resonance spectroscopy and electrospray ionization (ESI) mass spectrometry. Betavulgarin suppressed the proliferation, migration, colony formation, and mammosphere formation of breast cancer cells and reduced the size of the CD44+/CD24&minus, subpopulation and the expression of the self-renewal-related genes, C-Myc, Nanog, and Oct4. This compound decreased the total level and phosphorylated nuclear level of signal transducer and activator of transcription 3 (Stat3) and reduced the mRNA and protein levels of sex determining region Y (SRY)-box 2 (SOX2), in mammospheres. These data suggest that betavulgarin inhibit the Stat3/Sox2 signaling pathway and induces BCSC death, indicating betavulgarin might be an anticancer agent against breast cancer cells and BCSCs.

Breast cancer stem cells (BCSCs) are responsible for tumor chemoresistance and recurrence. Targeting CSCs using natural compounds is a novel approach for cancer therapy. A CSC-inhibiting compound was purified from citrus extracts using silica gel, gel filtration and high-pressure liquid chromatography. The purified compound was identified as tangeretin by using nuclear magnetic resonance (NMR). Tangeretin inhibited cell proliferation, CSC formation and tumor growth, and modestly induced apoptosis in CSCs. The frequency of a subpopulation with a CSC phenotype (CD44+/CD24&minus, ) was reduced by tangeretin. Tangeretin reduced the total level and phosphorylated nuclear level of signal transducer and activator of transcription 3 (Stat3). Our results in this study show that tangeretin inhibits the Stat3 signaling pathway and induces CSC death, indicating that tangeretin may be a potential natural compound that targets breast cancer cells and CSCs.

In the complex tumor microenvironment, cancer stem cells (CSCs), a rare population of cells, are responsible for malignant tumor initiation, metastasis, drug resistance and recurrence. Controlling breast CSCs (BCSCs) using natural compounds is a novel potential therapeutic strategy for clinical cancer treatment. In this study, a mammosphere assay-guided isolation protocol including silica gel, a C18 column, gel filtration, and high-pressure liquid chromatography was used to isolate an inhibitory compound from Cynanchum auriculatum extracts. The isolated inhibitory compound was identified as caudatin. Caudatin inhibited breast cancer cell proliferation, mammosphere formation and tumor growth. Caudatin decreased the CD44+/CD24− and aldehyde dehydrogenase+ cell proportions and the levels of c-Myc, Oct4, Sox2, and CD44. Caudatin induced ubiquitin (Ub)-dependent glucocorticoid receptor (GR) degradation and blocked subsequent Yes-associated protein (YAP) nuclear accumulation and target gene transcription signals in BCSCs. These results show that the GR/YAP signaling pathway regulates BCSC formation and that caudatin may be a potential chemopreventive agent that targets breast cancer cells and CSCs.

Ciclesonide is an FDA-approved glucocorticoid (GC) used to treat asthma and allergic rhinitis. However, its effects on cancer and cancer stem cells (CSCs) are unknown. Our study focuses on investigating the inhibitory effect of ciclesonide on lung cancer and CSCs and its underlying mechanism. In this study, we showed that ciclesonide inhibits the proliferation of lung cancer cells and the growth of CSCs. Similar glucocorticoids, such as dexamethasone and prednisone, do not inhibit CSC formation. We show that ciclesonide is important for CSC formation through the Hedgehog signaling pathway. Ciclesonide reduces the protein levels of GL1, GL2, and Smoothened (SMO), and a small interfering RNA (siRNA) targeting SMO inhibits tumorsphere formation. Additionally, ciclesonide reduces the transcript and protein levels of SOX2, and an siRNA targeting SOX2 inhibits tumorsphere formation. To regulate breast CSC formation, ciclesonide regulates GL1, GL2, SMO, and SOX2. Our results unveil a novel mechanism involving Hedgehog signaling and SOX2 regulated by ciclesonide in lung CSCs, and also open up the possibility of targeting Hedgehog signaling and SOX2 to prevent lung CSC formation.

Cancer stem cells are responsible for breast cancer initiation, metastasis, and relapse. Targeting breast cancer stem cells (BCSCs) using phytochemicals is a good strategy for the treatment of cancer. A silica gel, a reversed-phase C18 column (ODS), a Sephadex LH-20 gel, thin layer chromatography, and high-performance liquid chromatography (HPLC) were used for compound isolation from Saururus chinensis extracts. The isolated compound was identified as machilin D by mass spectrometry and nuclear magnetic resonance (NMR). Machilin D inhibited the growth and mammosphere formation of breast cancer cells and inhibited tumor growth in a xenograft mouse model. Machilin D reduced the proportions of CD44+/CD24- and aldehyde dehydrogenase 1 (ALDH1)-positive cells. Furthermore, this compound reduced the nuclear localization of the NF-&kappa, B protein and decreased the IL-6 and IL-8 secretion in mammospheres. These results suggest that machilin D blocks IL-6 and IL-8 signaling and induces CSC death and thus may be a potential agent targeting BCSCs.

Breast cancer stem cells (BCSCs) are tumor-initiating cells that possess the capacity for self-renewal. Cancer stem cells (CSCs) are responsible for poor outcomes caused by therapeutic resistance. In our study, we found that sulconazole&mdash, an antifungal medicine in the imidazole class&mdash, inhibited cell proliferation, tumor growth, and CSC formation. This compound also reduced the frequency of cells expressing CSC markers (CD44high/CD24low) as well as the expression of another CSC marker, aldehyde dehydrogenase (ALDH), and other self-renewal-related genes. Sulconazole inhibited mammosphere formation, reduced the protein level of nuclear NF-&kappa, B, and reduced extracellular IL-8 levels in mammospheres. Knocking down NF-&kappa, B expression using a p65-specific siRNA reduced CSC formation and secreted IL-8 levels in mammospheres. Sulconazole reduced nuclear NF-&kappa, B protein levels and secreted IL-8 levels in mammospheres. These new findings show that sulconazole blocks the NF-&kappa, B/IL-8 signaling pathway and CSC formation. NF-&kappa, B/IL-8 signaling is important for CSC formation and may be an important therapeutic target for BCSC treatment.

Cancer stem cells (CSCs) are known to mediate metastasis and recurrence and are therefore a promising therapeutic target. In this study, we found that dihydrotanshinone (DHTS) inhibits CSC formation. DHTS inhibited mammosphere formation in a dose-dependent manner and showed significant tumor growth inhibition in a xenograft model. This compound reduced the CD44high/CD24low- and aldehyde dehydrogenase- (ALDH-) expressing cell population and the self-renewal-related genes Nanog, SOX2, OCT4, C-Myc, and CD44. DHTS induced NOX5 activation by increasing calcium, and NOX5 activation induced reactive oxygen species (ROS) production. ROS production reduced the nuclear phosphorylation levels of Stat3 and secreted IL-6 levels in the mammospheres. DHTS deregulated the dynamic equilibrium from non-stem cancer cells to CSCs by dephosphorylating Stat3 and decreasing IL-6 secretion and inhibiting CSC formation. These novel findings showed that DHTS-induced ROS deregulated the Stat3/IL-6 pathway and induced CSC death. NOX5 activation by DHTS inhibits CSC formation through ROS/Stat3/IL-6 signaling, and DHTS may be a promising potential therapeutic agent against breast CSCs.

Cancer stem cells (CSCs) as a subpopulation of cancer cells are drug-resistant and radiation-resistant cancer cells to be responsible for tumor progress, maintenance and recurrence of cancer, and metastasis. This study isolated and investigated a new cancer stem cell (CSC) inhibitor derived from lactic acid fermentation products using culture broth with 2% aronia juice. The anti-CSC activity of aronia-cultured broth was significantly higher than that of the control. Activity-guided fractionation and repeated chromatographic preparation led to the isolation of one compound. Using nuclear magnetic resonance and ESI mass spectrometry, we identified the isolated compound as catechol. In this study, we report that aronia-fermented catechol has a novel inhibitory effect on human breast CSCs. Catechol inhibited breast cancer cell proliferation and mammosphere formation in a dose-dependent manner. This compound reduced the CD44high /CD24low subpopulation, ALDH-expressing cell population and the self-renewal-related genes nanog, sox2, and oct4. Catechol preferentially reduced mRNA transcripts and protein levels of Stat3 and did not induce c-Myc degradation. These findings support the novel utilization of catechol for breast cancer therapy via the Stat3/IL-6 signaling pathway. Our results suggest that catechol can be used for breast cancer therapy and that Stat3 expression is a marker of CSCs. Catechol inhibited Stat3 signaling by reducing Stat3 expression and secreted IL-6, a CSC survival factor. These findings support the novel utilization of catechol for breast cancer therapy via Stat3/IL-6 signaling.

Cancer stem cells (CSCs) are drug-resistant and radiation-resistant cancer cells that are responsible for tumor progression and maintenance, cancer recurrence, and metastasis. Targeting breast CSCs with phytochemicals is a new paradigm for cancer prevention and treatment. In this study, activity-guided fractionation from mammosphere formation inhibition assays, repeated chromatographic preparations over silica gel, preparatory thin layer chromatography, and HPLC using aronia extracts led to the isolation of one compound. Using 1H and 13C 2-dimensional nuclear magnetic resonance (NMR) as well as electrospray ionization (ESI) mass spectrometry, the isolated compound was identified as 3-O-p-coumaroyltormentic acid. This compound inhibits breast cancer cell proliferation and mammosphere formation in a dose-dependent manner and reduces the CD44high/CD24low subpopulation and aldehyde dehydrogenase (ALDH)-expressing cell population as well as the expression of the self-renewal-related genes CD44, SOX2, and OCT4. 3-O-p-Coumaroyltormentic acid preferentially reduced the protein levels of c-Myc, which is a CSC survival factor, by inducing c-Myc degradation. These findings indicate the novel utilization of 3-O-p-coumaroyltormentic acid for breast cancer therapy via disruption of c-Myc protein, which is a CSC survival factor.