Medical Oncology最新文献

Cancer cells show abnormal nucleotide metabolism and prefer the de novo synthesis pathway. As the key enzymes, Carbamoyl-phosphate synthetase 2, Aspartate transcarbamoylase, and Dihydroorotase (CAD) is overactivated in cancer and promotes pyrimidine de novo synthesis, supplying cancer cells with DNA and RNA biosynthesis precursors. Therefore, the development of drugs targeting CAD might inhibit cancer progression and transformation. Icaritin (ICT) is an isoprenoid flavonoid derivative with a wide range of anticancer activities, however, the mechanism of ICT in regulating pyrimidine biosynthesis in cancer remains unclear. MicroRNAs are involved in carcinogenesis by regulating the expression of target genes, and ICT has been shown to regulate the expression of miRNAs leading to suppressing cancer progression. Using both human normal hepatocytes and liver cancer cells, we found that CAD expression was significantly elevated in cancer cells. Interestingly, although ICT treatment reduced CAD protein levels in liver cancer cells, it increased CAD transcriptional activity. Dual-luciferase reporter assays confirmed miR-18b-5p as a direct regulator of CAD. By transfecting miR-18b-5p mimics or inhibitors, we showed ICT upregulates miR-18b-5p to suppress CAD, inhibiting liver cancer cell proliferation, migration, and colony formation. Furthermore, in a human liver cancer xenograft mouse model, ICT treatment markedly reduced tumor growth and decreased Ki-67 expression, consistent with the in vitro results, CAD protein expression was downregulated, while its mRNA level was upregulated, further supporting a post-transcriptional regulatory mechanism. Overall, ICT plays an anti-liver cancer role by increasing miR-18b-5p at the post-transcriptional level to inhibit CAD expression, which may interfere with the de novo synthesis of pyrimidine and development of liver cancer.

AKR1Cs, as a reductase enzyme family, play a pro-carcinogenic role in various types of cancers, including hormone-related malignancies and non-hormonal tumors. However, there exists a notable scarcity of literature concerning AKR1Cs expression in pancreatic cancer and the subsequent impacts on its progression. Analyzing pancreatic cancer database information by employing advanced bioinformatics techniques to unravel AKR1Cs' intricate involvement in cancer malignancy, their correlation with clinical pathology, prognostic implications, as well as their responsiveness to conventional and immune-based therapies. Furthermore, the role of AKR1C1 in promoting the malignant progression of pancreatic cancer cell lines was validated using cell proliferation assays (EdU labeling and colony formation), and cell migration and invasion experiments including scratch wound healing and Transwell migration/invasion assays. AKR1Cs are not only significantly overexpressed in pancreatic cancer, but also closely associated with poor clinical grading, clinical chemoresistance and poor immune response in pancreatic cancer.Moreover, regulating the expression of AKR1C1 in pancreatic cancer cells will affect its proliferation, migration, invasion and the occurrence of epithelial-mesenchymal transformation (EMT). Our findings are expected to establish AKR1Cs, especially AKR1C1 as a promising therapeutic target for the clinical treatment of pancreatic cancer.

Glucocorticoids are cornerstone agents in oncology due to their potent anti-inflammatory, immunosuppressive, and antitumor properties. Glucocorticoids exert direct cytotoxic effects in hematologic malignancies such as lymphomas, acute lymphoblastic leukemia, and multiple myeloma by inducing apoptosis. Their role is primarily supportive in solid tumors, although glucocorticoid receptor signaling may influence tumor progression in cancers like breast and prostate. They are routinely employed to reduce cerebral edema, manage chemotherapy-induced nausea and vomiting, relieve spinal cord compression, and prevent hypersensitivity reactions to agents such as taxanes and monoclonal antibodies. In prostate cancer, they aid in managing adrenal suppression linked to androgen deprivation therapy. However, routine premedication with glucocorticoids before immunotherapy may impair treatment efficacy and should be avoided unless managing immune-related adverse events. Long-term use is associated with significant toxicities, including osteoporosis, metabolic complications, and increased susceptibility to infections. Judicious use-employing the lowest effective dose for the shortest necessary duration-is crucial to strike a balance between therapeutic benefit and harm. Despite their risks, glucocorticoids remain indispensable in oncology, highlighting the need for personalized and evidence-guided approaches to their use. This narrative review outlines their mechanisms, clinical applications, associated risks, and evolving considerations in cancer care.

This review provides a summary of recent evidence on vitamin D and osteosarcoma, aiming to elucidate the molecular mechanisms of vitamin D in osteosarcoma and explore its potential role in patient management. Osteosarcoma, a malignant bone neoplasm, is characterized by its aggressive nature, poor prognosis, and metastatic potential, often spreading to the lungs. Its clinical severity highlights the need for early detection, prompt intervention, and comprehensive treatment strategies to improve outcomes and quality of life for individuals affected by it. Circulating 25-hydroxyvitamin D [25(OH)D] is quantified as a measure of vitamin D status. Vitamin D status is utilized as a clinical biomarker to identify vitamin D deficiency. The role of vitamin D in bone health and development is well known, specifically its regulation of calcium-phosphate homeostasis. Furthermore, recent findings identified vitamin D's role in carcinogenesis by regulating cancer cell differentiation, proliferation, apoptosis, and metastatic potential. The involvement of vitamin D-binding protein (VDBP) and its polymorphisms in regulating vitamin D bioavailability has also been recognized. However, these findings are primarily in major cancers such as breast cancer, lung cancer, and colorectal cancer. Evidence pertaining to the fundamental role of bone cancer, in particular osteosarcoma, and vitamin D remains scarce. Nevertheless, the limited evidence showed that maintaining circulating 25(OH)D in osteosarcoma patients is associated with a higher survival rate. Meanwhile, vitamin D supplementation as an adjuvant could potentially increase survival rates and quality of life.

Breast cancer is the most commonly diagnosed malignancy among women worldwide. Triple-negative breast cancer (TNBC), a particularly aggressive subtype, is unresponsive to endocrine and targeted therapies. It is characterized by high rates of invasion and recurrence, a poor prognosis, and limited treatment options. Resveratrol, a natural polyphenolic compound, possesses well-documented anticancer properties. Given the differential sensitivity of the MDA-MB-231 (TNBC) and MCF-7 (luminal) cell lines to resveratrol, we treated these cells with resveratrol and performed RNA sequencing followed by RT-qPCR validation. Our analysis revealed significantly elevated expression of ECSCR (Endothelial Cell Surface Expressed Chemotaxis and Apoptosis Regulator) in resveratrol-treated MDA-MB-231 cells compared to controls, whereas no significant change was observed in MCF-7 cells. Although the role of ECSCR in breast cancer remains poorly characterized, we investigated its functional significance by establishing lentiviral-mediated ECSCR overexpression in breast cancer cells. In vitro, ECSCR overexpression suppressed cellular proliferation and migration while promoting apoptosis. Consistently, in vivo experiments demonstrated a reduced tumorigenic capacity of ECSCR-overexpressing cells. Collectively, our findings indicate that ECSCR exerts tumor-suppressive effects by inhibiting proliferation and migration, inducing apoptosis, and suppressing tumorigenesis. Notably, the growth-inhibitory effects of resveratrol on TNBC may be mediated through the upregulation of ECSCR. These results identify ECSCR as a promising therapeutic target for breast cancer intervention strategies.

We formulated a micellar nanosystem for selective differentiation therapy of breast cancer stem cells (BCSCs). Hyaluronic acid (HA) coating was used to target CD44⁺ BCSCs, while codelivery of all-trans retinoic acid (ATRA) and histone deacetylase inhibitor (HDACi) was used to revert epigenetic silencing of the RARβ gene, sensitizing resistant tumor cells to treatment. Nanomicelles were formulated using the thin‑film hydration (TFH) method. The anti-cancer effects of nanoparticles (NPs) were evaluated on MDA-MB-231, MDA-MB-468, MCF-7 and MCF10-A cell lines with different stemness properties. The size of the NPs HA-PF127@ATRA, HA-PF127@SB and HA-PF127@ATRA@SB were determined to be 32.02 nm, 47.46 nm and 52.10 nm, respectively. HA-PF127@ATRA@SB NPs mitigated ATRA resistance in MDA-MB-231 cells, significantly inhibited migration, promoted maximum spheroid size reduction, and achieved lower IC₅₀ values compared to the blank drugs. Importantly, it reduced stemness markers ALDH1A1, CD24 and restored retinoic acid receptor beta (RARβ) gene expression in MDA-MB-231 cells, whereas opposite trends were observed in MDA‑MB‑468 and MCF‑7 cells. Finally, nanomicell therapy favored the induction of late apoptosis in MDA-MB-231 cells, while most of the MDA-MB-468 and MCF-7 cells were in the early apoptosis phase. The nanomicelles demonstrate favorable physicochemical characteristics, and elicit maximum and tumor-specific anti-cancer effects based on differentiation therapy upon BCSC-enriched tumors.

Lung cancer is among the most prevalent types of cancer globally and in Türkiye. Basically, lung cancer is divided into 2 different types, of which non-small cell lung cancer (NSCLC) accounts for about 85% of cases. With the elucidation of the mechanism of NSCLC, there is an urgent need to identify effective non-toxic drugs and new target biomarkers. Therefore, an immediate need exists to clarify the mechanism of NSCLC and identify effective, nontoxic drugs and novel target biomarkers. In this study, we aimed to determine intracellular lipid level changes caused by N-Oleoylethanolamine (NOE) and N-Oleoylethanolamine Solid Lipid Nanoparticle (NOESLN) formulations in test cell lines determined by mass spectrometry LC-MS/MS lipidomic analysis. Lipid level changes induced by N-Oleoylethanolamine (NOE) and N-Oleoylethanolamine Solid Lipid Nanoparticle (NOESLN) formulations in test cell lines have been determined by mass spectrometry LC-MS/MS lipidomics analysis. The particle size of the nanoparticle formulation was found to be 100 times smaller compared to the NOE particle size. According to MTT results, IC₅₀ values obtained in Beas-2B and A549 cells treated with NOE were higher than those treated with NOESLN. It was found that an raise in intracellular ceramide concentrations due to ceramidase inhibition can cause apoptotic death of cancer cells in A549 cells induced by N-Oleoylethanolamine (NOE), a unique inhibitor of ceramidase enzymes, and a newly synthesized solid lipid nanoform. This study demonstrates that NOE-loaded solid lipid nanoparticles (NOESLN) significantly enhance cytotoxic effects in NSCLC cells by inducing intracellular ceramide accumulation, suggesting their potential as effective and novel therapeutic agents for lung cancer treatment.

Chordoma resection is challenging due to proximity to the brainstem or spinal cord, and chemotherapy offers limited efficacy. Combining surgery with radiotherapy, particularly using carbon ions (C-ions) for their higher biological effectiveness, improves local control and survival rates. To investigate cellular mechanisms, two human sacral chordoma cell lines were irradiated with varying C-ions doses. Growth, cell cycle, DNA damage response, and protein phosphorylation were analyzed using flow cytometry, protein, and gene expression profiling. The potential of combining treatment with the ALK/MET inhibitor crizotinib to enhance radiosensitivity was also evaluated. C-ions irradiation resulted in a slight dose-dependent decrease in proliferation, a clear G₂/M cell cycle arrest, and a significant activation of key regulators involved in DNA repair and damage response. The ALK/MET inhibitor crizotinib, considered a potential treatment for chordomas, reduced proliferation markers and modulated important genes related to DNA repair and cell cycle regulation, with CDC20 and FOXO4 being particularly significant. The phosphorylation of key regulators involved in DNA repair and damage prevention, as well as MAPKs activated by C-ions irradiation, was partially inhibited by the combination treatment with crizotinib. While crizotinib shows promise as a therapeutic agent for sacral chordomas, its capacity to enhance radiosensitivity appears limited.

Osteosarcoma (OS) is the most prevalent and aggressive primary malignant bone tumor, characterized by early metastasis and a poor prognosis, particularly in patients resistant to conventional multimodal therapies. As survival rates have plateaued, identifying novel therapeutic vulnerabilities is imperative. Ferroptosis, an iron-dependent form of regulated cell death driven by lethal lipid peroxidation, offers a distinct mechanism to overcome drug resistance in OS cells, which frequently exhibit metabolic dependency on iron. This review comprehensively elucidates the regulatory networks of ferroptosis in OS, with a specific focus on the System Xc^-/Glutathione Peroxidase 4 (GPX4) antioxidant axis and lipid metabolism. Beyond direct cytotoxicity, we critically examine the synergistic interplay between ferroptosis and the tumor immune microenvironment (TME). Ferroptosis induction triggers immunogenic cell death (ICD) and the release of damage-associated molecular patterns (DAMPs), which promotes dendritic cell maturation and enhances CD8⁺ T cell cytotoxicity. Furthermore, we discuss the mechanistic crosstalk by which ferroptosis remodels the immunosuppressive landscape, specifically affecting the polarization of tumor-associated macrophages (TAMs) and the stability of regulatory T cells (Tregs). Finally, the review addresses critical challenges for clinical translation, including tumor heterogeneity, safety concerns regarding off-target toxicity, and the urgent need for predictive biomarkers and advanced nanodelivery systems. This integrated perspective highlights ferroptosis-based combination immunotherapy as a promising frontier for personalized medicine in osteosarcoma.