Targeting ERK induced cell death and p53/ROS-dependent protective autophagy in colorectal cancer

In recent years, many studies have shown that autophagy plays a vital role in the resistance of tumor chemotherapy. However, the interaction between autophagy and cell death has not yet been clarified. In this study, a new specific ERK inhibitor CC90003 was found to suppress colorectal cancer growth by inducing cell death both in vitro and in vivo. Studies have confirmed that higher concentrations of ROS leads to autophagy or cell death. In this research, the role of CC90003-induced ROS was verified. But after inhibiting ROS by two kinds of ROS inhibitors NAC and SFN, the autophagy induced by CC90003 decreased, while cell death strengthened. In parallel, protective autophagy was also induced, while in a p53-dependent manner. After silencing p53 or using the p53 inhibitor PFTα, the autophagy induced by CC90003 was weakened and the rate of cell death increases. Therefore, we confirmed that CC90003 could induce autophagy by activating ROS/p53. Furthermore, in the xenograft mouse model, the effect was obtained remarkably in the combinational treatment group of CC90003 plus CQ, comparing with that of the single treatment groups. In a word, our results demonstrated that targeting ERK leads to cell death and p53/ROS-dependent protective autophagy simultaneously in colorectal cancer, which offers new potential targets for clinical therapy.

Combination of Dexmedetomidine and Tramadol in Patient-Controlled Intravenous Analgesia Strengthens Sedative Effect in Pregnancy-Induced Hypertension

Objective: The aim of the present study is to explore the combination of dexmedetomidine (DXM) and tramadol (TMD) on sedative effect in patients with pregnancy-induced hypertension (PIH).Methods: A total of 356 patients with pregnancy-induced hypertension (PIH) were randomly divided into three groups: DXM, TMD and DXM + TMD groups. These patients were treated with different doses of DXM, TMD or combination of DXM and TMD by a patient-controlled intravenous injection device. The scores of static pain and dynamic pain, sedation degree, and adverse reaction were recorded. The plasma levels of inflammatory mediators IL-10 and C-reactive protein (CRP), and the serum level of p-p38-MAPK were evaluated.Results: It was found that administration with DXM 1.0 µg/kg/h + TMD 700 mg and DXM 2.0 µg/kg/h + TMD 600 mg result in stronger sedative effect than single administration with DXM or TMD. The mean arterial pressure (MAP) and heart rate (HR) of patients with PIH were decreased with the combinational treatment of DXM and TMD. Interestingly, the PIH patients injected with DXM 1.0 µg/kg/h + TMD 700 mg and DXM 2.0 µg/kg/h + TMD 600 mg showed stronger sedative effect. In addition, the plasma level of level of IL-10 was increased and CRP decreased. The serum level of p-p38/MAPK was decreased.Conclusion: Taken together, our study indicates that combination of DXM and TMD effectively lowers blood pressure and reduces inflammation through increasing the level of IL-10, reducing CRP and inhibiting p-p38/MAPK in patients with PIH. This study suggests that the combination of DXM and TMD could be an anesthetic choice in the management of PIH.

Chemical hybridization of sulfasalazine and dihydroartemisinin promotes brain tumor cell death

Gliomas are primary brain tumors with still poor prognosis for the patients despite a combination of cytoreduction via surgery followed by a radio-chemotherapy. One strategy to find effective treatment is to combine two different compounds in one hybrid molecule via linker to add to or at best potentiate their impact on malignant cells. Here, we report on the effects of a newly synthesized hybrid of sulfasalazine (SAS) and dihydroartemisinin (DHA), called AC254. In previous studies, both SAS and DHA have already proved to have anti-tumor properties themselves and to have sensitizing respectively potentiating effects on other treatments against malignant tumors. We investigated the impact of individual drugs SAS and DHA, their 1:1 combination and a novel SAS-DHA hybrid compound (AC254) on rodent and human glioma cells. In our study SAS alone showed no or only a mild effect on glioma, whereas DHA led to a significant reduction of cell viability in a dose-dependent manner. Next we compared the efficacy of the hybrid AC254 to the combinational treatment of its parent compounds SAS and DHA. The hybrid was highly efficient in combating glioma cells compared to single treatment strategies regarding cell viability and cell death. Interestingly, AC254 showed a remarkable advantage over the combinational treatment with both parent compounds in most used concentrations. In addition to its reduction of tumor cell viability and induction of cell death, the hybrid AC254 displayed changes in cell cycle and reduction of cell migration. Taken together, these results demonstrate that clinically established compounds such as SAS and DHA can be potentiated in their anti-cancer effects by chemical hybridization. Thus, this concept provides the opportunity to devise new effective chemotherapeutic agents.

Comparative Study between the Efficacy of Platelet Rich Plasma with Methotrexate and Methotrexate Alone in Treatment of Chronic Plaque Psoriasis

Background Psoriasis affects up to 3% of the world's population or more than 125 million people. There is an urgent need for new treatment strategy, as up to 50% of patients are not satisfied with current therapies. We evaluated the efficiency of combined platelet rich plasma (PRP) and methotrexate (MTX) injection in management of psoriasis vulgaris and combared it with methotrexate injection only. Objectives The aim of this work is to compare between the clinical efficacy of platelet rich plasma with methotrexate and methotrexate alone in treatment of chronic plaque psoriasis. Patients and Methods Forty patients with chronic plaque psoriasis were divided into two groups. Twenty patients were assigned into combinational treatment group (PRP + MTX) and monotherapy group (MTX alone) consisted of another tweenty patients. All patients in combinational therapy group received autologous intralesional PRP at 0,4 and 8 weeks combined with methotrethate im injection once every week for 12 weeks, while patients in monotherapy group received only methotrexate im injection once every week for 12 weeks. Results There were statistically significant decreased DLQI score after 6 and 12 weeks of treatment in females compared to males only in group B, while no significant differences were found between males and females in group A patients, This could be attributed to the greater concern in females as psoriasis is considered as a cosmotic problem. Conclusion Combination treatment of PRP with MTX is more effective than MTX alone in treatment of psoriasis vulgaris.

Combined Therapy for Paclitaxel and Curcumin by Nonionic Surfactant Vesicles Leading to Enhanced Efficacy of Chemotherapy in Ovarian Cancer Cells Through Inhibiting the Serine/threonine Kinase Akt and Nuclear Factor Kappab Activity

The combination therapy of cytotoxic drugs and chemosensitizing agents encapsulated in nanoparticles has been highlighted as an effective treatment for various cancers. Combination therapy is promising to produce synergistic anticancer effects, to magnify the treatment effect and overcome multidrug resistance. In this investigation, we have studied augmentation of therapeutic efficacy upon c combinational treatment of paclitaxel (PCL) and curcumin (Cur), an inhibitor of nuclear factor kappa B (NF-κB), in OVCAR-3 cell. PCL and Cur were encapsulated in nanoniosome formulations. Then, the effects of nanoniosome formulations on cytotoxicity, expression profile of AKT-1 gene and NF-κB activity were evaluated. The findings showed that nanoniosomes were highly efficient in delivering the PCL and Cur drugs to OVCAR-3 cell. A 3-fold and 3.6-fold reduction in Cur and PCL concentration were measured, respectively, when the Cur and PCL were administered in nanoniosomes compared to free Cur and free PCL solutions in OVCAR-3 cell. Moreover, curcumin could significantly increase cell growth inhibition of paclitaxel so that, in presence of NioCur, the IC50 of NioPCL was diminished to ∼2.4 –fold. AKT-1 gene expression studies showed that co-administration of curcumin/paclitaxel nanoniosome formulations caused 91.2% reduction in AKT-1 gene expression compared to control group. On the other hand, this co-administration caused 79.42% reduction in the amount of NF-κB activity and a 4-fold reduction in the activity of the MDR protein pumps in cancer cells compared to the control group. Our findings demonstrate that the combination therapy of PCL with Cur using the nanoniosomes delivery is a promising strategy for breast cancer more effective therapy

Combined Beneficial Effect of Genistein and Atorvastatin on Adipogenesis in 3T3-L1 Adipocytes

Genistein (4,5,7-trihydroxyisoflavone) is abundant in various dietary vegetables, especially soybeans, and is known to have not only an estrogenic effect but also an antiadipogenic effect. Atorvastatin (dihydroxy monocarboxylic acid) is a statin used to prevent heart disease. Although genistein and atorvastatin have been reported to possess antiadipogenic effects, their combined effects are still unclear. The aim of the current study was to explore whether the combination of genistein and atorvastatin at low concentrations significantly suppresses adipogenesis in a murine preadipocyte cell line (3T3-L1) compared to treatment with genistein or atorvastatin alone. Our results showed that cotreatment with 50 µM genistein and 50 nM atorvastatin significantly suppressed preadipocyte differentiation, whereas when each compound was used alone, there was no inhibitory effect. Additionally, cotreatment with genistein and atorvastatin significantly downregulated adipogenic marker proteins, including mitogen-activated protein kinases (MAPKs), peroxisome proliferator-activated receptor γ (PPARγ), CCAAT/enhancer-binding protein alpha (C/EBPα), glucocorticoid receptor (GR), and CCAAT/enhancer-binding protein β (C/EBPβ). This is the first evidence of the combined antiadipogenic effects of genistein and atorvastatin. Although additional experiments are required, combinational treatment with genistein and atorvastatin may be an alternative treatment for menopause-associated lipid metabolic disorders and obesity.

Interactions between Cancer-Associated Fibroblasts and T Cells in the Pancreatic Tumor Microenvironment and the Role of Chemokines

Less than 10% of patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) survive 5 years or more, making it one of the most fatal cancers. Accumulation of T cells in pancreatic tumors is associated with better prognosis, but immunotherapies to enhance the anti-tumor activity of infiltrating T cells are failing in this devastating disease. Pancreatic tumors are characterized by a desmoplastic stroma, which mainly consists of activated cancer-associated fibroblasts (CAFs). Pancreatic CAFs have emerged as important regulators of the tumor microenvironment by contributing to immune evasion through the release of chemokines, cytokines, and growth factors, which alters T-cell migration, differentiation and cytotoxic activity. However, recent discoveries have also revealed that subsets of CAFs with diverse functions can either restrain or promote tumor progression. Here, we discuss our current knowledge about the interactions between CAFs and T cells in PDAC and summarize different therapy strategies targeting the CAF–T cell axis with focus on CAF-derived soluble immunosuppressive factors and chemokines. Identifying the functions of different CAF subsets and understanding their roles in T-cell trafficking within the tumor may be fundamental for the development of an effective combinational treatment for PDAC.

Sequence-Defined Nanotubes Assembled from IR780-Conjugated Peptoids for Chemophototherapy of Malignant Glioma

Near-infrared (NIR) laser-induced phototherapy through NIR agents has demonstrated the great potential for cancer therapy. However, insufficient tumor killing due to the nonuniform heat or cytotoxic singlet oxygen (1O2) distribution over tumors from phototherapy results in tumor recurrence and inferior outcomes. To achieve high tumor killing efficacy, one of the solutions is to employ the combinational treatment of phototherapy with other modalities, especially with chemotherapeutic agents. In this paper, a simple and effective multimodal therapeutic system was designed via combining chemotherapy, photothermal therapy (PTT), and photodynamic therapy (PDT) to achieve the polytherapy of malignant glioma which is one of the most aggressive tumors in the brain. IR-780 (IR780) dye-labeled tube-forming peptoids (PepIR) were synthesized and self-assembled into crystalline nanotubes (PepIR nanotubes). These PepIR nanotubes showed an excellent efficacy for PDT/PTT because the IR780 photosensitizers were effectively packed and separated from each other within crystalline nanotubes by tuning IR780 density; thus, a self-quenching of these IR780 molecules was significantly reduced. Moreover, the efficient DOX loading achieved due to the nanotube large surface area contributed to an efficient and synergistic chemotherapy against glioma cells. Given the unique properties of peptoids and peptoid nanotubes, we believe that the developed multimodal DOX-loaded PepIR nanotubes in this work offer great promises for future glioma therapy in clinic.