Targeting Autophagy to Overcome Human Diseases Condello, Maria; Pellegrini, Evelin; Caraglia, Michele ...
International journal of molecular sciences,
02/2019, Letnik:
20, Številka:
3
Journal Article
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Autophagy is an evolutionarily conserved cellular process, through which damaged organelles and superfluous proteins are degraded, for maintaining the correct cellular balance during stress insult. ...It involves formation of double-membrane vesicles, named autophagosomes, that capture cytosolic cargo and deliver it to lysosomes, where the breakdown products are recycled back to cytoplasm. On the basis of degraded cell components, some selective types of autophagy can be identified (mitophagy, ribophagy, reticulophagy, lysophagy, pexophagy, lipophagy, and glycophagy). Dysregulation of autophagy can induce various disease manifestations, such as inflammation, aging, metabolic diseases, neurodegenerative disorders and cancer. The understanding of the molecular mechanism that regulates the different phases of the autophagic process and the role in the development of diseases are only in an early stage. There are still questions that must be answered concerning the functions of the autophagy-related proteins. In this review, we describe the principal cellular and molecular autophagic functions, selective types of autophagy and the main in vitro methods to detect the role of autophagy in the cellular physiology. We also summarize the importance of the autophagic behavior in some diseases to provide a novel insight for target therapies.
Anti-Inflammatory Drugs as Anticancer Agents Zappavigna, Silvia; Cossu, Alessia Maria; Grimaldi, Anna ...
International journal of molecular sciences,
04/2020, Letnik:
21, Številka:
7
Journal Article
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Inflammation is strictly associated with cancer and plays a key role in tumor development and progression. Several epidemiological studies have demonstrated that inflammation can predispose to ...tumors, therefore targeting inflammation and the molecules involved in the inflammatory process could represent a good strategy for cancer prevention and therapy. In the past, several clinical studies have demonstrated that many anti-inflammatory agents, including non-steroidal anti-inflammatory drugs (NSAIDs), are able to interfere with the tumor microenvironment by reducing cell migration and increasing apoptosis and chemo-sensitivity. This review focuses on the link between inflammation and cancer by describing the anti-inflammatory agents used in cancer therapy, and their mechanisms of action, emphasizing the use of novel anti-inflammatory agents with significant anticancer activity.
Mitochondria are the key energy-producing organelles and cellular source of reactive species. They are responsible for managing cell life and death by a balanced homeostasis passing through a network ...of structures, regulated principally via fission and fusion. Herein we discuss about the most advanced findings considering mitochondria as dynamic biophysical systems playing compelling roles in the regulation of energy metabolism in both physiologic and pathologic processes controlling cell death and survival. Precisely, we focus on the mitochondrial commitment to the onset, maintenance and counteraction of apoptosis, autophagy and senescence in the bioenergetic reprogramming of cancer cells. In this context, looking for a pharmacological manipulation of cell death processes as a successful route for future targeted therapies, there is major biotechnological challenge in underlining the location, function and molecular mechanism of mitochondrial proteins. Based on the critical role of mitochondrial functions for cellular health, a better knowledge of the main molecular players in mitochondria disfunction could be decisive for the therapeutical control of degenerative diseases, including cancer.
The balance between synthesis and degradation is crucial to maintain cellular homeostasis and different mechanisms are known to keep this balance. In this review, we will provide a short overview on ...autophagy as an intracellular homeostatic degradative machinery. We will also describe the involvement of downregulation of autophagy in numerous diseases including neurodegenerative diseases, cancer, aging, metabolic disorders, and other infectious diseases. Therefore, modulation of autophagic processes can represent a promising way of intervention in different diseases including neurodegeneration and cancer. Trehalose, also known as mycose, is a natural disaccharide found extensively but not abundantly among several organisms. It is described that trehalose can work as an important autophagy modulator and can be proficiently used in the control several diseases in which autophagy plays an important role. On these bases, we describe here the role of trehalose as an innovative drug in the treatment of neurodegenerative diseases and other illnesses opening a new scenario of intervention in conditions difficult to be treated.
We describe here the role of trehalose as an innovative drug in the treatment of neurodegenerative diseases and other illnesses opening a new scenario of intervention in conditions difficult to be treated.
Extracellular Vesicles (EVs) represent a heterogeneous population of membranous cell-derived structures, including cargo-oriented exosomes and microvesicles. EVs are functionally associated with ...intercellular communication and play an essential role in multiple physiopathological conditions. Shedding of EVs is frequently increased in malignancies and their content, including proteins and nucleic acids, altered during carcinogenesis and cancer progression. EVs-mediated intercellular communication between tumor cells and between tumor and stromal cells can modulate, through cargo miRNA, the survival, progression, and drug resistance in cancer conditions. These consolidated suggestions and EVs' stability in bodily fluids have led to extensive investigations on the potential employment of circulating EVs-derived miRNAs as tumor biomarkers and potential therapeutic vehicles. In this review, we highlight the current knowledge about circulating EVs-miRNAs in human cancer and the application limits of these tools, discussing their clinical utility and challenges in functions such as in biomarkers and instruments for diagnosis, prognosis, and therapy.
Mir-34: A New Weapon Against Cancer? Misso, Gabriella; Di Martino, Maria Teresa; De Rosa, Giuseppe ...
Molecular therapy. Nucleic acids,
09/2014, Letnik:
3, Številka:
9
Journal Article
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The microRNA(miRNA)-34a is a key regulator of tumor suppression. It controls the expression of a plethora of target proteins involved in cell cycle, differentiation and apoptosis, and antagonizes ...processes that are necessary for basic cancer cell viability as well as cancer stemness, metastasis, and chemoresistance. In this review, we focus on the molecular mechanisms of miR-34a-mediated tumor suppression, giving emphasis on the main miR-34a targets, as well as on the principal regulators involved in the modulation of this miRNA. Moreover, we shed light on the miR-34a role in modulating responsiveness to chemotherapy and on the phytonutrients-mediated regulation of miR-34a expression and activity in cancer cells. Given the broad anti-oncogenic activity of miR-34a, we also discuss the substantial benefits of a new therapeutic concept based on nanotechnology delivery of miRNA mimics. In fact, the replacement of oncosuppressor miRNAs provides an effective strategy against tumor heterogeneity and the selective RNA-based delivery systems seems to be an excellent platform for a safe and effective targeting of the tumor.
Pentose phosphate pathway (PPP) is a major glucose metabolism pathway, which has a fundamental role in cancer growth and metastasis. Even though PPP blockade has been pointed out as a very promising ...strategy against cancer, effective anti-PPP agents are not still available in the clinical setting. Here we demonstrate that the natural molecule polydatin inhibits glucose-6-phosphate dehydrogenase (G6PD), the key enzyme of PPP. Polydatin blocks G6PD causing accumulation of reactive oxygen species and strong increase of endoplasmic reticulum stress. These effects are followed by cell cycle block in S phase, an about 50% of apoptosis, and 60% inhibition of invasion in vitro. Accordingly, in an orthotopic metastatic model of tongue cancer, 100 mg/kg polydatin induced an about 30% tumor size reduction with an about 80% inhibition of lymph node metastases and 50% reduction of lymph node size (p < 0.005). Polydatin is not toxic in animals up to a dose of 200 mg/kg and a phase II clinical trial shows that it is also well tolerated in humans (40 mg twice a day for 90 days). Thus, polydatin may be used as a reliable tool to limit human cancer growth and metastatic spread.
The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is a central hub for the regulation of cell proliferation, apoptosis, cell cycle, metabolism, and ...angiogenesis. Several studies have recently suggested that the PI3K/Akt/mTOR signaling pathway is implicated in the pathogenesis and progression of neuroendocrine tumors. Medullary thyroid cancer (MTC) is a neuroendocrine tumor developing from the C cells of the thyroid. Mutations in the RET proto-oncogene are involved in the pathogenesis of several forms of MTC. The deregulation of the PI3K/Akt/mTOR pathway seems to contribute to the tumorigenic activity of RET proto-oncogene mutations. Targeting this pathway through specific inhibitors at simple or multiple sites may represent an attractive potential therapeutic approach for patients with advanced MTCs. The aim of this review is to examine the role of the PI3K/Akt/mTOR pathway in the development and progression of MTC and the new therapeutic options that target this signaling pathway.
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