Targeting PI3K/AKT/mTOR Signaling Pathway as a Radiosensitization in Head and Neck Squamous Cell Carcinomas.

Globally, there are over half a million new patients with head and neck squamous cell carcinomas (HNSCC) every year. The current therapeutic approaches to HNSCC are surgery and adjuvant radiotherapy. These approaches carry a high incidence of metastasis or recurrence from HNSCC cells' radioresistance. Recent studies have revealed that a combination with radiosensitizers can be used to improve the radioresistance in HNSCC; however, few agents are approved as radiosensitizers. The constitutive activation of phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is a vitally oncogenic type of signaling that promotes tumorigenesis, metastasis, and radiotherapy resistance in HNSCC. Pharmacological targeting of PI3K/AKT/mTOR signaling pathway is considered a promising strategy of radiosensitization in HNSCC. In this review, we summarize the oncogenic significance of PI3K/AKT/mTOR signaling in HNSCC with radiotherapy resistance and highlight the therapeutic potential of small molecule inhibitors against PI3K/AKT/mTOR signaling for the radiosensitization in HNSCC treatment. It provides a mechanistic framework for the development of new drugs for radiosensitization in HNSCC radiotherapy via targeting PI3K/AKT/mTOR signaling pathway.

16-Hydroxycleroda-3,13-dien-15,16-olide Induces Apoptosis in Human Bladder Cancer Cells through Cell Cycle Arrest, Mitochondria ROS Overproduction, and Inactivation of EGFR-Related Signalling Pathways.

A clerodane diterpene compound 16-hydroxycleroda-3,13-dien-15,16-olide (CD) is considered a therapeutic agent with pharmacological activities. The present study investigated the mechanisms of CD-induced apoptosis in T24 human bladder cancer cells. CD inhibited cell proliferation in a concentration and time-dependent manner. CD-induced overproduction of reactive oxygen species and reduced mitochondrial membrane potential, associated with reduced expression of Bcl-2 and increased levels of cytosolic cytochrome c, cleaved PARP-1 and caspase-3. In addition, CD treatment led to cell cycle arrest at the G0/G1 phase and inhibited expression of cyclin D1 and cyclin-dependent kinases 2 and 4 and led to increased levels of p21, p27Kip1 and p53. All of these events were accompanied with a reduction of pEGFR, pMEK1/2, pERK1/2, pAkt, pmTOR, pP70S6K1, HIF-1α, c-Myc and VEGF. RNAseq-based analysis revealed that CD-induced cell death was characterised by an increased expression of stress and apoptotic-related genes as well as inhibition of the cell cycle-related genes. In summary, CD induces apoptosis in T24 bladder cancer cells through targeting multiple intracellular signaling pathways as a result of oxidative stress and cell cycle arrest.

Unraveling the Molecular Mechanism of Traditional Chinese Medicine: Formulas Against Acute Airway Viral Infections as Examples.

Herbal medicine, including traditional Chinese medicine (TCM), is widely used worldwide. Herbs and TCM formulas contain numerous active molecules. Basically, they are a kind of cocktail therapy. Herb-drug, herb-food, herb-herb, herb-microbiome, and herb-disease interactions are complex. There is potential for both benefit and harm, so only after understanding more of their mechanisms and clinical effects can herbal medicine and TCM be helpful to users. Many pharmacologic studies have been performed to unravel the molecular mechanisms; however, basic and clinical studies of good validity are still not enough to translate experimental results into clinical understanding and to provide tough evidence for better use of herbal medicines. There are still issues regarding the conflicting pharmacologic effects, pharmacokinetics, drug interactions, adverse and clinical effects of herbal medicine and TCM. Understanding study validation, pharmacologic effects, drug interactions, indications and clinical effects, adverse effects and limitations, can all help clinicians in providing adequate suggestions to patients. At present, it would be better to use herbs and TCM formulas according to their traditional indications matching the disease pathophysiology and their molecular mechanisms. To unravel the molecular mechanisms and understand the benefits and harms of herbal medicine and TCM, there is still much work to be done.

Study of chondrogenesis of umbilical cord mesenchymal stem cells in curdlan- poly(vinyl alcohol) composite hydrogels and its mechanical properties of freezing-thawing treatments.

The curdlan gel is a natural material produced by bacteria. It utilizes chemical cross-linking reactions to form a 3D porous composite hydrogel, increasing its porosity and water content, and improving its mechanical properties. It can be used in tissue repair and regenerative medicine. Curdlan-Poly(vinyl alcohol) (PVA) composite hydrogel can rapidly swell within 1 min due to its porous structure. Compression tests confirmed that it still maintains its original mechanical strength, even after five repeated freeze-thaw (FT) processes, making it suitable for long-term cryopreservation. The purpose of this study is to transplant umbilical cord mesenchymal stem cells (UC-MSCs) on Curdlan-PVA composite hydrogel and observe the chondrocytes on the material. The results of using 4',6-diamidino-2-phenylindole (DAPI), hematoxylin and eosin (H&E), calcein-acetoxymethyl ester (calcein AM), and Collagen type II-Fluorescein isothiocyanate (FITC) staining, confirmed that UC-MSCs can attach and differentiate into chondrocytes on 3D Curdlan-PVA composite hydrogel.

Hinokitiol Inhibits the Viability of Oral Squamous Carcinoma Cells by Inducing Apoptosis and Autophagy.

BACKGROUND/AIM: Oral squamous cell carcinoma (OSCC) is one of the deadliest cancers, with approximately ~500,000 new diagnosed cases and 145,000 deaths worldwide, per year. The incidence of new cases continues to increase in developing countries. This study aimed to investigate the effect of hinokitiol on cell viability in OSCC cells. MATERIALS AND METHODS: The anticancer effect and mechanism of action of hinokitiol in OSCC cells were analyzed by cell viability assays and cell cycle analysis using flow cytometry, while apoptosis and autophagy-related protein expression was measured using western blot. RESULTS: The results showed that hinokitiol concentration-dependently reduced the viability of SCC4 and SCC25 cells by downregulating the levels of cell-cycle mediators, such as cyclin B1, cyclin D1 and cyclin-dependent kinase-1 (CDK1). Furthermore, hinokitiol promoted apoptosis in SCC25 cells based on the presence of active cleaved caspase-3. Hinokitiol also induced autophagy by promoting the accumulation of the microtubule-associated protein light chain 3B (LC3B) and the expression of the sequestosome-1 (p62/SQSTM). CONCLUSION: Hinokitiol exhibits anti-proliferation activity and has pro-apoptotic effects on OSCC cell lines.

16-Hydroxycleroda-3,13-dien-15,16-olide induces anoikis in human renal cell carcinoma cells: involvement of focal adhesion disassembly and signaling.

BACKGROUND: Clerodane diterpene, 16-hydroxycleroda-3,13-dien-15,16-olide (CD) isolated from Polyalthia longifolia Benth. & Hook. f. var. pendula was found to be a potential apoptotic inducer in human leukemia, lung cancer, and colon cancer cells. However, the molecular mechanism remains elusive in renal system. Thus, in the present study, the regulatory mechanisms of CD-induced apoptosis in clear cell renal cell carcinoma (ccRCC) cells were investigated. MATERIALS AND METHODS: Cell proliferation was evaluated by colony formation assay and cell cycle analyses. Protein expressions of focal adhesion (FA) related complexes were examined by immunofluorescence staining and Western blot analyses. Cell migration and invasion capabilities of renal cell carcinoma (RCC) cells were determined by wound healing and Transwell assays. RESULTS: CD inhibited cell colony formations, induced cell arrest at G2/M phase, and increased subG1 cell population both in 786-O and A-498. During CD treatment, the "rounded-up" cells were observed. The immune-staining of phosphorylated focal adhesion kinase (pFAK), vinculin, and paxillin displayed disassembly of the FA. Moreover, disruption of actin stress fibers was noted after CD treatment. Consistent with the findings, the expressions of pSrc, pFAK, FAK, vinculin, vimentin, and paxillin were all downregulated by CD. In addition, CD attenuated cell migration and invasion activities accompanied by the reductions of pNF-κB, matrix metallo-proteinase (MMP)-2, MMP-9 as well as vascular endothelial growth factor expressions. CONCLUSION: CD induced cell cycle arrest, FA complex disassembly, and the inactivation of migratory-related signaling pathways to induce apoptosis in ccRCC cells.

16-Hydroxycleroda-3, 13-dien-15, 16-olide inhibits the proliferation and induces mitochondrial-dependent apoptosis through Akt, mTOR, and MEK-ERK pathways in human renal carcinoma cells.

BACKGROUND: Renal cell carcinoma (RCC) is well known that it cannot be treated with traditional chemotherapy or radiotherapy. 16-Hydroxycleroda-3,13-dien-15,16-olide (CD), isolated from Polyalthia longifolia Benth. & Hook. f. var. pendula had been reported to display significant efficacy against cancer cell lines. PURPOSE: To determine the anti-tumour activities of CD in two clear cell type RCC (ccRCC) cell lines (A-498 and 786-O). In addition, the underlying mechanisms were also examined. METHODS: The cell viabilities of CD-treated ccRCC cells were examined by MTT assay. The apoptotic features were confirmed by acridine orange and ethidium bromide staining. 2',7'-dichlorofluorescin diacetate was used to check reactive oxygen species (ROS) involvement. Mitochondria membrane potential (MMP) were determined by using fluorescent dyes, rhodamine 123 and 5',6,6'-tetrachloro-1,1',3,3'-tetraethyl benzimidazolylcarbocyanine iodide (JC-1). Proapoptotic, anti-apoptotic proteins and intracellular signaling molecules involved in CD-induced apoptosis were examined by Western blot analysis. RESULTS: CD inhibited both 786-O and A-498 cell proliferation and induced a series apoptotic characteristics expressions, ROS accumulation, caspase-3 activation as well as poly-(ADP-ribose) polymerase cleavage in both ccRCC cells. Additionally, CD caused MMP reduction and cytochrome c release from mitochondria as well as inhibition of anti-apoptotic proteins, including B cell lymphoma 2 and heat shock protein 70. Mechanically, we address that CD suppressed cell proliferation and induced apoptosis via induction of FOXO3a as well as decreased phosphorylation of Akt, mTOR, MEK/ERK and their downstream molecules, cMyc and hypoxia inducible factor 2α expression in a concentration- and time-dependent trend. CONCLUSION: CD caused cell death through ROS overproduction and induction of mitochondria-dependent apoptotic pathway in ccRCC cells that accompanied with multiple oncogenic signals inactivation.

Neoadjuvant hormone therapy following treatment with robotic-assisted radical prostatectomy achieved favorable in high-risk prostate cancer.

PURPOSE: Patients with a high risk of prostate carcinoma typically have higher rates of positive surgical margins and biochemical failure following radical prostatectomy and adjuvant hormone therapy. In this study, we assessed the effects of neoadjuvant hormone therapy (NHT) on prostate carcinoma in high-risk patients following robotic-assisted radical prostatectomy (RARP). METHODS: This retrospective study investigated the medical records of 28 patients who underwent RARP between January 2009 and October 2013. Twenty-two patients underwent NHT prior to RARP. Furthermore, six patients did not undergo NHT prior to RARP. Parameters including age, operating time, blood loss, blood transfusion status, and cancer stage were checked against anatomical correlations. Potential predictors of prolonged operating time and prolonged surgical procedures were assessed using multiple logistic regressions. RESULTS: NHT was shown to be an independent predictor of prolonged total operating time. Tumor stage alterations did not appear to be associated with NHT followed by RARP. The patients who underwent NHT were not more likely to have positive surgical margins, and an increase in patients requiring blood transfusion was not seen. CONCLUSION: NHT appears to increase operative time during RARP. However, the perioperative morbidity of NHT patients undergoing RARP appears to be equivalent with that of non-NHT patients.

Prostatectomy using different lasers for the treatment of benign prostate hyperplasia in aging males.

PURPOSE: Endoscopic lasers have become a treatment option for benign prostate hyperplasia (BPH). The study reported here sought to elucidate the benefits and drawbacks of different laser systems in the treatment of patients with BPH. METHODS: The study enrolled 741 patients diagnosed with lower urinary tract symptoms secondary to BPH during the period January 2005 to December 2011. The techniques used in the study were photoselective vaporization of the prostate, thulium laser prostatectomy, and diode laser prostatectomy. Patients were assigned to one of three groups according to the type of laser treatment they received. Outcomes were evaluated using the International Prostate Symptom Score (IPSS), quality of life, maximal urinary flow rate, post-voiding residual urine volume, and prostate-specific antigen (PSA) level. RESULTS: The baseline characteristics of patients who received diode laser prostatectomy show a significant elevated risk and high American Society of Anesthesiology score (P=0.001). Operative time and catheter removal time differed significantly between the three groups (P=0.001). No cases were converted to transurethral resection of the prostate intraoperatively due to bleeding (P=0.142). Among the three groups, there were no significant differences in maximal flow rate, lower post-void residual urine, and postoperative PSA level during the entire follow-up period (P<0.05). Further, no significant differences in postoperative IPSS, quality of life, or bladder neck contracture (P=0.23) were observed. However, a significant difference was observed with regard to prolonged use of Foley catheters and prolonged hospital stay among patients in the diode laser group (P=0.001). CONCLUSION: Laser prostatectomies are effective in dealing with lower urinary tract symptoms. Early subjective functional results (maximal flow rate, IPSS, and post-void residual urine) appeared the same as those obtained following laser prostatectomy. Thus, it appears that lasers are safe and effective as long as the patients are carefully selected for treatment.