Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie最新文献

Multiple Myeloma (MM) is a malignancy characterized by an uncontrolled proliferation of malignant plasma cells in the bone marrow and remains incurable. Treatment typically consists of a multimodal approach, with glucocorticoids (GC) as a crucial treatment pillar in the diagnosis and relapsed settings. Inevitably, patients become therapy resistant, but to which component of the treatment armamentarium the tumor becomes refractory is unknown. Here we used different in cellulo models of GC resistance to gain insights into the mechanistic processes of emerging GC therapy resistance. We found that differential baseline GC responsiveness of the cells is associated with significant differences in the timing and the degree to which myeloma cell lines become resistant to GCs. We corroborated that the chemokine receptor CCR1 is a shared biomarker between MM cell lines upon the emergence of GC resistance. Significant overlap exists between pathways enriched in partial GC-resistant MM.1S cells and those enriched in relapsed patients whose treatment included GCs. In addition, enrichment analyses demonstrated that alterations in metabolism and plasma cell expression signatures are associated with decreased sensitivity to GCs. From these analyses, we validated a biomarker, fatty acid synthase (FASN), and pinpointed its pivotal role in determining the GC sensitivity of myeloma cells, offering future opportunities for enforcement of GC sensitivity and re-sensitization.

Immunosuppression within the tumor microenvironment (TME) is a major obstacle for effective cancer immunotherapy. This is largely driven by myeloid suppressor cells, specifically Myeloid-Derived Suppressor Cells (MDSCs) and Tumor-Associated Macrophages (TAMs), which create an environment that inhibits the immune response. The presence of these cells is strongly correlated with poor patient outcomes and resistance to treatment, highlighting the need for new strategies to mitigate their effects. In this study, we investigated the therapeutic potential of Cannabidivarin (CBDV), a less-studied non-psychoactive cannabinoid, to reprogram these immunosuppressive cells. We found that CBDV directly targets myeloid suppressor cells, significantly impairing their immunosuppressive function both in vitro and in vivo. Mechanistically, CBDV reduces the key immunosuppressive markers inducible, Nitric Oxide Synthase (iNOS) and Arginase-1 (Arg-1) in murine MDSCs and promotes the differentiation of TAMs into M1-like macrophages. This shift in myeloid cell function leads to restored CD8 + T-cell proliferation and activation. Furthermore, our results show that CBDV treatment in tumor-bearing mice reduces tumor progression and improves the anti-tumor immune response within the TME. We also confirmed the clinical relevance of our findings, demonstrating that CBDV effectively reduces the immunosuppressive phenotype of human-derived myeloid cells. Altogether, these results establish CBDV as a new immunotherapeutic agent that directly neutralizes myeloid suppressor cells, thereby enhancing the immune system's response against cancer.

Pancreatic cancer, characterized by aggressive progression and poor prognosis, is a highly lethal malignancy, ranking among the leading causes of cancer-related deaths. Conventional treatments provide limited efficacy, presenting ongoing therapeutic challenges. Advances in immunotherapy have recognized natural killer (NK) cells as a promising avenue for cancer treatment owing to their ability to selectively target tumor cells. However, despite progress in ex vivo expansion techniques for NK-cell-based therapies, their cytotoxic efficacy can vary significantly depending on the functional variability among individual donors, which presents a notable limitation. In this study, we optimized a large-scale ex vivo expansion protocol for NK cells derived from the peripheral blood of patients. On implementation, the expanded NK cells demonstrated high purity and viability after 20 days of culture and had potent cytotoxic activity against pancreatic cancer cell lines and patient-derived cells (PDCs). Through transcriptomic analysis, the gene expression patterns and functional characteristics associated with differences in inhibition efficacy were investigated. Furthermore, the addition of cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), significantly enhanced antibody-dependent cellular cytotoxicity (ADCC), particularly in low-activity NK cells (NK-LA)-resulting in performance comparable to high-activity NK cells. In xenograft models using cell lines and PDCs, the combination therapy with cetuximab had enhanced tumor-suppressive effects of NK-LA compared to monotherapy. These findings highlight the therapeutic potential of integrating expanded patient-derived NK cells with cetuximab in the treatment of pancreatic cancer and underscore the requirement for clinical translation of this strategy.

Hypothesis-driven academic research identifies interventions with likely disease-specific effects. Yet, many candidate drugs fail upon further development, emphasizing the need for acquisition of more robust preclinical data. We demonstrate that planning and executing multicentre confirmatory preclinical studies in an academic setting by applying the quality standards of early phase clinical trials is feasible. Randomization, blinding, stratification by sex of and quality control measures were carried out successfully. The primary objective of our specific study - to confirm synergistic effects of BET bromodomain protein 4 (BRD4) and cyclin-dependent kinase 9 (CDK9) inhibitors against PAX3::FOXO1 (P3F)-positive rhabdomyosarcoma (RMS) - was not met. Post-hoc analyses support that single-agent BRD4 inhibition by JQ1 effectively reduced the growth and viability of P3F+ RMS cells ex vivo with adequate on-target activity as evidenced by reduced expression of P3F, MYCN, MYOG, and MYOD. The antiproliferative effects of JQ1 and vincristine were comparable, and there was trend towards reduced and delayed xenograft growth in JQ1-treated mice. Yet, in vivo assays were flawed by lower xenograft penetrance, variable xenograft latency, gastrointestinal toxicity, and inadequate on-target activity of drugs. We conclude that confirmatory preclinical trials allow for robust assessment of the efficacy of candidate interventions and reduce bias in academic research. The study platform established here provides a framework that may be of particular benefit for the development of new drugs for rare cancers.

Intracellular vitamin C (ascorbic acid, AA) uptake by sodium-dependent vitamin C transporter (SVCT2) is critical for high-dose AA therapy in colorectal cancer. However, hormetic responses to AA treatment are dependent on SVCT2 expression level. In low-SVCT2-expressing colorectal cancer cells, low intracellular AA enhances cancer cell proliferation. Therefore, SVCT2 induction is necessary to increase intracellular AA and thus improve its anti-cancer effects. We report the anticancer effects of combined tannic acid (TA) and AA treatment. In HCT-15 colorectal cancer cells with low SVCT2 expression, TA treatment upregulated SVCT2 expression, which increased the expression of transcription factor and its co-activator, resulting in high intracellular levels of AA (exerting a pro-oxidant effect), thus inducing reactive oxygen species (ROS) generation and increasing the percentage of apoptosis cells. Expression of apoptosis-related markers (Bcl-2, BAX, cleaved caspase-9, and cleaved caspase-3) was regulated after treatment with the combination. Furthermore, in a mouse xenograft model, TA induced SVCT2 expression in the tumor, and combined administration of TA with AA impaired tumor growth. These results suggest that TA suppresses the hormetic effects of AA by upregulating SVCT2 expression, which induces intracellular AA uptake and improves the potential for high-dose AA cancer therapy.

The critical pathogenic factors in the initiation and progression of diabetic nephropathy (DN) include hyperglycemia, oxidative stress, and inflammatory responses. Current therapeutic interventions for DN remain constrained by the intricate pathophysiological mechanisms that are involved in the dysregulations of multiple renal signaling pathways. Zinc (Zn) is an essential trace element that participates in diverse physiological processes, exhibits protective effects against oxidative stress-induced apoptosis, and plays a pivotal role in insulin biosynthesis and secretion. In our exploratory study, we aimed to develop targeted intervention in diabetes-associated DN pathogenesis by engineering metformin (MET)-encapsulated Zn-MOF nanoparticles conjugated with a renal-targeting protein (KTP-Zn-MOF/MET). In vivo imaging analyses revealed that renal accumulation of these multifunctional nanoparticles was significantly enhanced in BALB/c nude mice. The nephroprotective efficacy was preliminary explored in a rat model with renal injury induced using streptozotocin. Intravenous administration of KTP-Zn-MOF/MET ameliorated multiple DN-related pathological manifestations, including renal functional impairment, cellular apoptosis, lipid peroxidation, and oxidative stress. Our findings indicated that KTP-Zn-MOF/MET is a novel therapeutic strategy for precise renal targeting and multi-target intervention in DN management, with significant potential for clinical translation.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by mitochondrial dysfunction and chronic neuroinflammation. G-protein coupled receptor 40 (GPR40), primarily known for its role in metabolic regulation, has recently emerged as a modulator of neuronal activity and inflammatory signaling. In this study, we investigated the therapeutic potential of the selective GPR40 agonist TUG469 in both in vitro and in vivo models of AD. Treatment with amyloid-β oligomers (AβO) induced mitochondrial dysfunction in primary hippocampal neurons, as evidenced by disrupted mitochondrial morphology and membrane potential. TUG469 treatment restored mitochondrial integrity and membrane potential. Moreover, TUG469 significantly reduced AβO-induced reactive oxygen species (ROS) production. In the 5xFAD mouse model of AD, TUG469 administration improved cognitive performance and reduced Aβ plaque burden. Furthermore, TUG469 rescued impaired autophagy flux, as demonstrated by the regulation of LC3, p62, and LAMP1 expression, and attenuated neuroinflammatory responses by inhibiting NLRP3 inflammasome activation and modulating microglial reactivity. These findings indicate that GPR40 activation mitigates mitochondrial dysfunction and neuroinflammation, thereby alleviating AD-related pathology. Our results highlight the therapeutic potential of TUG469 as a multi-target modulator for AD.