G. Cicero

Geldanamycin and its derivatives as Hsp90 inhibitors.

The Hsp90 molecule, one of the most abundant heat shock proteins in mammalian cells, maintains homeostasis and prevents stress-induced cellular damage. Hsp90 is expressed under normal conditions at a level of about 1-2 Percent of total proteins, while its expression increases 2-10 fold in cancer cells. The two main constitutively expressed isoforms of Hsp90 are known as Hsp90-alpha and Hsp90-beta, and their upregulation is associated with tumor progression, invasion and formation of metastases, as well as development of drug resistance. The Hsp90 is a key target for many newly established, potent anticancer agents containing Hsp90 N-terminal ATP binding inhibitors, such as geldanamycin, and its analogues 17AAG and 17DMAG. The therapeutic usage of geldanamycin has been limited due to its poor water solubility and severe hepatotoxicity. Therefore, its analogues, including 17AAG, 17DMAG, Tanespimycin and Retaspimycin hydrochloride, with improved pharmacokinetic profiles, have been developed.

MicroRNAs in colorectal cancer stem cells: new regulators of cancer stemness?

Recently, the hypothesis that colorectal tumors originate from a subpopulation of cells called ‘cancer stem cells’ (CSCs) or tumor-initiating cells, which exhibit stem-like features, has been confirmed experimentally in various human cancers. Several studies have confirmed the existence of colorectal CSCs (CRCSCs) and have demonstrated that this rare cell population can be isolated by the expression of specific cell surface biomarkers. MicroRNAs (miRNAs) are a class of small non-coding RNAs, which are crucial for post-transcriptional regulation of gene expression and participate in a wide variety of biological functions, including development, cell proliferation, differentiation, metabolism and signal transduction. Moreover, new evidences suggest that miRNAs could contribute to preserve stemness of embryonic stem cells and could be involved in maintaining stemness of CSCs. Recent studies have begun to outline the role of miRNAs in regulation of CRCSCs. This review aims to summarize the recent advancement about the roles of miRNAs in CRCSCs that may represent a step forward in understanding the molecular mechanisms and the possible approaches for colorectal cancer therapy.

Targeted therapies in hepatocellular carcinoma.

The onset of hepatocellular carcinoma (HCC) is related to the development of non-neoplastic liver disease, such as viral infections and cirrhosis. Even though patients with chronic liver diseases undergo clinical surveillance for early diagnosis of HCC, this cancer is often diagnosed in advanced stage. In this case locoregional treatment is not possible and systemic therapies are the best way to control it. Until now sorafenib, a Raf and multi-kinase inhibitor has been the best, choice to treat HCC systemically. It showed a survival benefit in multicenter phase III trials. However the proper patient setting to treat is not well defined, since the results in Child-Pugh B patients are conflicting. To date various new target drugs are under developed and other biological treatments normally indicated in other malignancies are under investigation also for HCC. These strategies aim to target the different biological pathways implicated in HCC development and progression. The target drugs studied in HCC include anti-VEGF and anti-EGFR monoclonal antibodies, tyrosine kinase inhibitors and mTOR inhibitors. The most important challenge is represented by the best integration of these drugs with standard treatments to achieve improvement in overall survival and quality of life.

Bortezomib: A New Pro-Apoptotic Agent in Cancer Treatment

Bortezomib is a proteasome inhibitor. It targets the ubiquitin-proteasome pathway with subsequent inhibition of the degradation of proteins involved in cell cycle regulation and cancer cell survival. The best known molecular mechanism concerns the inhibition of IkappaB breakdown and the related stabilization of NFkappaB, thus preventing its translocation to the nucleus for the activation of downstream pathways. Bortezomib is the only drug in this class which has been approved for clinical use. It has shown an efficient antitumor effect in a phase III clinical trial (APEX) involving relapsed multiple myeloma patients. Response rate, time to progression and overall survival have been improved in patients treated with bortezomib and dexamethasone compared to dexamethasone alone. These results have induced several researchers to suggest preclinical and clinical studies for the application of bortezomib in solid tumors. Preclinical data have proved useful in the identification of several of the biological processes implicated, including cell cycle arrest at the G2/M phase, upregulation of p21, apoptosis regulation, microvessel density reduction, overcoming chemotherapy resistance. The clinical results obtained so far with the use of bortezomib in patients with solid malignancies are still not sufficient for the introduction of the drug into clinical practice. Furthermore, the results obtained with the use of bortezomib combined with cytotoxic drugs have not proved any more satisfactory than those obtained with bortezomib used as a single agent. Other preclinical studies are required in order to reach a clearer understanding of the relevance of bortezomib in the therapy of solid tumors.

Unusual case of dorsal vertebral metastases from a male breast cancer

ROSARIO MAUGERI1, GIUSEPPE ROBERTO GIAMMALVA1, GIUSEPPE CICERO2, ROSSELLA DE LUCA2, CARLO GULÌ1, FRANCESCA GRAZIANO1, LUIGI BASILE1, ANTONELLA GIUGNO1, DOMENICO GERARDO IACOPINO1 1Department of Experimental Biomedicine and Clinical Neurosciences, School of Medicine, Neurosurgical Clinic, University of Palermo, Italy 2Department of Surgical, Oncological and Oral Science, DICHIRONS, University of Palermo, Policlinico Paolo Giaccone, Palermo, Italy University of Palermo, Italy

The patient-physician relationship in the face of oncological disease: A review of literature on the emotional and psychological reactions of patients and physician

The Cancer diagnosis, as Cianfarini (2007) affirmed, often arrives like “a bolt from the blue” that puts a strain on the search for a relational continuity and is substantiated such an extremely difficult time which nobody is prepared for. It represents a very stressful event for both patient and physician, albeit with a different emotional: for the patient it represents an existential challenge that destabilizes all his own certainties and his life’s features like, for example, the relationship with his body, with his feelings and the meaning given up to them, to suffering, disease and death. On the other hand, instead, physician feels suffocated by the unremitting requests of patients and the responsibilities he is not sometimes able to hold up because of his own personal, technical and scientific limits with consequent frustrations and demotivation. This confirms the truth of results of many researches, that in recent years showed how to consider the cancer in its own complexity is important, not only being limited to the analysis of biological factors, but considering it as a disease involving both psyche and body. Therefore, it requires a multidisciplinary approach that is able to assess its different features and implications. A good physician-patient relationship depends on the physician’s ability to demonstrate a clinical expertise that is not limited only Acta Medica Mediterranea, 2016, 32: 1827