The analysis of dihydroptychantol (DHA) and its chemically synthesized macrocyclic bisbibenzyl derivatives (DHA1, 2 and 3) led to the selection of DHA2 as a potential drug candidate for ovarian cancer. The exposure of ovarian cancer SKOV3 cells to DHA2 resulted in the downregulation of the anti-apoptotic X-linked inhibitor of apoptosis protein (XIAP) and Bcl-2 and led to caspase-independent cell death. The overexpression of XIAP reversed DHA2-induced cell death, and the depletion of XIAP had the opposite effect. DHA2 could induce autophagy, as evidenced by increases in the formation of acidic vesicular organelles and the processing of LC3B-I to LC3B-II. Pretreatment with autophagy inhibitors potentiated DHA2-mediated cell death. We showed that typical PI3K/Akt signaling was involved in DHA2-mediated cell death. The overexpression of Akt almost completely reversed DHA2-induced cell death, and the inactivation of Akt significantly facilitated DHA2-induced cell death. The administration of DHA2 to xenograft mice reduced tumor growth by causing Akt inactivation, the conversion of LC3B and proliferation inhibition. Our study demonstrates that the inhibition of XIAP and the inactivation of Akt/mTOR facilitate the efficacy of DHA2 in ovarian cancer cells. 相似文献
Dietary supplementation exerts beneficial effects in reducing incidence of chronic neurodegenerative diseases. The purpose of this study was to examine protective effects of mussel (Mytilus edulis) oligopeptides supplementation on brain function in d-galactose induced aging mice. Sixty female 8-month-old mice were randomly divided into five groups: vehicle control, d-galactose, and d-galactose combined with 200, 500, 1000 mg/kg mussel oligopeptides. The results showed that mussel oligopeptides could improve cognitive learning and memory ability and protect the hippocampal neurons. In addition, GSH, SOD and GSH-pX activities were increased and MDA level was significantly decreased in mice fed with mussel oligopeptides. It was also found that mussel oligopeptides supplementation prevented d-galactose-induced elevations of iNOS activity and NO production and lactate acid levels in brain. Moreover, PI3K and Akt genes were up-regulated by mussel oligopeptides supplementation. These findings suggest that mussel oligopeptides are able to enhance exercise capacity and protect against oxidative damage caused by d-galactose in aging model mice through regulating oxidation metabolism and PI3K/Akt/NOS signal pathway. Therefore, mussel oligopeptides are good materials for future development of healthcare products to combat age-related brain dysfunction and to improve healthy life span. 相似文献
Activated in response to chemotherapy, senescence is a tumor suppressive mechanism that induces a permanent loss of proliferation. However, in response to treatment, it is not really known how cells can escape senescence and how irreversible or incomplete this pathway is. We have recently described that cells that escape senescence are more transformed than non-treated parental cells, they resist anoikis and rely on Mcl-1. In this study, we further characterize this emergence in response to irinotecan, a first line treatment used in colorectal cancer. Our results indicate that Akt was activated as a feedback pathway during the early step of senescence. The inhibition of the kinase prevented cell emergence and improved treatment efficacy, both in vitro and in vivo. This improvement was correlated with senescence inhibition, p21waf1 downregulation and a concomitant activation of apoptosis due to Noxa upregulation and Mcl-1 inactivation. The inactivation of Noxa prevented apoptosis and increased the number of emergent cells. Using either RNA interference or p21waf1-deficient cells, we further confirmed that an intact p53-p21-senescence pathway favored cell emergence and that its downregulation improved treatment efficacy through apoptosis induction. Therefore, although senescence is an efficient suppressive mechanism, it also generates more aggressive cells as a consequence of apoptosis inhibition. We therefore propose that senescence-inducing therapies should be used sequentially with drugs favoring cell death such as Akt inhibitors. This should reduce cell emergence and tumor relapse through a combined induction of senescence and apoptosis. 相似文献
Introduction: Agonists of peroxisome proliferator-activated receptor gamma (PPARγ) have been examined as chemopreventive and chemotherapeutic agents. The aim was to investigate the cytotoxicity and action mechanisms of 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), one of endogenous ligands for PPARγ, in terms of PPARγ-dependency and the mitogen-activated protein kinase (MAPK) and Akt pathway in three human renal cell carcinoma (RCC)-derived cell lines.Methods: 786-O, Caki-2 and ACHN cells were used as human RCC-derived cell lines. Cell viability and caspase-3 activity was detected by fluorescent reagents, and chromatin-condensation was observed with a brightfield fluorescent microscope after staining cells with Hoechst33342. The expression levels of proteins were detected by Western blot analysis.Results: 15d-PGJ2 showed cytotoxicity in dose-dependent manner. 15d-PGJ2 induced chromatin-condensation and elevated caspase-3 activity, and the cell viability was restored by co-treatment with a pan-caspase inhibitor, Z-VAD-FMK, indicating the involvement of caspase-dependent apoptosis. The cytotoxicity was not impaired by a PPARγ inhibitor, GW9662, suggesting that 15d-PGJ2 exerted the cytotoxicity in a PPARγ-independent manner. Some antioxidants rescued cells from cell death induced by 15d-PGJ2, but some did not, suggesting that reactive oxygen species (ROS) did not contribute to the apoptosis. 15d-PGJ2 also increased the expression levels of phospho-c-Jun N terminal kinase (JNK) in Caki-2 cells, and decreased those of phospho-Akt in 786-O cells, indicating that the JNK MAPK and the Akt pathways participated in the anticancer effects of 15d-PGJ2 in some cell lines.Conclusion: 15d-PGJ2 exerted cytotoxic effects accompanying caspase-dependent apoptosis, and this effect was elicited in a PPARγ-independent manner in three cell lines. In addition, the JNK MAPK and Akt pathway was involved in the cytotoxicity of 15d-PGJ2 to some extent in some cell line. Therefore, our study showed the 15d-PGJ2 to potentially be an interesting approach for RCC treatment. 相似文献
Glioblastoma tumor cells release microvesicles, which contain mRNA, miRNA and angiogenic proteins. These tumor-derived microvesicles transfer genetic information and proteins to normal cells. Previous reports demonstrated that the increased microvesicles in cerebrospinal fluid (CSF) of patients with glioblastoma up-regulate procoagulant activity. The concentration of microvesicles was closely related to thromboembolism incidence and clinical therapeutic effects of glioblastoma patients. However, it is still not clear how CSF microvesicles and what factors affect glioblastoma development. In this study, we collected the plasma and CSF from glioblastoma patients and healthy volunteers. Microvesicles acquired from serum or CSF were added to cultured endothelial cells. And the effects of these microvesicles on endothelial cells were examined. Our results showed that microvesicles from CSF of patients, but not from circulating blood, promoted endothelial cells migration and proliferation in vitro. In addition, the degree of endothelial cell proliferation triggered by microvesicles from CSF was reduced when treated with siRNA targeting Akt/beta-catenin, suggesting that the Akt/beta-catenin pathway is involved in the microvesicle-initiated endothelial cell proliferation. In conclusion, glioblastoma mainly affects microvesicles within CSF without showing significant impact on microvesicles in circulating blood. Microvesicles from the CSF of glioblastoma patients may initiate endothelial cell growth and thus promote cell invasion. This effect may be directly exerted by activated Akt/beta-catenin pathway. 相似文献
Introduction: 3-Phosphoinositide-dependent kinase 1 (PDK1), the ‘master kinase of the AGC protein kinase family’, plays a key role in cancer development and progression. Although it has been rather overlooked, in the last decades a growing number of molecules have been developed to effectively modulate the PDK1 enzyme.
Areas covered: This review collects different PDK1 inhibitors patented from October 2014 to December 2018. The molecules have been classified on the basis of the chemical structure/type of inhibition, and for each general structure, examples have been discussed in extenso.
Expert opinion: The role of PDK1 in cancer development and progression as well as in metastasis formation and in chemoresistance has been confirmed by many studies. Therefore, the pharmaceutical discovery in both public and private institutions is still ongoing despite the plentiful molecules already published. The majority of the new molecules synthetized interact with binding sites different from the ATP binding site (i.e. PIF pocket or DFG-out conformation). However, many researchers are still looking for innovative PDK1 modulation strategy such as combination of well-known inhibitory agents or multitarget ligands, aiming to block, together with PDK1, other different critical players in the wide panorama of proteins involved in tumor pathways. 相似文献
The phosphatidylinositol-3-kinase (PI3K) pathway is well known to regulate a wide variety of essential cellular functions, including glucose metabolism, translational regulation of protein synthesis, cell proliferation, apoptosis, and survival. Aberrations in the PI3K pathway are among the most frequently observed in cancer, and include amplifications, rearrangements, mutations, and loss of regulators. As a net result of these anomalies, the PI3K pathway is activated in many malignancies, including in Hodgkin and non-Hodgkin lymphomas, and yields a competitive growth and survival advantage, increased metastatic ability, and resistance to conventional therapy. Numerous inhibitors targeting various nodes in the PI3K pathway are undergoing clinical development, and their current status in lymphoma will be the focus of this review. 相似文献