Cisplatin is currently used as the central agent in several cancer chemotherapy protocols because of its broad antitumor spectrum and potent antitumor effects; however, preventing cisplatin-induced renal damage and other adverse events is challenging. Recently, several clinical studies have shown that a short hydration method could prevent cisplatin-induced renal damage. In addition, appropriate magnesium supplementation and administration of forced diuretics have been shown to be renoprotective. The Japanese Lung Cancer Society Guidelines Committee has summarized the evidence of renal protection regarding cisplatin administration to provide optimal administration guidance for the cisplatin short hydration method.

The PARP inhibitor olaparib is effective in breast cancer patients; however, its efficacy is reduced in triple-negative breast cancer (TNBC) due to mechanisms of drug resistance. Recent studies demonstrate that the CDK4 inhibitor palbociclib can enhance the sensitivity of cancer cells to PARP inhibitors. We designed 43 hybrid compounds by combining the pyrido[3,4-d]pyrimidine moiety from palbociclib with the phthalazinone ring from olaparib. Pharmacokinetic profiling and molecular docking revealed compound 17 as a promising candidate, demonstrating a binding affinity of - 8.42 kcal/mol with PARP1 and - 10.05 kcal/mol with CDK4, in contrast to the native inhibitors. Furthermore, the induced fit docking validated its superiority compared to the native inhibitors. Molecular dynamics simulations over 500 ns confirmed the structural stability of compound 17 with both targets. Moreover, the QM/MM, DFT, TD-DFT, and MEP analyses yielded significant insights into charge transfer and electronic transitions, augmenting our understanding of the electronic and bonding properties of the hybrid compound.

Customizing drug treatments based on individual tumor susceptibility and patient-specific factors is a complex task, highlighting the need for better predictive models tailored to each patient. Preserving tumor architecture is one strategy to address the intricate interactions between stromal cells and tumor cell populations within a patient. In this study, we explored the feasibility of using pretherapeutic endoscopic tissue cultures from patients (ePDTCs) with gastric and esophagogastric junction cancers to assess individual drug susceptibility. We treated these endoscopic tissue slice cultures with 5-FU (1 µM), a modified FLOT regimen comprising 5-FU (10 µM), leucovorin (10 µM), oxaliplatin (20 µM), and docetaxel (0.1 µM), the active metabolite of irinotecan (SN38, at 1 µM and 10 µM) and the PD-1 inhibitor nivolumab (3 µg/ml). Analysis of the tumor tissue revealed stable adaptations to the culture environment, which were further enhanced by adding 2% autologous human serum to the culture media. Dose-dependent responses were observed with SN38 across all samples and individual susceptibility at low concentrations. Both 5-FU and the FLOT regimen as well as PD-1 inhibition, tested at bioavailable dosages, further demonstrated individualized responses in ePDTCs. This study shows that ePDTCs can effectively assess tissue susceptibility to drugs, warranting further investigation in larger cohorts to validate this model's potential alongside clinical treatments.

Pancreatic ductal adenocarcinoma (PDAC) is a cancer with dismal prognosis due to resistance to most current therapies. Although immunotherapy has improved the treatment of many solid cancers, pancreatic cancer remains resistant to immunotherapy due to immunosuppressive tumor microenvironment, limited lymphocyte infiltration and lack of neoantigens. Oncolytic adenoviruses are a possible solution to treatment resistance in PDAC due to their ability to elicit lymphocyte trafficking and epitope spreading. Herein, we tested if an oncolytic adenovirus encoding a variant interleukin-2 molecule (Ad5/3-E2F-d24-vIL2), could enable immune checkpoint inhibitor (ICI) therapy in PDAC when combined with chemotherapy. Rationale for Ad5/3-E2F-d24-vIL2 was tested in vitro, where increase in programmed death ligand 1 (PD-L1) expression was seen after virotherapy and chemotherapy. Expression of other B7 family proteins was characterized in mono- and co-culture settings of cancer cells, fibroblasts, and macrophages. The combination therapy of virotherapy, chemotherapy and ICI was characterized in freshly resected ex vivo pancreatic tumor samples. Combination of ICI with virotherapy showed increased interferon and chemokine production in samples, with expansion of cytotoxic CD8 + T cells seen by flow cytometry. In vivo evaluation of the triple combination therapy in a Syrian hamster model showed improved tumor growth control and overall survival, with concurrent increase in intratumoral lymphocytes during therapy. Animals cured with the therapy showed resistance to re-challenge with the same cell line, supportive of successful generation of anti-tumor immunity in the animals. The combination treatment of Ad5/3-E2F-d24-vIL2, chemotherapy, and checkpoint inhibition is a promising treatment modality to tackle treatment resistance in PDAC.

This study explored the effectiveness of cannabidiol (CBD) alone and in combination with multi-modal exercise (MME) to improve signs and symptoms of chemotherapy-induced peripheral neuropathy (CIPN), quality of life (QoL), and functional capacity in cancer survivors.

The Centers for Medicare & Medicaid Services Hospital Outpatient Quality Reporting Program's OP-35 rule penalizes health systems that have a higher-than-expected rate of emergency department (ED) visits or inpatient admissions for 10 potentially preventable conditions within 30 days of receiving chemotherapy. Identifying patients at risk for toxicities and resultant acute care could lead to reducing the rate of such events, improving patient care, and reducing costs. We identified patients with cancer seen in the ED at our institution between January 1, 2018, and December 31, 2021, for one of the OP-35 toxicities who had received chemotherapy within the previous 30 days and analyzed demographic factors using zero-truncated Poisson regression. We further analyzed comorbid conditions for risk factors by matching by demographics and cancer type a cohort of patients without ED visits due to OP-35 events. A total of 1,618 patients were identified. The most frequent events were pain, sepsis, and fever. Thirty-nine percent had two or more visits during the study, and among those patients, the most frequent cancer types were gastrointestinal (32%) and breast (22%) cancers. Race, age, and sex were associated with an increased risk of events. In the matched cohort analysis, five comorbidities were statistically significant (P < 0.05) with event risk: history of coagulopathy/pulmonary emboli, myocardial infarction, cardiac arrhythmias, depression, and weight loss (concordance = 0.58). Forty-seven percent of patients with an event had at least one of these five comorbidities. Future interventions may concentrate on resources to monitor patients based on the risk assessment established in this study.

Cisplatin remains a cornerstone chemotherapy for many solid tumors but is limited by dose-limiting toxicities, including nephrotoxicity, peripheral neuropathy, and ototoxicity-the latter of which disproportionately affects pediatric patients and lacks effective prevention strategies. Although therapeutic approaches to mitigate cisplatin-induced toxicity are urgently needed, the underlying mechanisms driving organ-specific injury remain incompletely understood. We previously identified apurinic/apyrimidinic endonuclease (APE) 2 as a critical mediator of cisplatin-induced acute kidney injury through disruption of mitochondrial integrity. In this study, we extend these findings to cisplatin-induced hearing loss (C-HL). We demonstrate that cisplatin selectively induces APE2, but not APE1, overexpression in murine and human outer hair cells. Using an inducible, outer hair cell-specific APE2 transgenic mouse model, we show that APE2 overexpression alone is sufficient to cause high-frequency hearing loss, accompanied by hair cell loss and stereocilia disorganization visualized by electron microscopy. Mechanistically, we identified a direct interaction between APE2 and MYH9, mapped the critical MYH9-binding domains, and demonstrated that APE2 knockdown preserved mitochondrial metabolism and protected cochlear cells from cisplatin-induced apoptosis. Notably, APE2 depletion activated an ATR-p53 signaling axis, promoting nuclear p53 localization and suppressing mitochondrial apoptotic pathways. Together, these findings reveal a noncanonical, APE2-dependent mechanism driving C-HL and suggest that targeting APE2 may offer a novel therapeutic strategy to prevent cisplatin-induced ototoxicity.

Frequent drug resistance seriously limits the therapeutic efficacy of sorafenib in advanced hepatocellular carcinoma (HCC). Strategies to increase the response to sorafenib are limited, and the underlying mechanism to facilitate such an increase is not entirely understood. Homeobox (HOX) transcript antisense intergenic RNA (HOTAIR) expression is high in HCC, promoting the occurrence and progression of HCC. In this study, we explored the mechanism through which HOTAIR knockdown affects the response of HCC cells to the chemotherapeutic sorafenib.

The chick embryo chorioallantoic membrane (CAM) model is gaining increasing attention from cancer researchers worldwide. Its affordability, short experimental duration, robustness, and ease of tumor xenograft visualization make it a valuable tool in cancer research. This review explores recent advancements and potential applications of the avian CAM model, including the following: (1) studying tumor growth and metastasis, (2) investigating mechanisms of tumor chemoresistance, (3) optimizing drug delivery methods, (4) improving bioimaging techniques, (5) evaluating immuno-oncology drug efficacy, (6) examining tumor-extracellular matrix interactions, (7) analyzing tumor angiogenesis, and (8) exploring the roles of microRNAs in cancer. Additionally, we compare the in ovo CAM model with other in vivo animal models and in vitro cell culture systems. Positioned between in vitro and in vivo models in terms of cost-effectiveness and accuracy in cancer recapitulation, the CAM model enhances both preclinical and translational research. Its expanding use in cancer studies and therapy development is expected to continue growing.

The medicinal phytochemical oleandrin (Ole) is obtained from the Nerium oleander plant. The exact relationship between Ole-induced apoptosis and autophagy in gastric cancer (GC) is unclear despite the fact that it has outstanding anti-tumor capabilities. This research aimed to demonstrate how autophagy and Ole-induced apoptosis interact in GC.

Murine double minute 2 (MDM2) is an oncogene that plays a crucial role in regulating the activity of the tumor suppressor protein p53. By binding to p53, MDM2 promotes its degradation, thus promoting the malignant proliferation. The MDM2-p53 interaction has thus generated interest as a therapeutic target, particularly in some sarcomas characterized by the amplification of the MDM2 gene. In this manuscript, we provide an overview of the current and emerging targeted therapies for MDM2-amplified sarcomas.

Patients with advanced head and neck squamous cell carcinoma (HNSCC) remain at high risk of developing local recurrence and distant metastases. Some patients do respond well to treatment but still have residual disease or develop locoregional failure within 1-2 years. Treatment options are limited in such cases with dismal survival outcomes. This study was done to assess the role of Gefitinib in residual, recurrent, and metastasis HNSCC.

Trastuzumab resistance remains a challenge for HER2-positive breast cancer treatment. Targeting metabolic reprogramming would provide novel insights for therapeutic strategies. Here, we integrated metabolomics, transcriptomics, and epigenomics data of trastuzumab-sensitive and primary-resistant HER2-positive breast cancer to identify metabolic alterations. Aberrant cysteine metabolism was discovered in trastuzumab primary-resistant breast cancer at both circulating and intracellular levels. The inhibition of SLC7A11 and cysteine starvation could synergize with trastuzumab to induce ferroptosis. Mechanistically, increased H3K4me3 and decreased DNA methylation enhanced SLC7A11 transcription and cystine uptake in trastuzumab-resistant breast cancer. The regulation of epigenetic modifications modulated cysteine metabolism and ferroptosis sensitivity. These results revealed an innovative approach for overcoming trastuzumab resistance by targeting specific amino acid metabolism.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, posing significant therapeutic challenges due to the lack of effective targets. Elevating intracellular calcium levels is a promising strategy in cancer therapy, and highly expressed calreticulin (CALR) in tumors has emerged as a potential target for inducing calcium overload. However, few studies on CALR ligands have been reported. Herein, we designed, synthesized, and evaluated pyrazolopyridine derivatives as potential CALR ligands. Among them, the leading compound 2a was identified as a high binding affinity ligand (Kd = 2.6 μM) with potent antitumor activity (IC50 = 0.1 μM). Mechanistic studies demonstrated that 2a could interact with CALR, inducing calcium overload and leading to apoptosis in TNBC cells. Further in vivo pharmacodynamic evaluations confirmed the safety and antitumor activity of 2a. In conclusion, our findings developed a novel CALR ligand and provided a new anti-TNBC strategy via inducing calcium dysregulation.

Aclarubicin (also called aclacinomycin A) is an antineoplastic from the anthracycline class that is used in China and Japan but not in Europe nor in the USA. Aclarubicin induces much less DNA damage than the classical anthracyclines doxorubicin, daunorubicin, epirubicin, idarubicin, and the anthracene mitoxantrone, but is equally effective in inhibiting DNA-to-RNA transcription and in eliciting immunogenic stress in malignant cells. Accordingly, aclarubicin lacks the DNA damage-associated cardiotoxicity that is dose-limiting for classical anthracyclines. Conversely, aclarubicin is at least as potent as other anthracyclines in inducing immunogenic cell death (ICD), which is key for the mode of action of efficient chemotherapeutics. This combination of reduced toxicity and equivalent ICD-stimulatory activity may explain why, as compared to other anthracyclines, aclarubicin is particularly efficient against acute myeloid leukemia. As a result, we advocate for clinical studies seeking to replace the anthracyclines used in Western medicine by aclarubicin-like compounds. Such clinical studies should not only embrace hematological malignancies but should also concern solid cancers, including those in which ICD-inducing chemotherapies are followed by immunotherapies targeting the PD-1/PD-L1 interaction.

Malignant tumors, as a major challenge in global public health, have posed a significant threat to human life and health. Although traditional chemotherapy can inhibit tumor growth, it is often associated with serious adverse effects and tolerance. Against this background, Chinese medicine therapies have gradually gained wide recognition, and they play an important role in the treatment of gastric cancer (GC). As the core combination of the traditional prescription "Dajianzhong Tang", the medicinal pair of Zanthoxyli Pericarpium and Zingiberis Rhizoma (ZP-ZR) has shown unique advantages in tumor treatment.

Immune checkpoint inhibitors (ICIs) are widely used for cancer immunotherapy; however, the clinical efficacy of anti-PD-1/PD-L1 monotherapy is generally limited, highlighting the need to develop combination therapies. Dogs develop spontaneous tumors in immunocompetent settings, and anti-PD-1/PD-L1 antibodies exert similar clinical benefits. However, no clinically relevant anti-CTLA-4 antibody has been reported, limiting the value of canine tumors as comparative models for human ICI research. Here, canine CTLA-4 was molecularly characterized, and a caninized anti-CTLA-4 antibody (ca1C5) that blocks CTLA-4/ligand binding was developed. Treatment with ca1C5 increased cytokine production in canine immune cell cultures, and the immunostimulatory effect was enhanced when used in combination with the anti-PD-L1 antibody c4G12. As a proof-of-concept, a veterinary clinical study was conducted to demonstrate the safety and clinical efficacy of anti-CTLA-4 antibody as salvage combination therapy in dogs with advanced tumors refractory to prior c4G12 monotherapy. The combination treatment (c4G12 plus ca1C5) was well-tolerated, and evidence of antitumor activity was observed in one dog with oral malignant melanoma. Further studies are warranted to advance veterinary care for dogs and to better characterize canine ICI models for human onco-immunology research.

Immunotherapies targeting the programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) have shown great promise for a subset of patients with non-small cell lung cancer (NSCLC). However, safe and robust combination therapies are still needed to bring the benefit to broader patient populations.

To investigate the potential factors contributing to chemotherapy-related cognitive impairment in elderly lung cancer patients and to offer insights for the creation of an intervention program aimed at enhancing the cognitive abilities of this vulnerable population.

Nanophosphors have gained substantial attention in recent years for both the diagnosis and treatment of cancer. Near-infrared optical imaging based on Nd3+-doped rare-earth nanophosphors is widely used for deep penetration tissue imaging. The present work aims to develop a hierarchical structure of polydopamine (PDA)-coated alginate microspheres encapsulated with NaGdF4@NaYF4:Nd3+ and cisplatin to achieve enhanced photothermal therapy (PTT) alongside providing optical imaging, MRI, and CT multimodal imaging capabilities. The obtained microspheres were subjected to physicochemical characterization, absorption/emission features, radical scavenging potential, drug release, and antibacterial efficacy. Further, the irradiation of microspheres under an 808 nm NIR laser revealed an effective conversion of light energy into a temperature upsurge to 51.3 °C with a conversion efficiency of 53.3%. The hydrophilic NaGdF4@NaYF4:Nd3+ nanophosphors demonstrated significant fluorescence in the NIR range, longitudinal and transverse magnetic resonance relaxivity (r1 = 12.65 mM-1 s-1, r2 = 17.1 mM-1 s-1), and X-ray attenuation capacity of 132 HU. Moreover, cell culture analysis in the presence and absence of NIR irradiation against MG63 cell lines highlights the anticancer potential of the microspheres. These results suggest the potential of prepared microspheres as multifunctional nanotheranostic agents.