Search Results (684)

Background: Undifferentiated pleomorphic sarcoma (UPS) is a highly malignant mesenchymal tumor that ranks as one of the most common types of soft tissue sarcoma. Even though chemotherapy increases the 5-year survival rate in UPS, high tumor heterogeneity frequently leads to chemotherapy resistance and consequently to recurrences. In this study, we characterized the cell composition and the transcriptional profile of UPS with resistance to chemotherapy at the single cell resolution. Methods: A 58-year-old woman was diagnosed with a 13.6 × 9.3 × 6.0 cm multi-nodular tumor with heterogeneous cysto-solid structure at the level of the distal metadiaphysis of the left thigh during magnetic resonance tomography. Morphological and immunohistochemical analysis led to the diagnosis of high-grade (G3) UPS. Neoadjuvant chemotherapy, surgery (negative resection margins), and adjuvant chemotherapy were conducted, but tumor recurrence developed. The UPS sample was used to perform single-cell RNA sequencing by chromium-fixed RNA profiling. Results: Four subpopulations of tumor cells and seven subpopulations of tumor microenvironment (TME) have been identified in UPS. The expression of chemoresistance genes has been detected, including KLF4 (doxorubicin and ifosfamide), ULK1, LUM, GPNMB, and CAVIN1 (doxorubicin), and AHNAK2 (gemcitabine) in tumor cells and ETS1 (gemcitabine) in TME. Conclusions: This study provides the first description of the single-cell transcriptome of UPS with resistance to two lines of chemotherapy, showcasing the gene expression in subpopulations of tumor cells and TME, which may be potential markers for personalized cancer therapy. Full article

There is a growing prevalence of pancreatic cancer, accompanied by accelerated disease progression and diminished survival rates. Radical resection with clear margins remains the sole viable option for achieving a long-term cure in patients. In cases of advanced, unresectable, and metastatic disease, chemotherapy based on leucovorin, 5-fluorouracil, irinotecan, oxaliplatin, gemcitabine, or nab-paclitaxel represents the cornerstone of the treatment. Considering the limited treatment options available following initial therapy, the strategy of repurposing commonly prescribed drugs such as antihypertensives into anti-cancer therapies in palliative treatment represents a promising avenue for enhancing survival in patients with pancreatic ductal adenocarcinoma. The repurposing of existing drugs is typically a more cost-effective and expedient strategy than the development of new ones. The potential for antihypertensive drugs to be employed as adjunctive therapies could facilitate a more comprehensive treatment approach by targeting multiple pathways involved in cancer progression and acquired resistance to treatment. Antihypertensive medications, particularly those belonging to the pharmacological classes of angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and calcium channel blockers, are commonly prescribed and have well-established safety profiles, particularly among patients with pancreatic cancer who are affected by multiple comorbidities. Therefore, we emphasize the preclinical and clinical evidence supporting the use of antihypertensive agents in the treatment of pancreatic cancer, emphasizing their beneficial chemosensitizing effects. Full article

Background: Pancreatic ductal adenocarcinoma acquired resistance to chemotherapy poses a major limitation to patient survival. Despite understanding some biological mechanisms of chemoresistance, much about those mechanisms remains to be uncovered. Mechanobiology, which studies the physical properties of cells, holds promise as a potential target for addressing the challenges of chemoresistance in PDAC. Therefore, we, here in an initial step, assessed the altered mechanobiology of PDAC cells with acquired chemoresistance to gemcitabine and paclitaxel. Methods: Five PDAC cell lines and six stably resistant subclones were assessed for force generation on elastic micropillar arrays. Those measurements of mechanical phenotype were complemented by single-cell motility and invasion in 3D collagen-based matrix assays. Further, the nuclear translocation of Yes-associated protein (YAP), as a measure of active mechanical status, was compared, and biomarkers of the epithelial-to-mesenchymal transition (EMT) were evaluated using RT-qPCR. Results: The PDAC cells with acquired chemoresistance exert higher traction forces than their parental/wild-type (WT) cells. In 2D, single-cell motility was altered for all the chemoresistant cells, with a cell-type specific pattern. In 3D, the spheroids of the chemoresistant PDAC cells were able to invade the matrix and remodel collagen more than their WT clones. However, YAP nuclear translocation and EMT were not significantly altered in relation to changes in other physical parameters. Conclusions: This is the first study to investigate and report on the altered mechanobiological features of PDAC cells that have acquired chemoresistance. A better understanding of mechanical features could help in identifying future targets to overcome chemoresistance in PDAC. Full article

Desmoplasia is a hallmark feature of pancreatic ductal adenocarcinoma (PDAC) that contributes significantly to treatment resistance. Approaches to enhance drug delivery into fibrotic PDAC tumors continue to be an important unmet need. In this study, we have engineered a tumor-colonizing E. coli-based agent that expresses both collagenase and hyaluronidase as a strategy to reduce desmoplasia and enhance the intratumoral perfusion of anticancer agents. Overall, we observed that the tandem expression of both these enzymes by tumor-colonizing E. coli resulted in the reduced presence of intratumoral collagen and hyaluronan, which likely contributed to the enhanced chemotherapeutic efficacy observed when used in combination. These results highlight the importance of combination treatments involving the depletion of desmoplastic components in PDAC before or during treatment. Full article

Dicer, a cytoplasmic type III RNase, is essential for the maturation of microRNAs (miRNAs) and is implicated in cancer progression and chemoresistance. Our previous research demonstrated that phosphorylation of Dicer at S1016 alters miRNA maturation and glutamine metabolism, contributing to gemcitabine (GEM) resistance in pancreatic ductal adenocarcinoma (PDAC). In this study, we focused on the role of Dicer phosphorylation at S1728/S1852 in GEM-resistant PDAC cells. Using shRNA to knock down Dicer in GEM-resistant PANC-1 (PANC-1 GR) cells, we examined cell viability through MTT and clonogenic assays. We also expressed phosphomimetic Dicer 2E (S1728E/S1852E) and phosphomutant Dicer 2A (S1728A/S1852A) to evaluate their effects on GEM resistance and metabolism. Our results show that phosphorylation at S1728/S1852 promotes GEM resistance by reprogramming glutamine metabolism. Specifically, phosphomimetic Dicer 2E increased intracellular glutamine, driving pyrimidine synthesis and raising dCTP levels, which compete with gemcitabine’s metabolites. This metabolic shift enhanced drug resistance. In contrast, phosphomutant Dicer 2A reduced GEM resistance. These findings highlight the importance of Dicer phosphorylation in regulating metabolism and drug sensitivity, offering insights into potential therapeutic strategies for overcoming GEM resistance in pancreatic cancer. Full article

Background: The interaction between cancer cells and cancer-associated fibroblasts (CAFs) is a key determinant of the rapid progression, high invasiveness, and chemoresistance of aggressive desmoplastic cancers such as pancreatic ductal adenocarcinoma (PDAC). Tumor cells are known to reprogram fibroblasts into CAFs by secreting transforming growth factor beta (TGF-β), amongst other cytokines. In turn, CAFs produce soluble factors that promote tumor-cell invasiveness and chemoresistance, including TGF-β itself, which has a major role in myofibroblastic CAFs. Such a high level of complexity has hampered progress toward a clear view of the TGFβ signaling loop between stromal fibroblasts and PDAC cells. Methods: Here, we tackled this issue by using co-culture settings that allow paracrine signaling alone (transwell systems) or paracrine and contact-mediated signaling (3D spheroids). Results: We found that TGF-β is critically involved in the activation of normal human fibroblasts into alpha-smooth muscle actin (α-SMA)-positive CAFs. The TGF-β released by CAFs accounted for the enhanced proliferation and resistance to gemcitabine of PDAC cells. This was accompanied by a partial epithelial-to-mesenchymal transition in PDAC cells, with no increase in their migratory abilities. Nevertheless, 3D heterospheroids comprising PDAC cells and fibroblasts allowed monitoring the pro-invasive effects of CAFs on cancer cells, possibly due to combined paracrine and physical contact-mediated signals. Conclusions: We conclude that TGF-β is only one of the players that mediates the communication between PDAC cells and fibroblasts and controls the acquisition of aggressive phenotypes. Hence, these advanced in vitro models may be exploited to further investigate these events and to design innovative anti-PDAC therapies. Full article

Lung cancer (LC) is the leading cause of cancer death worldwide. LC can be classified into small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC), with the last subtype accounting for approximately 85% of all diagnosed lung cancer cases. Despite the existence of different types of treatment for this disease, the development of resistance to therapies and tumor recurrence in patients have maintained the need to find new therapeutic options to combat this pathology, where natural products stand out as an attractive source for this search. Nordihydroguaiaretic acid (NDGA) is the main metabolite extracted from the Larrea tridentata plant and has been shown to have different biological activities, including anticancer activity. In this study, H1975, H1299, and A549 cell lines were treated with NDGA, and its effect on cell viability, proliferation, and metabolism was evaluated using a resazurin reduction assay, incorporation of BrdU, and ki-67 gene expression and glucose uptake measurement, respectively. In addition, the combination of NDGA with clinical chemotherapeutics was investigated using an MTT assay and Combenefit software (version 2.02). The results showed that NDGA decreases the viability and proliferation of NSCLC cells and differentially modulates the expression of genes associated with different metabolic pathways. For example, the LDH gene expression decreased in all cell lines analyzed. However, GLUT3 gene expression increased after 24 h of treatment. The expression of the HIF-1 gene decreased early in the H1299 and A549 cell lines. In addition, the combination of NDGA with three chemotherapeutics (carboplatin, gemcitabine, and taxol) shows a synergic pattern in the decrease of cell viability on the H1299 cell line. In summary, this research provides new evidence about the role of NDGA in lung cancer. Interestingly, using NDGA to enhance the anticancer activity of antitumoral drugs could be an improved therapeutic resource against lung cancer. Full article

Introduction: Although panniculitis-like T cell lymphoma (SPTCL) and hemophagocytic syndrome (HSP) have been described as complications following immunosuppressive treatments, there are no reported cases of concomitant SPTCL/HSP and multiple sclerosis (MS). Materials and Methods: We describe the case of a patient affected by an aggressive phenotype of relapsing remitting MS, characterized by consecutive severe relapses with no complete remission. He developed panniculitis-like T cell lymphoma (SPTCL) and hemophagocytic syndrome (HSP) after receiving multiple immunosuppressive treatments in sequence. Despite the aggressive nature of these complications, the patient responded well to a combination of Gemcitabine and Cisplatin. Discussion and Conclusions: With this case, we suggest that physicians always consider blood diseases as possible MS therapy complications, especially in the sequencing setting, and also consider uncommon treatments in those with autoimmune predispositions. Full article

Arsenic trioxide (ATO) has been shown to inhibit pancreatic cancer (PC) cell growth in vitro and to promote the inhibitory effects of gemcitabine (Gem) on PC in vivo. However, the high toxicity of ATO associated with the required high doses and indiscriminate targeting has limited its clinical application. This study aimed to determine whether coupling arsenic to a tumor homing peptide would increase the inhibitory potency against PC cells. The effects of this peptide-linked arsenic compound (PhAs-LHP), the analogous non-targeting arsenic compound (phenylarsine oxide, PAO), and marketed ATO on PC growth were tested in vitro and in a mouse model. The data demonstrated that PhAs-LHP inhibited PC cell growth in vitro more potently, with IC₅₀ values 10 times lower than ATO. Like ATO, PhAs-LHP induced cell death and cell cycle arrest. This cytotoxic effect of PhAs-LHP was mediated via a macropinocytosis-linked uptake pathway as amiloride (a macropinocytosis inhibitor) reduced the inhibitory effect of PhAs-LHP. More importantly, PhAs-LHP inhibited PC growth in mice and enhanced the inhibitory effect of Gem on PC growth at 2 times lower molar concentration than PAO. These results indicate that PhAs-LHP inhibited PC more potently than ATO/PAO and suggest a potential clinical use for the combination of Gem with the peptide-linked arsenic compound for the treatment of pancreatic cancer. Full article

Cancer and infectious diseases are two of the world’s major public health problems. Gemcitabine (GEM) is an effective chemotherapeutic agent against several types of cancer. In this study, we developed macrocapsules incorporating GEM into a chitosan matrix blended with magnetite and zeolite by ionic gelation. Physicochemical characterization was performed using HRTEM-ED, XRD, FESEM–EDS, FT-IR, TGA, encapsulation efficiency (%E.E.), and release profiles at pHs 7.4 and 5.0. Cell viability tests against A549 and H1299 cell lines, and microbiological properties against staphylococcal strains were performed. Our results revealed the successful production of hemispherical capsules with an average diameter of 1.22 mm, a rough surface, and characteristic FT-IR material interaction bands. The macrocapsules showed a high GEM encapsulation efficiency of over 86% and controlled release over 24 h. Cell viability assays revealed that similar cytotoxic effects to free GEM were achieved with a 45-fold lower GEM concentration, suggesting reduced dosing requirements and potentially fewer side effects. Additionally, the macrocapsules demonstrated potent antimicrobial activity, reducing Staphylococcus epidermidis growth by over 90%. These results highlight the macrocapsules dual role as a chemotherapeutic and antimicrobial agent, offering a promising strategy for treating lung cancer in patients at risk of infectious diseases or who are immunosuppressed. Full article

The combination of paclitaxel (PTX) with other chemotherapy drugs (e.g., gemcitabine, GEM) or genetic drugs (e.g., siRNA) has been shown to enhance therapeutic efficacy against tumors, reduce individual drug dosages, and prevent drug resistance associated with single-drug treatments. However, the varying solubility of chemotherapy drugs and genetic drugs presents a challenge in co-delivering these agents. In this study, nanoparticles loaded with PTX were prepared using the biodegradable polymer material poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBHHx). These nanoparticles were surface-modified with target proteins (Affibody molecules) and RALA cationic peptides to create core-shell structured microspheres with targeted and cationic functionalization. A three-drug co-delivery system (PTX@PHBHHx-ARP/siRNA_GEM) were developed by electrostatically adsorbing siRNA chains containing GEM onto the microsphere surface. The encapsulation efficiency of PTX in the nanodrug was found to be 81.02%, with a drug loading of 5.09%. The chemogene adsorption capacity of siRNA_GEM was determined to be 97.3%. Morphological and size characterization of the nanodrug revealed that PTX@PHBHHx-ARP/siRNA_GEM is a rough-surfaced microsphere with a particle size of approximately 150 nm. This nanodrug exhibited targeting capabilities toward BT474 cells with HER2 overexpression while showing limited targeting ability toward MCF-7 cells with low HER2 expression. Results from the MTT assay demonstrated that PTX@PHBHHx-ARP/siRNA_GEM exhibits high cytotoxicity and excellent combination therapy efficacy compared to physically mixed PTX/GEM/siRNA. Additionally, Western blot analysis confirmed that siRNA-mediated reduction of Bcl-2 expression significantly enhanced cell apoptosis mediated by PTX or GEM in tumor cells, thereby increasing cell sensitivity to PTX and GEM. This study presents a novel targeted nanosystem for the co-delivery of chemotherapy drugs and genetic drugs. Full article

Chronic venous disease (CVD) is a prevalent condition in adults, significantly affecting the global elderly population, with a higher incidence in women than in men. The modulation of gene expression through microRNA (miRNA) partly regulated the development of cardiovascular disease (CVD). Previous research identified a functional analysis of seven genes (CDS2, HDAC5, PPP6R2, PRRC2B, TBC1D22A, WNK1, and PABPC3) as targets of miRNAs related to CVD. In this context, miRNAs emerge as essential candidates for CVD diagnosis, representing novel molecular and biological knowledge. This work aims to identify, by network analysis, the miRNAs involved in CVD as potential biomarkers, either by interacting with small molecules such as toxins and pollutants or by searching for new drugs. Our study shows an updated landscape of the signaling pathways involving miRNAs in CVD pathology. This latest research includes data found through experimental tests and uses predictions to propose both miRNAs and genes as potential biomarkers to develop diagnostic and therapeutic methods for the early detection of CVD in the clinical setting. In addition, our pharmacological network analysis has, for the first time, shown how to use these potential biomarkers to find small molecules that may regulate them. Between the small molecules in this research, toxins, pollutants, and drugs showed outstanding interactions with these miRNAs. One of them, hesperidin, a widely prescribed drug for treating CVD and modulating the gene expression associated with CVD, was used as a reference for searching for new molecules that may interact with miRNAs involved in CVD. Among the drugs that exhibit the same miRNA expression profile as hesperidin, potential candidates include desoximetasone, curcumin, flurandrenolide, trifluridine, fludrocortisone, diflorasone, gemcitabine, floxuridine, and reversine. Further investigation of these drugs is essential to improve the treatment of cardiovascular disease. Additionally, supporting the clinical use of miRNAs as biomarkers for diagnosing and predicting CVD is crucial. Full article

Ritonavir is a protease inhibitor initially developed for HIV treatment that is now used as a pharmacokinetic booster for other antiretrovirals due to it being a cytochrome P450 3A4 enzyme and P-glycoprotein inhibitor. Consequently, ritonavir is of special interest for repurposing in other diseases. It had an important role in battling the COVID-19 pandemic as a part of the developed drug Paxlovid^® in association with nirmatrelvir and has shown effects in hepatitis and other pathogenic diseases. Ritonavir has also shown promising results in overcoming drug resistance and enhancing the efficacy of existing chemotherapeutic agents in oncology. Evidence of cancer repurposing potential was demonstrated in cancers such as ovarian, prostate, lung, myeloma, breast, and bladder cancer, with several mechanisms of action presented. In vitro studies indicate that ritonavir alone can inhibit key pathways involved in cancer cell survival and proliferation, causing apoptosis, cell cycle arrest, endoplasmic reticulum stress, and metabolic stress due to the inhibition of molecules like heat shock protein 90 and cyclin-dependent kinases. Ritonavir also causes resistant cells to become sensitized to anticancer drugs like gemcitabine or docetaxel. These findings indicate that repurposing ritonavir, either on its own or in combination with other medications, could be a promising approach for treating various diseases. This is particularly relevant in cancer therapy, where ritonavir repurposing is the central focus of this review. Full article

A 54-year-old female patient diagnosed with Stage IIIb squamous cell carcinoma (cT2aN3M0) initially received chemoradiotherapy. Two years after initial treatment, cancer relapse led to the administration of nivolumab, which was halted due to the development of drug-induced pneumonitis. Subsequent management with prednisolone and eight different cytotoxic agents failed to prevent metastasis to the cervical lymph nodes. The tumor’s programmed death-ligand 1 (PD-L1) expression rate was recorded at 10%. Four years after her diagnosis, the patient received a ninth-line therapy combining cisplatin, gemcitabine, and necitumumab, followed by palliative neck radiation due to increasing lymph node size. Remarkable tumor regression occurred three months after introducing atezolizumab as the tenth-line treatment, suggesting that previous treatments, particularly radiotherapy and cisplatin, might have enhanced PD-L1 expression, aligning with the existing literature. This case highlights the urgent need for further research to elucidate the intricate interplay between treatment history and PD-L1 expression in squamous cell carcinoma, emphasizing the importance of accumulating case studies to inform therapeutic strategies. Full article

The primary treatment for operable pancreatic cancer (PC) involves surgery followed by adjuvant therapy. Nevertheless, perioperative or neoadjuvant chemotherapy (CT) may be used to mitigate the likelihood of recurrence and mortality. This network meta-analysis (NMA) assesses the comparative efficacy of various treatment approaches for resectable PC. A thorough search was carried out on January 31, 2023, encompassing PubMed/MEDLINE, Cochrane Library, and Embase databases. We incorporated randomized clinical trials (RCTs) that compared surgical interventions with or without (neo)adjuvant or perioperative therapies for operable PC. We conducted a fixed-effects Bayesian NMA. We presented the effect sizes in terms of hazard ratios (HRs) for overall survival (OS) along with 95% credible intervals (95% CrIs). The treatment was deemed statistically superior when the 95% credible interval (CrI) did not encompass a null value (hazard ratio < 1). Treatment rankings were established based on the surface under the cumulative ranking curve (SUCRA). A total of 24 studies were incorporated, comparing 21 treatments with surgery in isolation. Eleven treatments showed superior efficacy compared to surgery alone, with HRs ranging from 0.38 for perioperative treatments to 0.73 for adjuvant 5-fluorouracil. After the exclusion of studies conducted in Asia, it was found that the perioperative regimen of gemcitabine combined with nab-paclitaxel was the most effective regimen (SUCRA, p = 0.99). The findings endorse the utilization of perioperative CT, especially multi-agent CT, as the favored intervention for operable PC in Western nations. Full article