In this study, we investigated the role of intracellular heme metabolism in regulating artesunate (ATS)-induced cytotoxicity to overcome therapeutic resistance in refractory cervical cancer. CD44v-positive CaSki cells exhibited resistance to both cisplatin and the ferroptosis inducer erastin, associated with elevated antioxidant capacity and impaired iron mobilization. Although ATS cytotoxicity was enhanced by exogenous heme, stimulation of endogenous heme biosynthesis with 5-aminolevulinic acid (ALA) increased intracellular heme levels and lipid peroxidation but failed to significantly enhance cell death. Targeting canonical antioxidant pathways, including reduction of glutathione (GSH) availability and inhibition of nuclear factor erythroid 2-related factor 2 (NRF2) or glutathione peroxidase 4 (GPX4), produced variable but incomplete sensitization to ATS in CaSki cells. In contrast, simultaneous stimulation of heme biosynthesis with ALA and inhibition of heme degradation with zinc protoporphyrin IX markedly increased intracellular labile heme levels and produced the strongest sensitization to ATS among the treatment conditions examined in CaSki cells. These findings support a role for intracellular heme availability in modulating the heme-dependent bioactivation and cytotoxic efficacy of ATS and suggest that the extent of labile heme accumulation may influence ATS responsiveness in CaSki cells. Collectively, our results suggest that coordinated modulation of heme biosynthesis and degradation can enhance ATS cytotoxicity and may provide a strategy for sensitizing therapy-resistant cervical cancer cells to ATS.

Localized nanopore electroporation improves intracellular delivery by concentrating membrane permeabilization at nanoscale cell-substrate interfaces. For nanopore-based substrates, the voltage fraction coupled to the cell-pore region contributes to local transmembrane potential (TMP), which determines the electroporation threshold. Here, we propose conical nanopores to enhance electric field focusing and facilitate electroporation. This effect was studied by varying the taper ratio of the nanopores from α = 1 to α = 4 through directional chemical etching to nanopore membranes. Lumped-parameter and finite-element simulations showed that this geometry doubled the estimated TMP under the same pulse condition. When performing electroporation to A549 cells, α = 4 structure achieved 62.1% propidium iodide (PI) delivery rate at a pulse voltage of 10 V, while ∼20 V was required to obtain a similar efficiency for α = 1. Besides, the PI delivery efficiency was greatly improved by increasing the taper ratio, from 55.3% to 80.4% for α = 4 at 15 V while maintaining 90.4% cell viability. In cisplatin electrochemotherapy, high-taper nanopores produced stronger growth inhibition and reduced 7-day outgrowth to over 34%. These results show that conical nanopore geometry improves voltage utilization and supports enhanced localized membrane permeabilization at lower applied voltages, and provide a viable strategy for practical applications such as drug delivery and transfection.

Gastric cancer (GC) is a leading cause of cancer death globally. Platinum‑based drugs, fluoropyrimidines, and docetaxel are standard for advanced disease, but intrinsic and acquired resistance limit the efficacy. This review summarizes chemoresistance mechanisms, focusing on the roles of various cell death pathways in GC chemoresistance, as well as the involvement of non-coding RNAs (ncRNAs) in modulating drug resistance through multiple regulatory mechanisms. We also describe models for establishing resistant cell lines (stepwise dose escalation, high-dose intermittent pulse selection, gene transfection).

Background: Neuroblastoma arising within an ovarian immature teratoma is exceptionally rare, with only three prior cases reported and only one in a pediatric patient. Patient: We describe a 16-year-old female with a large ovarian mass. Histopathologic evaluation showed an immature teratoma containing tissues from all three germ layers with immature neuroepithelium. A distinct primitive cell population was noted with findings supporting a diagnosis of poorly differentiated neuroblastoma arising within the teratoma. Extraovarian involvement was identified on peritoneal surfaces and in a regional lymph node. Tumor genetic analysis demonstrated 17q gain, consistent with higher-risk neuroblastoma. She initially received bleomycin, cisplatin, and etoposide per AGCT1531 before transitioning to intermediate-risk neuroblastoma therapy per ANBL0531. Post-treatment imaging showed no definitive recurrent disease, and she remains under surveillance. Conclusions: This case highlights a rare pediatric example of neuroblastoma arising within an ovarian immature teratoma with extraovarian involvement, offering clinically relevant diagnostic, pathologic, and therapeutic insights.

Breast cancer, especially triple-negative breast cancer (TNBC), remains a significant clinical challenge due to limited treatment options, chemoresistance, and the toxic side effects of standard chemotherapy. Cisplatin (Cis) is commonly used but faces limitations from resistance and dose-related toxicity. Berberine chloride (BRB), a natural alkaloid derived from Berberis vulgaris, shows promising anticancer effects. This study examined the antitumor activity and chemosensitizing potential of BRB combined with Cis. We initially examined the effects of BRB and Cis on murine 4T1 breast cancer cells. The results showed that both treatments inhibited cell viability, with IC50 values around 10 µM for BRB and 2.5 µM for Cis. Subsequently, we tested the synergistic effects using the Chou-Talalay method, which indicated that most of the 16 drug combinations exhibited synergy (CI < 1). The most effective combination (IC50/8) had a CI of 0.12 and a Fa of 0.8, greatly reducing cell viability compared to individual treatments. The combined BRB and Cis therapy was then tested in a BALB/c mouse xenograft model via intraperitoneal injection. Cis alone at 1 mg/kg weekly lowered tumor growth by 43.13% but caused notable systemic toxicity, including body weight loss and kidney and liver damage. BRB alone at 10 mg/kg every 2 days resulted in greater tumor suppression (61.17%) with fewer side effects. The BRB/Cis combo achieved the highest tumor growth inhibition (87.05%) and markedly reduced Cis-related toxicity, evidenced by weight recovery and improved kidney and liver biochemical markers. These results indicate that BRB enhances cisplatin's antitumor effects while decreasing systemic toxicity, positioning BRB as a promising chemosensitizer for TNBC therapy.

Ovarian cancer is the deadliest gynecologic malignancy globally, partly due to its nonspecific presentation resulting in late diagnosis. Early in treatment, platinum drugs such as cisplatin are the main chemotherapeutic choice. Unfortunately, with repeated exposure, cancer cells frequently develop platinum resistance through various genetic and epigenetic mechanisms, limiting the use of platinum agents as a treatment option. This poses a major problem in ovarian cancer treatment as it significantly reduces the efficacy of platinum drugs and ultimately worsens the prognosis of these patients. Recent advances in nanotechnology for platinum-resistant ovarian cancers have created new opportunities to overcome this barrier. In particular, nanoparticle-based technology can help resensitize cancer cells to platinum drugs, allowing these potent cytotoxic agents to become effective again. The authors reviewed 41 peer-reviewed articles on nanomedicine-based approaches for platinum resensitization identified through searches of the MEDLINE, Embase, Web of Science, and CENTRAL databases. Nanoparticle-based strategies may be promising options for overcoming platinum-resistant ovarian cancer, although more research is needed to establish safety and clinical feasibility.

Cisplatin (CDDP) chemosensitivity and severe toxicity severely limit its clinical application in muscle-invasive bladder cancer (MIBC) and non-muscle-invasive bladder cancer (NMIBC). To address these unmet clinical needs, we synthesized a series of melatonin-conjugated platinum(IV) prodrugs functionalized with isocyanate chains (compounds 5‒12), and identified MP-12C (compound 11) as the lead candidate with optimal potency and safety. In vitro assays showed that MP-12C exhibited far stronger antiproliferative activity than CDDP and mitomycin C in parental and CDDP-resistant bladder cancer cells. Multiple in vivo models, including subcutaneous xenograft, orthotopic, and chemically induced spontaneous bladder cancer models, were adopted. Both intravenous injection and intravesical instillation of MP-12C achieved robust tumor suppression while reducing toxicity compared to conventional chemotherapeutics. Mechanistically, MP-12C downregulated the TCF4/COL6A3 axis to suppress collagen VI secretion by bladder cancer cells, thereby remodeling the extracellular matrix (ECM) and enhancing the sensitivity of bladder cancer cells to CDDP. MP-12C triggered immunogenic cell death and persistently activated the cGAS-STING pathway, promoting dendritic cell maturation and CD8[+] T cell infiltration to remodel the antitumor immune microenvironment. Collectively, MP-12C integrates ECM modulation and immune activation to exert superior anti-bladder cancer efficacy with favorable safety, thus providing a promising platinum(IV) prodrug strategy for NMIBC and MIBC.

Adrenocortical carcinoma is a rare and aggressive malignancy for which high-quality evidence to guide clinical decision-making remains limited. This scoping review aimed to map and synthesize the extent, nature, and direction of evidence across five therapeutic domains in the management of adrenocortical carcinoma. Following the Joanna Briggs Institute methodology and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews guidance, MEDLINE, Embase, and the Cochrane Library were searched without date restrictions. Eligible sources included clinical trials, observational studies, systematic reviews, and clinical guidelines addressing any treatment modality for adrenocortical carcinoma. Data were extracted using a standardized form and synthesized narratively across domains. Evidence visualizations and an intervention-by-domain matrix were developed to identify areas of consistency, uncertainty, and research gaps. Forty-nine studies met the inclusion criteria. Complete tumor resection with negative margins consistently emerged as the strongest prognostic factor. Minimally invasive adrenalectomy showed comparable outcomes only in carefully selected low-risk patients. Adjuvant mitotane demonstrated potential benefit in high-risk disease but not in low- to intermediate-risk patients. In metastatic disease, multimodal management incorporating etoposide, doxorubicin, cisplatin, and mitotane, together with metastasectomy and local therapies, was associated with improved outcomes in selected cases. Recurrence was frequent and often occurred early, particularly in large or invasive tumors. Cortisol-secreting tumors were associated with higher postoperative morbidity and earlier recurrence. Although the available evidence is predominantly retrospective and heterogeneous, consistent patterns emerge that can inform clinical management. This review provides a structured evidence base for future consensus development and highlights priorities for further research.