Cisplatin liposome and 6-amino nicotinamide combination to overcome drug resistance in ovarian cancer cells

Ovarian cancer is an aggressive and lethal cancer usually treated by cytoreductive surgery followed by chemotherapy. Unfortunately, after an initial response, many patients relapse owing mainly to the development of resistance against the standard chemotherapy regime, carboplatin/paclitaxel, which is also affected by heavy side effects. In view to addressing such issues here, an association of liposomal cisplatin with 6-amino nicotinamide is investigated. It is known that resistant cells increase their demand for glucose, which is partially redirected toward the pentose phosphate pathway (PPP). Interestingly, we have found that also a cisplatin-resistant subclone of the ovarian cancer cells IGROV1 switch their metabolism toward the glycolytic pathway and rely on PPP to elude cisplatin cytotoxicity. The drug 6-amino nicotinamide, an inhibitor of the enzyme glucose-6-phosphate dehydrogenase (the rate-limiting step of the PPP) can restore the sensitivity of resistant cells to cisplatin. Then, to reduce the toxicity of cisplatin and prolong its action, a lyophilized stealth liposomal formulation of cisplatin was developed. The combination treatment of liposomal cisplatin and 6-amino nicotinamide showed promising cytotoxic activities in drug-resistant cells and a prolonged pharmacokinetics in rats, thus opening the way for a new therapeutic option against ovarian cancer

Plumbagin Induces Cell Cycle Arrest and Apoptosis in A431 Cisplatin-Resistant Cancer Cells

The onset of drug resistance represents the leading cause of chemotherapy failure in clinics. In the last decades, natural compounds have emerged as possible anticancer strategies used either alone or in combination with chemotherapeutic drugs, in order to overcome drug resistance. In fact, plant-derived therapies present biological activity and minimal side effects showing promising roles in the resensitization of resistant cancer cells. This work was aimed at investigating the anticancer potential of the natural naphthoquinone plumbagin in a cisplatin-resistant cancer cell line. The results indicated cytotoxic and pro-oxidant activity of plumbagin in both sensitive (A431wt) and cisplatin-resistant (A431/Pt) human cervix squamous carcinoma cell lines. Moreover, plumbagin treatment induced cell cycle arrest and apoptosis in A431/Pt cells and the inhibition of retinoblastoma complex, suggesting a stronger activity on the cisplatin-resistant cell line. Taken together, the data indicate appreciable in vitro anticancer activity of plumbagin, suggesting that this natural compound could become a tool to overcome cisplatin resistance. Although further studies are necessary, this work underlines a promising role of plumbagin in the resensitization of cisplatin-resistant cancer cells

Protective effects of \u3c8 taraxasterol 3-O-myristate and arnidiol 3-O-myristate isolated from Calendula officinalis on epithelial intestinal barrier

The triterpene esters psi taraxasterol-3-O-myristate (1) and amidio1-3-O-myristate (2) were tested for their ability to protect epithelial intestinal barrier in an in vitro model. Their effects on ROS production and on trans-epithelial resistance were investigated on CaCo-2 cell monolayers both in basal and stress -induced conditions. Both compounds were able to modulate the stress damage induced by H2O2 and INF gamma + TNF alpha, showing a potential use as model compounds for the study of new therapeutic agents for intestinal inflammations

Effects of Boswellia Serrata Roxb. and Curcuma longa L. in an In Vitro Intestinal Inflammation Model Using Immune Cells and Caco-2

Inflammatory bowel diseases, which consist of chronic inflammatory conditions of the colon and the small intestine, are considered a global disease of our modern society. Recently, the interest toward the use of herbal therapies for the management of inflammatory bowel diseases has increased because of their effectiveness and favourable safety profile, compared to conventional drugs. Boswellia serrata Roxb. and Curcuma longa L. are amongst the most promising herbal drugs, however, their clinical use in inflammatory bowel diseases is limited and little is known on their mechanism of action. The aim of this work was to investigate the effects of two phytochemically characterized extracts of B. serrata and C. longa in an in vitro model of intestinal inflammation. Their impact on cytokine release and reactive oxygen species production, as well as the maintenance of the intestinal barrier function and on intestinal mucosa immune cells infiltration, has been evaluated. The extracts showed a good protective effect on the intestinal epithelium at 1 µg/mL, with TEER values increasing by approximately 1.5 fold, compared to LPS-stimulated cells. C. longa showed an anti-inflammatory mechanism of action, reducing IL-8, TNF-α and IL-6 production by approximately 30%, 25% and 40%, respectively, compared to the inflammatory stimuli. B. serrata action was linked to its antioxidant effect, with ROS production being reduced by 25%, compared to H₂O₂-stimulated Caco-2 cells. C. longa and B. serrata resulted to be promising agents for the management of inflammatory bowel diseases by modulating in vitro parameters which have been identified in the clinical conditions

Cisplatin resistance can be curtailed by blunting Bnip3-mediated mitochondrial autophagy

Cisplatin (CDDP) is commonly used to treat a multitude of tumors including sarcomas, ovarian and cervical cancers. Despite recent investigations allowed to improve chemotherapy effectiveness, the molecular mechanisms underlying the development of CDDP resistance remain a major goal in cancer research. Here, we show that mitochondrial morphology and autophagy are altered in different CDDP resistant cancer cell lines. In CDDP resistant osteosarcoma and ovarian carcinoma, mitochondria are fragmented and closely juxtaposed to the endoplasmic reticulum; rates of mitophagy are also increased. Specifically, levels of the mitophagy receptor BNIP3 are higher both in resistant cells and in ovarian cancer patient samples resistant to platinum-based treatments. Genetic BNIP3 silencing or pharmacological inhibition of autophagosome formation re-sensitizes these cells to CDDP. Our study identifies inhibition of BNIP3-driven mitophagy as a potential therapeutic strategy to counteract CDDP resistance in ovarian carcinoma and osteosarcoma

The SARS-CoV-2 spike protein binds and modulates estrogen receptors

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein binds angiotensin-converting enzyme 2 as its primary infection mechanism. Interactions between S and endogenous proteins occur after infection but are not well understood. We profiled binding of S against >9000 human proteins and found an interaction between S and human estrogen receptor alpha (ER alpha). Using bioinformatics, supercomputing, and experimental assays, we identified a highly conserved and functional nuclear receptor coregulator (NRC) LXD-like motif on the S2 sub-unit. In cultured cells, S DNA transfection increased ER alpha cytoplasmic accumulation, and S treatment induced ER-dependent biological effects. Non-invasive imaging in SARS-CoV-2-infected hamsters localized lung pathology with increased ER alpha lung levels. Postmortem lung experiments from infected hamsters and humans confirmed an increase in cytoplasmic ER alpha and its colocalization with S in alveolar macrophages. These findings describe the discovery of a S-ER alpha interaction, imply a role for S as an NRC, and advance knowledge of SARS-CoV-2 biology and coronavirus disease 2019 pathology

Mitochondrial Involvement in Cisplatin Resistance

Cisplatin is one of the worldwide anticancer drugs and, despite its toxicity and frequent recurrence of resistance phenomena, it still remains the only therapeutic option for several tumors. Circumventing cisplatin resistance remains, therefore, a major goal for clinical therapy and represents a challenge for scientific research. Recent studies have brought to light the fundamental role of mitochondria in onset, progression, and metastasis of cancer, as well as its importance in the resistance to chemotherapy. The aim of this review is to give an overview of the current knowledge about the implication of mitochondria in cisplatin resistance and on the recent development in this research field. Recent studies have highlighted the role of mitochondrial DNA alterations in onset of resistance phenomena, being related both to redox balance alterations and to signal crosstalk with the nucleus, allowing a rewiring of cell metabolism. Moreover, an important role of the mitochondrial dynamics in the adaptation mechanism of cancer cells to challenging environment has been revealed. Giving bioenergetic plasticity to tumor cells, mitochondria allow cells to evade death pathways in stressful conditions, including chemotherapy. So far, even if the central role of mitochondria is recognized, little is known about the specific mechanisms implicated in the resistance. Nevertheless, mitochondria appear to be promising pharmacological targets for overcoming cisplatin resistance, but further studies are necessary

New insights in cisplatin-resistance: role of metabolic reprogramming in cancer cells

Cisplatin 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