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Malignant glioma (MG) is a poor prognostic brain tumor with inevitable recurrence after multimodality treatment. Searching for more effective treatment is urgently needed. Differentiation induction via epigenetic modification has been proposed as a potential anticancer strategy. Natural products are known as fruitful sources of epigenetic modifiers with wide safety margins. We thus explored the effects of oligo-fucoidan (OF) from brown seaweed on this notion in MG cells including Grade III U87MG cells and Grade IV glioblastoma multiforme (GBM)8401 cells and compared to the immortalized astrocyte SVGp12 cells. The results showed that OF markedly suppress the proliferation of MG cells and only slightly affected that of SVGp12 cells. OF inhibited the protein expressions of DNA methyltransferases 1, 3A and 3B (DNMT1, 3A and 3B) accompanied with obvious mRNA induction of differentiation markers (MBP, OLIG2, S100β, GFAP, NeuN and MAP2) both in U87MG and GBM8401 cells. Accordingly, the methylation of p21, a DNMT3B target gene, was decreased by OF. In combination with the clinical DNMT inhibitor decitabine, OF could synergize the growth inhibition and MBP induction in U87MG cells. Appropriated clinical trials are warranted to evaluate this potential complementary approach for MG therapy after confirmation of the effects in vivo.

Non-small cell lung cancer (NSCLC)-carrying specific epidermal growth factor receptor (EGFR) mutations can be effectively treated by a tyrosine kinase inhibitor such as gefitinib. However, the inevitable development of acquired resistance leads to the eventual failure of therapy. In this study, we show the combination effect of omega-3 fatty acid-enriched fish oil (FO) and selenium (Se) on reversing the acquired gefitinib-resistance of HCC827 NSCLC cells. The gefitinib-resistant subline HCC827GR possesses lowered proapoptotic CHOP (CCAAT/enhancer-binding protein homologous protein) and elevated cytoprotective GRP78 (glucose regulated protein of a 78 kDa molecular weight) endoplasmic reticulum (ER) stress response elements, and it has elevated β-catenin and cyclooxygenase-2 (COX-2) levels. Combining FO and Se counteracts the above features of HCC827GR cells, accompanied by the suppression of their raised epithelial-to-mesenchymal transition (EMT) and cancer stem markers, such as vimentin, AXL, N-cadherin, CD133, CD44, and ABCG2. Accordingly, an FO and Se combination augments the gefitinib-mediated growth inhibition and apoptosis of HCC827GR cells, along with the enhanced activation of caspase -3, -9, and ER stress-related caspase-4. Intriguingly, gefitinib further increases the elevated ABCG2 and cancer stem-like side population in HCC827GR cells, which can also be diminished by the FO and Se combination. The results suggest the potential of combining FO and Se in relieving the acquired resistance of NSCLC patients to targeted therapy.

Glioblastoma multiforme (GBM) is the most common adult malignant glioma with poor prognosis due to the resistance to radiotherapy and chemotherapy, which might be critically involved in the repopulation of cancer stem cells (CSCs) after treatment. We had investigated the characteristics of cancer stem-like side population (SP) cells sorted from GBM cells, and studied the effect of Honokiol targeting on CSCs. GBM8401 SP cells possessed the stem cell markers, such as nestin, CD133 and Oct4, and the expressions of self-renewal related stemness genes, such as SMO, Notch3 and IHH (Indian Hedgehog). Honokiol inhibited the proliferation of both GBM8401 parental cells and SP cells in a dose-dependent manner, the IC50 were 5.3±0.72 and 11±1.1 μM, respectively. The proportions of SP in GBM8401 cells were diminished by Honokiol from 1.5±0.22% down to 0.3±0.02% and 0.2±0.01% at doses of 2.5 μM and 5 μM, respectively. The SP cells appeared to have higher expression of O6-methylguanine-DNA methyltransferase (MGMT) and be more resistant to Temozolomide (TMZ). The resistance to TMZ could be only slightly reversed by MGMT inhibitor O6-benzylguanine (O6-BG), but markedly further enhanced by Honokiol addition. Such significant enhancement was accompanied with the higher induction of apoptosis, greater down-regulation of Notch3 as well as its downstream Hes1 expressions in SP cells. Our data indicate that Honokiol might have clinical benefits for the GBM patients who are refractory to TMZ treatment.

Integrin αvβ3, a key member of the integrin family, plays a crucial role in cell localization, mobilization, and signal transduction through collaborating with extracellular proteins. Its unique expression and activation in tumor cells and rapidly dividing endothelial cells suggest its potential role in cancer cell growth and metastasis, making it a promising therapeutic target. In genomic pathways, estrogen binds to its receptors to form transcription complexes that bind to the promoters of steroid hormone-receptive genes. Conversely, G protein-coupled estrogen receptor 1 (GPER) and integrin αvβ3 have been shown to play oles in non-genomic actions that contribute to estrogen-induced cancer growth. The molecular mechanisms of these non-genomic functions involve signal transduction via focal activated kinase (FAK), mitogen-activated protein kinase (ERK1/2), and phosphatidylinositol 3-kinase (PI3K), as well as the differential expression of multiple genes associated with various cellular processes. As a hormone receptor, integrin αvβ3, collaborating with ER-α and GPER, exhibits a wide range of cellular effects relevant to cancer biology.

Accumulating evidence has revealed that fucoidan exhibits anti-tumor activities by arresting cell cycle and inducing apoptosis in many types of cancer cells including hepatocellular carcinoma (HCC). Exploring its effect on microRNA expression, we found that fucoidan markedly upregulated miR-29b of human HCC cells. The induction of miR-29b was accompanied with suppression of its downstream target DNMT3B in a dose-dependent manner. The reduction of luciferase activity of DNMT3B 3′-UTR reporter by fucoidan was as markedly as that by miR-29b mimic, indicating that fucoidan induced miR-29b to suppress DNMT3B. Accordingly, the mRNA and protein levels of MTSS1 (metastasis suppressor 1), a target silenced by DNMT3B, were increased after fucoidan treatment. Furthermore, fucoidan also down-regulated TGF-β receptor and Smad signaling of HCC cells. All these effects leaded to the inhibition of EMT (increased E-cadherin and decreased N-cadherin) and prevention of extracellular matrix degradation (increased TIMP-1 and decreased MMP2, 9), by which the invasion activity of HCC cells was diminished. Our results demonstrate the profound effect of fucoidan not only on the regulation of miR-29b-DNMT3B-MTSS1 axis but also on the inhibition of TGF-β signaling in HCC cells, suggesting the potential of using fucoidan as integrative therapeutics against invasion and metastasis of HCC.

Background Eliminating cancer stem cells (CSCs) has been suggested for prevention of tumor recurrence and metastasis. Honokiol, an active compound of Magnolia officinalis , had been proposed to be a potential candidate drug for cancer treatment. We explored its effects on the elimination of oral CSCs both in vitro and in vivo. Methods By using the Hoechst side population (SP) technique, CSCs-like SP cells were isolated from human oral squamous cell carcinoma (OSCC) cell lines, SAS and OECM-1. Effects of honokiol on the apoptosis and signaling pathways of SP-derived spheres were examined by Annexin V/Propidium iodide staining and Western blotting, respectively. The in vivo effectiveness was examined by xenograft mouse model and immunohistochemical tissue staining. Results The SP cells possessed higher stemness marker expression ( ABCG2 , Ep-CAM , Oct-4 and Nestin ), clonogenicity, sphere formation capacity as well as tumorigenicity when compared to the parental cells. Treatment of these SP-derived spheres with honokiol resulted in apoptosis induction via Bax/Bcl-2 and caspase-3-dependent pathway. This apoptosis induction was associated with marked suppression of JAK2/STAT3, Akt and Erk signaling pathways in honokiol-treated SAS spheres. Consistent with its effect on JAK2/STAT3 suppression, honokiol also markedly inhibited IL-6-mediated migration of SAS cells. Accordingly, honokiol dose-dependently inhibited the growth of SAS SP xenograft and markedly reduced the immunohistochemical staining of PCNA and endothelial marker CD31 in the xenograft tumor. Conclusions Honokiol suppressed the sphere formation and xenograft growth of oral CSC-like cells in association with apoptosis induction and inhibition of survival/proliferation signaling pathways as well as angiogenesis. These results suggest its potential as an integrative medicine for combating oral cancer through targeting on CSCs.

About 80% of lung cancer patients are diagnosed with non–small cell lung cancer (NSCLC). EGFR mutation and overexpression are common in NSCLC, thus making EGFR signaling a key target for therapy. While EGFR kinase inhibitors (EGFR–TKIs) are widely used and efficacious in treatment, increases in resistance and tumor recurrence with alternative survival pathway activation, such as that of AXL and MET, occur frequently. AXL is one of the EMT (epithelial–mesenchymal transition) signature genes, and EMT morphological changes are also responsible for EGFR–TKI resistance. MIG6 is a negative regulator of ERBB signaling and has been reported to be positively correlated with EGFR–TKI resistance, and downregulation of MIG6 by miR–200 enhances EMT transition. While MIG6 and AXL are both correlated with EMT and EGFR signaling pathways, how AXL, MIG6 and EGFR interplay in lung cancer remains elusive. Correlations between AXL and MIG6 expression were analyzed using Oncomine or the CCLE. A luciferase reporter assay was used for determining MIG6 promoter activity. Ectopic overexpression, RNA interference, Western blot analysis, qRT–PCR, a proximity ligation assay and a coimmunoprecipitation assay were performed to analyze the effects of certain gene expressions on protein–protein interaction and to explore the underlying mechanisms. An in vitro kinase assay and LC–MS/MS were utilized to determine the phosphorylation sites of AXL. In this study, we demonstrate that MIG6 is a novel substrate of AXL and is stabilized upon phosphorylation at Y310 and Y394/395 by AXL. This study reveals a connection between MIG6 and AXL in lung cancer. AXL phosphorylates and stabilizes MIG6 protein, and in this way EGFR signaling may be modulated. This study may provide new insights into the EGFR regulatory network and may help to advance cancer treatment.

Chemotherapy remains a cornerstone in lung cancer treatment, yet emerging evidence suggests that sublethal low doses may inadvertently enhance the malignancy. This study investigates the paradoxical effects of sublethal low-dose chemotherapy on non-small-cell lung cancer (NSCLC) cells, emphasizing the role of Aldo-keto reductase family 1 member B10 (AKR1B10). We found that sublethal doses of chemotherapy unexpectedly increased cancer cell migration approximately 2-fold and invasion approximately threefold, potentially promoting metastasis. Our analysis revealed a significant upregulation of AKR1B10 in response to taxol and doxorubicin treatment, correlating with poor survival rates in lung cancer patients. Furthermore, silencing AKR1B10 resulted in a 1–2-fold reduction in cell proliferation and a 2–3-fold reduction in colony formation and migration while increasing chemotherapy sensitivity. In contrast, the overexpression of AKR1B10 stimulated growth rate by approximately 2-fold via ERK pathway activation, underscoring its potential as a target for therapeutic intervention. The reversal of these effects upon the application of an ERK-specific inhibitor further validates the significance of the ERK pathway in AKR1B10-mediated chemoresistance. In conclusion, our findings significantly contribute to the understanding of chemotherapy-induced adaptations in lung cancer cells. The elevated AKR1B10 expression following sublethal chemotherapy presents a novel molecular mechanism contributing to the development of chemoresistance. It highlights the need for strategic approaches in chemotherapy administration to circumvent the inadvertent enhancement of cancer aggressiveness. This study positions AKR1B10 as a potential therapeutic target, offering a new avenue to improve lung cancer treatment outcomes by mitigating the adverse effects of sublethal chemotherapy.

This paper introduces a fully differential asynchronous successive approximation register analog-to-digital converter (SAR ADC) designed for biomedical signal processing. By extending the tracking time and utilizing fully differential inputs in the analog front-end circuit, the signal-to-noise ratio is enhanced in the system. Using an asynchronous clock can reduce power consumption across a wider range of sampling frequencies. In comparison to conventional architecture in high-speed SAR ADC, using an internal clock generator can operate at lower frequencies. A fully differential input can eliminate the DC offset of the analog front-end circuit and reduce the adverse effects of process variation, voltage variation, and temperature variation. The chip is implemented by TSMC 0.18 μm complementary metal-oxide-semiconductor (CMOS) technology, and the chip area is 0.680 mm2 (including ESD I/O PAD). At a 1.2 V supply, the maximum sampling rate is 10 Kilo Samples per second (KSps). The implemented ADC has an 11-bit resolution, while the input voltage range is 300∼900 mV. The total power consumption is 1.7 μW, with the core power consumption at 932 nW.

Background The non-small cell lung cancer (NSCLC) is the leading cause of cancer death worldwide. In NSCLC, the oncogenic AKT-mTOR, ERK and STAT3 pathways are commonly dysregulated and have emerged as attractive targets for therapeutic developments. In a relatively limited subset of NSCLC, these pathways driven by mutant EGFR can be treated by the tyrosine kinase inhibitors (TKIs)-mediated targeted therapy. However, for the most NSCLC, more novel targeted agents are imperatively needed. Therefore, we investigated the inhibitory effects of the active fraction HS7 from Taiwanofungus camphoratus , a unique medicinal fungus in Taiwan, on these pathways in CL1-0 EGFR wild-type human NSCLC cells. Methods The active fraction HS7 was prepared by n -hexane extraction of T. camphoratus followed by silica gel chromatography. Its effects on the cell viabilities were determined by sulforhodamine B colorimetric assay. Flow cytometry was used to analyze cell-cycle regulation and apoptosis induction. The changes in cellular protein levels were examined by Western blot. Results The active fraction HS7 vigorously inhibits AKT-mTOR, ERK and STAT3 signaling pathways in CL1-0 cells. At dose of 25 μg/mL, these signaling pathways were almost completely inhibited by HS7, accompanied with induction of cyclin-dependent kinase inhibitors such as p15, p21 and p27. Accordingly, the AKT-mTOR downstream targets p-p70S6K and HIF-1α were also suppressed as well. At this dose, the cell proliferation was profoundly suppressed to 23.4% of control and apoptosis induction was observed. Conclusions The active fraction HS7 from n -hexane extract of T. camphoratus exerts multi-targeting activity on the suppression of AKT-mTOR, ERK and STAT3 pathways and induction of p15, p21 and p27 in EGFR wild-type NSCLC cells. This multi-targeting activity of HS7 suggests its potential as an alternative medicine for the treatment of EGFR TKIs resistant NSCLC.