1,721,016 research outputs found
New insights in cisplatin-resistance: role of metabolic reprogramming in cancer cells
Full text linkCisplatin is one of the most potent anticancer agents used in the treatment of various solid tumors. Unfortunately, the onset of resistance still limits its use in therapy and severely compromises the treatment effectiveness. Although several studies have been performed, the molecular mechanisms involved in cisplatin resistance are not completely understood. Recently, a metabolic rewiring has been shown to play a prominent role in the response of cancer cells to first-line chemotherapeutic agents, indicating the metabolic pathways as powerful mediators of resistance to cancer treatments.
Previous studies of our laboratory had already demonstrated a metabolic switch of cisplatin-resistant cells toward glycolysis and to an altered mitochondrial functionality and morphology. So, in order to better characterize the metabolic fingerprint of cisplatin-resistant cells, in this work the lipid metabolic pathway and the glutamine metabolism have been investigated in models of gynecological cancer cells and Triple-negative breast cancer cells, sensitive and resistant to cisplatin. Aerobic glycolysis, mitochondrial reprogramming, and deregulation of lipid metabolism are not independent pathways but rather they cooperate to sustain cells proliferation and to allow cells survival in a challenging environment induced also by chemotherapeutic drugs. The characterization of the metabolic fingerprint of cells and the interconnection between the different pathways is essential to identify specific targets in cisplatin-resistant cancer cells useful to design pharmacological strategies to bypass resistance. Results indicate a deregulation of the lipid homeostasis in resistant cells which induces a significant lipid accumulation; moreover, preliminary results indicate that resistant cells rely more on glutamine for their survival. From this study and previous observations of our laboratory, different possible metabolic targets specific of cisplatin-resistant cells have been identified, and different pharmacological approaches able to target the identified alterations in lipid metabolism and mitochondria remodeling have been tested.
This work fits in the research panorama aimed at providing new insights into the differential metabolic dependencies of cisplatin-resistant tumors. Results may provide novel therapeutic targets exploitable to overcome cisplatin resistance and to enhance the efficacy of the current chemotherapy.Il cisplatino è uno dei più potenti agenti antitumorali utilizzati nel trattamento di vari tumori solidi. L’insorgenza di fenomeni di resistenza al farmaco è uno dei fattori che ne limita l’utilizzo in terapia e compromette gravemente l’efficacia del trattamento. Nonostante numerosi studi siano stati condotti negli ultimi anni, i meccanismi molecolari coinvolti nella resistenza al cisplatino non sono ancora stati completamente elucidati. Recentemente è stato dimostrato che un ruolo chiave nella risposta cellulare ai farmaci antitumorali è svolto da una riprogrammazione del metabolismo cellulare, indicando le vie metaboliche come potenti mediatori della resistenza ai trattamenti chemioterapici. Studi precedentemente condotti nel nostro laboratorio su cellule di carcinoma ovarico avevano già dimostrato uno shift metabolico verso la glicolisi e alterazioni a livello di funzionalità/morfologia mitocondriale nei cloni resistenti al cisplatino (C13).
L’obiettivo di questo lavoro quindi è stato quello di studiare i pathways del metabolismo lipidico e della glutammina allo scopo di ottenere una caratterizzazione più completa del profilo metabolico delle cellule resistenti. Per questo studio sono stati utilizzati diversi modelli cellulari di tumore ginecologico e diverse linee cellulari di tumore mammario triplo negativo, sensibili e resistenti al cisplatino. È importante sottolineare come glicolisi aerobica, riprogrammazione mitocondriale e del metabolismo lipidico non sono vie indipendenti, ma cooperano per sostenere l’omeostasi cellulare e consentire la sopravvivenza delle cellule in ambienti ostili, indotti anche da farmaci chemioterapici.
Caratterizzare il profilo metabolico delle cellule e le interconnessioni tra i diversi pathways è essenziale per l’identificazione di target molecolari tumore-resistente specifici sfruttabili per approcci farmacologici innovativi. I risultati ottenuti indicano come le cellule resistenti al cisplatino presentino una alterazione dell’omeostasi lipidica che induce un significativo accumulo intracellulare di lipidi; inoltre gli studi preliminari riguardanti il ruolo della glutammina indicano come la sopravvivenza delle cellule resistenti sia particolarmente dipendente dal metabolismo di questo aminoacido.
Da questo studio, e da precedenti osservazioni del nostro laboratorio, sono stati identificati diversi possibili target metabolici specifici delle cellule cisplatino-resistenti, sia a livello di vie metaboliche lipidiche sia a livello mitocondriale.
Questo lavoro si inserisce nel panorama di ricerca volto ad approfondire le specifiche dipendenze metaboliche di tumori cisplatino-resistenti. I risultati ottenuti potranno fornire nuovi target terapeutici sfruttabili al fine di superare la resistenza al cisplatino e migliorare l’efficacia dell’attuale trattamento chemioterapico
Antioxidant and anti-inflammatory activities of Cannabis Sativa in epithelial intestinal cell
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Clinical evidence of interaction between nutraceutical supplementation and platinum-based chemotherapy
No full textPlatinum agents, which include cisplatin, oxaliplatin and carboplatin, are chemotherapeutic drugs which represent the first-line treatment for different types of solid tumors, such as ovarian, head and neck, testicular, and bladder cancers. Their beneficial effect is limited by the onset of drug resistance and by severe toxicities, involving mainly ototoxicity, neurotoxicity and nephrotoxicity. Recent studies highlighted the supplementation of herbal products, vitamins and minerals with antioxidant properties to prevent and protect from side effects. In particular, the introduction of nutraceuticals associated with chemotherapy has improved the patients' quality of life. However, if from one side, complementary and alternative medicine ameliorates chemotherapeutics-induced toxicities, from the other side it is important to take into consideration the possible interference with drug metabolism. This review aims to consider the current literature focusing on clinical trials that report association between nutraceutical supplementation and platinum-based chemotherapy to prevent toxicities, highlighting both beneficial and side effects
Targeting glucose-6-phosphate dehydrogenase by 6-amino nicotinamide in combination with liposomal cisplatin as a strategy to sensitize ovarian resistant cancer cells
No full textCalu-3 cells as in vitro model of bronchial epithelium for pharmacological studies of natural compounds
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