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Despite significant advancements in understanding the causes and progression of tumors, cancer remains one of the leading causes of death worldwide. In light of advances in cancer therapy, there has been a growing interest in drug repurposing, which involves exploring new uses for medications that are already approved for clinical use. One such medication is edaravone, which is currently used to manage patients with cerebral infarction and amyotrophic lateral sclerosis. Due to its antioxidant and anti-inflammatory properties, edaravone has also been investigated for its potential activities in treating cancer, notably as an anti-proliferative and cytoprotective drug against side effects induced by traditional cancer therapies. This comprehensive review aims to provide updates on the various applications of edaravone in cancer therapy. It explores its potential as a standalone antitumor drug, either used alone or in combination with other medications, as well as its role as an adjuvant to mitigate the side effects of conventional anticancer treatments.

Amyotrophic lateral sclerosis (ALS) is a fatal condition characterized by the selective loss of motor neurons in the motor cortex, brainstem, and spinal cord. Muscle involvement, muscle atrophy, and subsequent paralysis are among the main features of this disease, which is defined as a neuromuscular disorder. ALS is a persistently progressive disease, and as motor neurons continue to degenerate, individuals with ALS experience a gradual decline in their ability to perform daily activities. Ultimately, muscle function loss may result in paralysis, presenting significant challenges in mobility, communication, and self-care. While the majority of ALS research has traditionally focused on pathogenic pathways in the central nervous system, there has been a great interest in muscle research. These studies were carried out on patients and animal models in order to better understand the molecular mechanisms involved and to develop therapies aimed at improving muscle function. This review summarizes the features of ALS and discusses the role of muscle, as well as examines recent studies in the development of treatments.

Facioscapulohumeral muscular dystrophy (FSHD) represents the third most common form of muscular dystrophy and is characterized by muscle weakness and atrophy. FSHD is caused by the altered expression of the transcription factor double homeobox 4 (DUX4), which is involved in several significantly altered pathways required for myogenesis and muscle regeneration. While DUX4 is normally silenced in the majority of somatic tissues in healthy individuals, its epigenetic de-repression has been linked to FSHD, resulting in DUX4 aberrant expression and cytotoxicity in skeletal muscle cells. Understanding how DUX4 is regulated and functions could provide useful information not only to further understand FSHD pathogenesis, but also to develop therapeutic approaches for this disorder. Therefore, this review discusses the role of DUX4 in FSHD by examining the possible molecular mechanisms underlying the disease as well as novel pharmacological strategies targeting DUX4 aberrant expression.

Amyotrophic lateral sclerosis (ALS) is a devastating progressive neurodegenerative disorder characterized by selective loss of lower and upper motor neurons (MNs) in the brain and spinal cord, resulting in paralysis and eventually death due to respiratory insufficiency. Although the fundamental physiological mechanisms underlying ALS are not completely understood, the key neuropathological hallmarks of ALS pathology are the aggregation and accumulation of ubiquitinated protein inclusions within the cytoplasm of degenerating MNs. Herein, we discuss recent insights into the molecular mechanisms that lead to the accumulation of protein aggregates in ALS. This will contribute to a better understanding of the pathophysiology of the disease and may open novel avenues for the development of therapeutic strategies.

La sclerosi laterale amiotrofica (SLA) è una malattia degenerativa di eziologia sconosciuta caratterizzata dalla compromissione dei motoneuroni superiori e inferiori. I fattori di rischio associati all'insorgenza e alla progressione della SLA rimangono sconosciuti. L'ipotesi più accreditata sull'eziopatogenesi della SLA prevede una concomitanza tra fattori genetici e ambientali che possono causare o contribuire allo sviluppo di forme familiari e sporadiche di SLA. Simile ad altre malattie neurodegenerative, la SLA è caratterizzata da un accumulo anomalo di proteine insolubili nel citoplasma dei motoneuroni in degenerazione. In particolare, nella SLA sporadica, si ritiene che l'aggregazione della proteina TDP-43 svolga un ruolo chiave nella degenerazione dei motoneuroni. In questo studio, abbiamo studiato un nuovo possibile biomarcatore per la SLA: double homeobox 4 (DUX4). Infatti, in uno studio di Homma del 2015, è stato dimostrato che la overespressione della proteina DUX4 nei mioblasti di pazienti con distrofia facioscapolomerale (FSHD) può contribuire all'aggregazione di TDP-43. Pertanto, nella prima parte del nostro studio, abbiamo valutato la possibile espressione di DUX4 e la sua correlazione con l'espressione di TDP-43 nelle cellule mononucleate del sangue periferico (PBMC) di pazienti con SLA. Successivamente, valutato l’espressione di DUX4 anche in campioni di post mortem, fibroblasti e sui motoneuroni derivati da iPSCs. In conclusione, è stata eseguita una trasfezione di DUX4 in linee cellulari di neuroblastoma umano e abbiamo valutato l'espressione di TDP-43. Nell'ultima parte, abbiamo valutato gli effetti dei farmaci approvati dalla FDA per il trattamento della SLA, Edaravone e Riluzolo, sull'espressione di DUX4. Inizialmente, abbiamo analizzato le cellule mononucleate del sangue periferico (PBMC) ottenute da 46 pazienti con SLA e 26 controlli possibili alterazioni nell'espressione di DUX4. Abbiamo riscontrato un aumento significativo dell'mRNA di, Amyotrophic lateral sclerosis (ALS) is a degenerative neuromuscular disease of unknown etiology characterized by the impairment of both upper and lower motor neurons. The risk factors associated with ALS onset and progression remain unknown. The most accepted hypothesis on the etiopathogenesis of ALS foresees a concomitance between genetic and environmental factors that can cause or contribute to the development of familial and sporadic forms of ALS. Similar to other neurodegenerative diseases, ALS is characterized by an abnormal accumulation of insoluble proteins in the cytoplasm of degenerating motor neurons. In particular, in sporadic ALS, the aggregation of TDP-43 protein is thought to play a key role in the degeneration of motor neurons. In this study, we investigated a novel possible biomarker for ALS: double homeobox 4 (DUX4). In fact, in a study by Homma and colleagues in 2015, it was shown that the overexpression of the DUX4 protein in myoblasts from patients with facioscapulohumeral muscular dystrophy (FSHD) can contribute to the accumulation and aggregation of TDP-43. Therefore, in the first part of our study, we evaluated the possible expression of DUX4 and its correlation with TDP-43 expression in peripheral blood mononuclear cells (PBMCs) from patients with ALS. Subsequently, we performed in neuroblastoma cell lines a DUX4 transfection and we evaluated the expression of TDP-43 before and after treatment. In the last part of this study, we assessed the possible effects of the two drugs approved by the FDA for the treatment of ALS, Edaravone and Riluzole, on DUX4 expression. We analyzed peripheral blood mononuclear cells (PBMC) obtained from 46 patients with ALS and 26 controls for possible alterations in DUX4 expression. We found a significant (about threefold) increase in DUX4 mRNA and protein levels in PBMCs from patients compared to controls. According to previous results from our group (Arosio et al., 2020), we subsequently confirmed an increase in

Availability of tumor and non-tumor patient-derived models would promote the development of more effective therapeutics for Non Small Cell Lung Cancer (NSCLC). Recently, conditionally reprogrammed cells (CRC) methodology demonstrated exceptional potential for the expansion of epithelial cells from patient tissues. However, the possibility to expand patient-derived lung cancer cells using CRC protocols is controversial. Here, we used CRC approach to expand cells from non-tumoral and tumor biopsies of patients with primary or metastatic NSCLC as well as pulmonary metastases of colorectal or breast cancers. CRC cultures were obtained from both tumor and non-malignant tissues with extraordinary high efficiency. Tumor cells were tracked in vitro through tumorigenicity assay, monitoring of tumor-specific genetic alterations and marker expression. Cultures were composed of EpCAM+ lung epithelial cells lacking tumorigenic potential. NSCLC biopsies-derived cultures rapidly lost patient-specific genetic mutations or tumor antigens. Similarly, pulmonary metastases of colon or breast cancer generated CRC cultures of lung epithelial cells. All CRC cultures examined displayed epithelial lung stem cell phenotype and function. In contrast, brain metastatic lung cancer biopsies failed to generate CRC cultures. In conclusion, patient-derived primary and metastatic lung cancer cells were negatively selected under CRC conditions, limiting the expansion to non-malignant lung epithelial stem cells either from tumor and non-tumor tissue sources. Thus, CRC approach cannot be applied for direct therapeutic testing of patient lung tumor cells, as the tumor- derived CRC cultures are composed of (non tumoral) airway basal cells.

Tyrosine kinase inhibitors (TKIs) have shown strong activity against non-small-cell lung cancer (NSCLC) patients harboring activating epidermal growth factor receptor (EGFR) mutations. However, a fraction of EGFR wild-type (WT) patients may have an improvement in terms of response rate and progression-free survival when treated with erlotinib, suggesting that factors other than EGFR mutation may lead to TKI sensitivity. However, at present, no sufficiently robust clinical or biological parameters have been defined to identify WT-EGFR patients with greater chances of response. Therapeutics validation has necessarily to focus on lung cancer stem cells (LCSCs) as they are more difficult to eradicate and represent the tumor-maintaining cell population. Here, we investigated erlotinib response of lung CSCs with WT-EGFR and identified EGFR phosphorylation at tyrosine1068 (EGFRtyr1068) as a powerful biomarker associated with erlotinib sensitivity both in vitro and in preclinical CSC-generated xenografts. In contrast to the preferential cytotoxicity of chemotherapy against the more differentiated cells, in EGFRtyr1068 cells, erlotinib was even more active against the LCSCs compared with their differentiated counterpart, acquiring potential value as CSC-directed therapeutics in the context of WT-EGFR lung cancer. Although tumor growth was inhibited to a similar extent during erlotinib or chemotherapy administration to responsive tumors, erlotinib proved superior to chemotherapy in terms of higher tolerability and reduced tumor aggressiveness after treatment suspension, substantiating the possibility of preferential LCSC targeting, both in adenocarcinoma (ADC) and squamous cell carcinoma (SCC) tumors. We conclude that EGFRtyr1068 may represent a potential candidate biomarker predicting erlotinib response at CSC-level in EGFR-WT lung cancer patients. Finally, besides its invariable association with erlotinib sensitivity in EGFR-WT lung CSCs, EG