Most women with ovarian cancer (OC) develop resistance to platinum chemotherapy, posing a significant challenge to treatment. Matrix metalloproteinase 3 (MMP3) is overexpressed in High-Grade Serous Ovarian Cancer (HGSOC) and is associated with poor survival outcomes; however, its role in platinum resistance remains underexplored. We evaluated the baseline and cisplatin-induced MMP3 transcript and protein levels in cisplatin-resistant OC cells, revealing significantly higher MMP3 levels in cisplatin-resistant cells than in cisplatin-sensitive cells. siRNA-mediated MMP3 knockdown in cisplatin-resistant OC cells significantly reduced viability, proliferation, and invasion, and these effects were further enhanced when combined with cisplatin treatment, indicating a possible synergistic impact on reducing cancer cell aggressiveness; however, chemical MMP3 inhibition did not replicate these effects. RNA sequencing of MMP3-siRNA-treated cisplatin-resistant HGSOC cells revealed 415 differentially expressed genes (DEGs) compared to the negative control, with an additional 440 DEGs identified in MMP3-siRNA HGSOC cells treated in combination with cisplatin. These DEGs were enriched in pathways related to cell cycle regulation, apoptosis, metabolism, stress response, and extracellular matrix organization. Co-immunoprecipitation-coupled mass spectroscopy (IP-MS) identified MMP3-interacting proteins that may contribute to cell survival and chemoresistance in cisplatin-resistant OC. While MMP3-siRNA monotherapy did not reduce tumor growth in vivo, its combination with cisplatin significantly inhibited tumor growth in a cisplatin-resistant HGSOC xenograft model. These findings underscore the multifaceted role of MMP3 in cisplatin resistance, suggesting its involvement in critical cellular processes driving chemoresistance and highlighting the challenges associated with direct MMP3 targeting in therapeutic strategies.

Acute myeloid leukemia (AML) is a devastating disease characterized by extensive inter-patient and intra-patient heterogeneity. Despite the introduction of intensive chemotherapy in the 1970s as the standard treatment, the development of mechanism-based targeted therapies since 2017 has been broadening the therapeutic landscape. However, both chemotherapy and targeted therapies continue to face the challenges of primary and secondary resistance. This review summarizes the mechanisms underlying resistance to chemotherapy and targeted therapies in AML and discusses the opportunities and challenges brought by the transition from chemotherapy to precision medicine.

Acute erythroid leukemia (AEL) is a rare and aggressive hematological malignancy managed with chemotherapy, targeted therapies, and stem cell transplantation. However, these treatments often suffer from limitations such as refractoriness, high toxicity, recurrence, and drug resistance, underscoring the urgent need for novel therapeutic approaches. Dibromo-edaravone (D-EDA) is a synthetic derivative of edaravone (EDA) with unreported anti-leukemic properties. In this study, D-EDA demonstrated potent cytotoxicity against HEL cells with an IC50 value of 8.17 ± 0.43 μM using an MTT assay. Morphological analysis via inverted microscopy revealed reductions in cell number and signs of cellular crumpling and fragmentation. Flow cytometry analysis, Hoechst 33258 staining, Giemsa staining, a JC-1 assay, and a reactive oxygen species (ROS) assay showed that D-EDA induced apoptosis in HEL cells. Furthermore, D-EDA induced S-phase cell cycle arrest. Western blot analysis showed significant upregulation of key apoptosis-related proteins, including cleaved caspase-9, cleaved caspase-3, and cleaved poly ADP-ribose polymerase (PARP), alongside a reduction in Bcl-2 expression. Additionally, oncogenic markers such as c-Myc, CyclinA2, and CDK2 were downregulated, while the cell cycle inhibitor p21 was upregulated. Mechanistic studies involving molecular docking, a cellular thermal shift assay (CETSA), the caspase inhibitor Z-VAD-FMK, JAK2 inhibitor Ruxolitinib, and STAT3 inhibitor Stattic revealed that D-EDA activates the caspase cascade and inhibits the JAK2-STAT3 signaling pathway in HEL cells. In vivo, D-EDA improved spleen structure, increased the hemolysis ratio, and extended survival in a mouse model of acute erythroleukemia. In conclusion, D-EDA induces apoptosis via the caspase cascade and JAK2-STAT3 signaling pathway, demonstrating significant anti-leukemia effects in vitro and in vivo. Thus, D-EDA may be developed as a potential therapeutic agent for acute erythroleukemia.

Advances in medicinal chemistry have led to the development of anticancer and anti-infectious drugs. However, many types of cancer and viral infections such as hepatitis B virus or SARS-CoV-2 are still treated ineffectively. Therefore, further development of effective and selective lead compounds as potential drugs is still highly demanded. In this study, we synthesized a novel series of piperazine-substituted pyranopyridines and evaluated their anticancer and antiviral properties. Antiproliferative activity was determined in a panel of various tumor cell lines as well as non-tumor hepatic HepaRG cells. Mechanisms of cytotoxicity were assessed by fluorescent microscopy techniques. Antiviral activity was analyzed towards DNA and RNA viruses in infectious cell culture systems. Several compounds showed antiproliferative activity towards various cancer cell lines at micromolar and submicromolar concentrations. Mechanisms of cytotoxicity involve the induction of apoptosis and are not mediated via ERK1/2 pathway or oxidative stress. Several compounds exhibit selective activity against hepatitis B virus by preventing the formation of virion particles. This study led to the identification of a novel class of piperazine-substituted pyranopyridines with antiproliferative activity towards a wide range of tumor cell lines as well as the non-toxic inhibitor of HBV virion production.

Chemotherapy-related cardiotoxicity (CTRTOX) is a profound and common side effect of cancer-based therapy in a subset of patients. The underlying factors and the associated mechanisms contributing to severe toxicity of the heart among these patients remain unknown. While challenges remain in accessing human subjects and their ventricular cardiomyocytes (CMs), advancements in human induced pluripotent stem cell (hiPSC)-technology-based CM differentiation protocols over the past few decades have paved the path for iPSC-based models of human cardiac diseases. Here, we offer a detailed analysis of the underlying mechanisms of CTRTOX. We also discuss the recent advances in therapeutic strategies in different animal models and clinical trials. Furthermore, we explore the prospects of iPSC-based models for identifying novel functional targets and developing safer chemotherapy regimens for cancer patients that may be beneficial for developing personalized cardioprotectants and their application in clinical practice.

Resveratrol is a naturally occurring phenolic compound found in various foods such as red wine, chocolate, peanuts, and blueberries. Both in-vitro and in-vivo studies have shown that it has a broad spectrum of pharmacological effects such as providing cellular protection and promoting longevity. These effects include antioxidant, anti-inflammatory, neuroprotective, and anti-viral properties, as well as improvements in cardio-metabolic health and anti-aging benefits. Additionally, resveratrol has demonstrated the ability to induce cell death and inhibit tumor growth across different types and stages of cancer. However, the dual effects of resveratrol-acting to support cell survival in some contexts, while inducing cell death in others-is still not fully understood. In this study, we identify a novel target for resveratrol: the voltage-dependent anion channel 1 (VDAC1), a multi-functional outer mitochondrial membrane protein that plays a key role in regulating both cell survival and death. Our findings show that resveratrol increased VDAC1 expression levels and promoted its oligomerization, leading to apoptotic cell death. Additionally, resveratrol elevated intracellular Ca2+ levels and enhanced the production of reactive oxygen species (ROS). Resveratrol also induced the detachment of hexokinase I from VDAC1, a key enzyme in metabolism, and regulating apoptosis. When VDAC1 expression was silenced using specific siRNA, resveratrol-induced cell death was significantly reduced, indicating that VDAC1 is essential for its pro-apoptotic effects. Additionally, both resveratrol and its analog, trans-2,3,5,4'-tetrahydroxystilbene-2-O-glucoside (TSG), directly interacted with purified VDAC1, as revealed by microscale thermophoresis, with similar binding affinities. However, unlike resveratrol, TSG did not induce VDAC1 overexpression or apoptosis. These results demonstrate that resveratrol-induced apoptosis is linked to increased VDAC1 expression and its oligomerization. This positions resveratrol not only as a protective agent, but also as a pro-apoptotic compound. Consequently, resveratrol offers a promising therapeutic approach for cancer, with potentially fewer side effects compared to conventional treatments, due to its natural origins in plants and food products.

Premature ovarian insufficiency (POI) poses a significant threat to female reproductive health and currently lacks effective interventions. Recent studies highlight the promising potential of human pluripotent stem cell-derived mesenchymal stem cells (hPSC-MSC) in regenerative medicine. However, research on hPSC-MSC-based treatments for POI remains limited, particularly in the characterization of the intermediate differentiation stages from hPSC to MSC. This study presents an accelerated differentiation protocol for generating hPSC-MSC via neural crest cells (NCC) and evaluates their therapeutic potential in chemotherapy-induced POI.

Gynostemma pentaphyllum (Thunb.), a traditional adaptogenic herb, is known for its bioactive components with potential anti-cancer properties. Acute myeloid leukemia (AML) progression is significantly influenced by Feline McDonough Sarcoma (FMS)-like tyrosine kinase 3 (FLT3) signaling, while Wilms' tumor 1 (WT1) serves as a key prognostic marker. This study investigates the anti-leukemia activities of active G. pentaphyllum leaf extracts and their components, focusing on the inhibition of FLT3 and WT1 activity.

Hepatitis E virus (HEV) typically induces self-limiting infection but can establish persistent infection, particularly in patients with compromised immune systems. However, the literature on HEV infection in patients undergoing chemotherapy is limited.

Hypomethylating agents (HMAs), such as 5-azacytidine (AZA), are valuable treatment options for patients with acute myeloid leukemia (AML). Despite providing significant extensions in survival when used alone or in combination with BCL-2 inhibitors, resistance and eventual relapse is observed. Reported mechanisms of these outcomes are inconsistent when focusing on leukemic populations within bone marrow, indicating a need for studies on the impact of HMAs on non-leukemic cells in the blood and other tissue compartments.

Dasatinib (DSB) is a second-generation tyrosine kinase inhibitor widely used for treating chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL). Though clinically effective, DSB has some pharmacokinetic drawbacks evidenced by rapid systemic clearance, low oral bioavailability, and poor aqueous solubility requiring high doses for therapeutic action. Novel formulation strategies like solid dispersions, liposomal formulations, and PEGylated and hybrid nanoparticles enhance DSB's pharmacokinetic and pharmacodynamic profiles by enhancing drug solubility, stability, and controlled release. In addition, through these targeted drug-delivery systems based on ligand-functionalized nanoparticles and antibody-drug conjugates-the tumor-targeted DSB is allowed selective accumulation at the tumor site, causing fewer off-target effects and lessening systemic toxicity while maximizing effectiveness. These approaches are geared toward utilizing nanotechnology to improve intracellular drug uptake and extend the circulation time to optimize antitumor efficacy. Overall, those advances in drug delivery systems could greatly boost the therapeutic efficacy of DSB by providing better bioavailability, controlled release, and targeted distribution. Such advances would increase treatment success in CML and Ph + ALL and expand DSB's potential clinical applications toward other malignancies. Research concerning the delivery of DSB with nanocarriers and ligand-mediated targeting strategies should bear further fruits to augment DSB therapy in oncology.

This study aims to comprehensively evaluate the hematologic toxicity profiles, toxicity spectrum, and safety rankings of immune checkpoint inhibitors (ICIs) used for digestive system tumors. The PubMed, Cochrane Library, Web of Science, and Embase databases were systematically searched from inception to August 2024 to identify randomized controlled trials (RCTs). The primary outcome was anemia, while secondary outcomes included neutropenia, neutrophil count decreased, thrombocytopenia, platelet count decreased, leukopenia, white blood cell (WBC) count decreased, lymphocyte count decreased, and febrile neutropenia (FN). Subgroup analyses were performed based on tumor type, country category, study phase, ICI regimen, control group, chemotherapy regimen, ICI plus different chemotherapy regimens. Two reviewers independently selected the studies, extracted data according to pre-specified criteria, and assessed the risk of bias using the Cochrane Collaboration risk of bias tool. RevMan 5.4 software was utilized to visualize the risk of bias assessments. Stata 16.0 was used to conduct network meta-analysis, sensitivity analysis and meta-regression. 25 phase II and III RCTs (n = 15216) were included. The general safety of ICIs ranked from high to low for grade 1-5 anemia were as follows: avelumab, nivolumab, pembrolizumab, sintilimab, camrelizumab, and tislelizumab. For grade 3-5 anemia, the general safety profile of the ICIs were as follows, from highest to lowest: avelumab, nivolumab, pembrolizumab, sintilimab, and camrelizumab. Compared to chemotherapy, treatment-related hematologic toxicities with ICIs occurred primarily in grade 1-5 anemia, neutropenia, thrombocytopenia, leukopenia, and WBC count decreased. Taking ICI monotherapy, nivolumab plus ipilimumab were generally safer than taking chemotherapy, one ICI drug with chemotherapy, or two ICI drugs with chemotherapy. In terms of grade 1-5 hematologic toxicities, tislelizumab had the highest risk of neutropenia and leukopenia; the primary treatment-adverse events (AEs) for sintilimab was neutrophil count decreased and WBC count decreased; the primary treatment-related AE associated with nivolumab was platelet count decreased; camrelizumab posed the highest risk for lymphocyte count decreased. In terms of grade 3-5 hematologic toxicities, pembrolizumab was predominantly linked to neutropenia; sintilimab showed the greatest risk for neutrophil count decreased, platelet count decreased, and lymphocyte count decreased; avelumab was most associated with WBC count decreased. FN primarily manifested as grade 3-5, with camrelizumab having the highest risk. Among agents used in gastric or gastroesophageal junction cancer, avelumab demonstrated the most favorable safety profile for anemia. Each treatment regimen has its unique safety profile. Early identification and management of ICI-related hematologic toxicities are essential in clinical practice.Systematic Review Registration: PROSPERO CRD42024571508.

Durvalumab has demonstrated significant efficacy in several types of malignancies, while large-scale real-world safety studies remain limited. This study aimed to systematically evaluate the safety of durvalumab through data mining of the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). We extracted reports of durvalumab as the primary suspected drug from the FAERS database (January 2017 to June 2024). Four disproportionality analysis algorithms were used to detect signals between durvalumab and adverse events (AEs). Durvalumab was recorded in 10,120 reports as the primary suspected drug. Of these, 43.6% of AEs occurred during the first month of treatment, with a median onset time of 40 days (IQR: 14-99 ). Among 181 potential signals, 64 were unexpected preferred terms not listed in the prescribing information, including cytokine release syndrome (CRS), pulmonary tuberculosis, radiation esophagitis, oesophageal fistula, oesophageal perforation, pleural effusion, pneumothorax, cerebral infarction, biliary tract infection, cholecystitis, psoriasiform dermatitis, portal vein thrombosis, acute cholangitis and pericarditis malignant. Serious adverse events accounted for 93.3% of cases. Males exhibited a significantly higher risk of experiencing serious outcomes compared to females (OR = 1.83, 95% CI: 1.52-2.19, P < 0.001). Older age groups demonstrated an elevated risk of severe outcomes relative to those under 65 years (65-74 years: OR = 1.52, 95% CI: 1.15-2.00, P = 0.003; ≥75 years: OR = 1.40, 95% CI: 1.02-1.92, P = 0.038). This study comprehensively assessed the safety of durvalumab and discovered potential new adverse event signals, which may provide critical support for risk identification and monitoring of durvalumab.

Hypomethylating agents are frontline therapies for myelodysplastic neoplasms (MDS), yet clinical responses remain unpredictable. We conducted a phase 2 trial comparing injectable and oral azacitidine (AZA) administered over one or three weeks per four-week cycle, with the primary objective of investigating whether response is linked to in vivo drug incorporation or DNA hypomethylation. Our findings show that injection results in higher drug incorporation, but lower DNA demethylation per cycle, while global DNA methylation levels in mononuclear cells are comparable between responders and non-responders. However, hematopoietic stem and progenitor cells (HSPCs) from responders exhibit distinct baseline and early treatment-induced CpG methylation changes at regulatory regions linked to tissue patterning, cell migration, and myeloid differentiation. By cycle six-when clinical responses typically emerge-further differential hypomethylation in responder HSPCs suggests marrow adaptation as a driver of improved hematopoiesis. These findings indicate that intrinsic baseline and early drug-induced epigenetic differences in HSPCs may underlie the variable clinical response to AZA in MDS.

Somatic cells can transform into tumors due to mutations, and the tumors further evolve towards increased aggressiveness and therapy resistance. We develop DiffInvex, a framework for identifying changes in selection acting on individual genes in somatic genomes, drawing on an empirical mutation rate baseline derived from non-coding DNA that accounts for shifts in neutral mutagenesis during cancer evolution. We apply DiffInvex to >11,000 somatic whole-genome sequences from ~30 cancer types or healthy tissues, identifying genes where point mutations are under conditional positive or negative selection during exposure to specific chemotherapeutics, suggesting drug resistance mechanisms occurring via point mutation. DiffInvex identifies 11 genes exhibiting treatment-associated selection for different classes of chemotherapies, linking selected mutations in PIK3CA, APC, MAP2K4, SMAD4, STK11 and MAP3K1 with drug exposure. Various gene-chemotherapy associations are further supported by differential functional impact of mutations pre- versus post-therapy, and are also replicated in independent studies. In addition to nominating drug resistance genes, we contrast the genomes of healthy versus cancerous cells of matched human tissues. We identify noncancerous expansion-specific drivers, including NOTCH1 and ARID1A. DiffInvex can also be applied to diverse analyses in cancer evolution to identify changes in driver gene repertoires across time or space.

Poly (ADP-ribose) polymerase inhibitors (PARPi) exploit DNA repair deficiency in germline BRCA1 and BRCA2 pathogenic variant (gBRCAm) cancers. Haematological toxicity limits chemotherapy-PARPi treatment combinations. In preclinical models we identified a schedule combining olaparib and carboplatin that avoids enhanced toxicity but maintains anti-tumour activity. We investigated this schedule in a neoadjuvant, phase II-III, randomised controlled trial for gBRCAm breast cancers (ClinicalTrials.gov ID:NCT03150576; PARTNER). The research arm included carboplatin (Area Under the Curve 5, 3-weekly); paclitaxel (80 mg/m2, weekly) day 1, plus olaparib (150 mg twice daily) day 3-14 (4 cycles), followed by anthracycline-containing chemotherapy (3 cycles); control arm gave chemotherapy alone. The primary endpoint, pathological complete response rate, showed no statistical difference between research 64.1% (25/39); control 69.8% (30/43) (p = 0.59). However, estimated survival outcomes at 36-months demonstrated improved event-free survival: research 96.4%, control 80.1% (p = 0.04); overall survival: research 100%, control 88.2% (p = 0.04) and breast cancer specific survival: research 100%, control 88.2% (p = 0.04). There were no statistical differences in relapse-free survival and distant disease-free survival, both were: research 96.4%, control 87.9% (p = 0.20). Similarly, local recurrence-free survival and time to second cancer were both: research 96.4%, control 87.8% (p = 0.20). The PARTNER trial identified a safe, tolerable schedule combining neoadjuvant chemotherapy with olaparib. This combination demonstrated schedule-dependent overall survival benefit in early-stage gBRCAm breast cancer. This result needs confirmation in larger trials.

Endogenous retroviruses (ERVs) are remnants of retrovirus germline infections that occurred over the course of evolution and constitute between 5% and 8% of the human genome. While ERVs tend to be epigenetically silenced in normal adult human tissues, they are often overexpressed in carcinomas and may represent novel immunotherapeutic targets. This study characterizes the ERV envelope protein ERVMER34-1 as a target for a therapeutic cancer vaccine.

EGFR, an important target in cancer chemotherapy, is an important component of the signaling system that regulates important cellular processes such as growth, differentiation, metabolism, and apoptosis in response to both internal and external stimuli. Based on this approach, comprehensive modeling studies targeting the EGFR protein were performed, and synthesized molecules were proposed. For this purpose, the synthesis of new 3,5-diphenyl-1H-1,2,4-triazole derivatives containing semicarbazide, thiosemicarbazide, 1,2,4-triazole-3-thione, and 1,2,4-triazole-3-one units was carried out. Among these compounds, 6a-6i presented in the present study exhibited EGFR inhibition in the nanomolar range. In addition, molecules 5e and 6e showed significant IC50 values. Compound 6e showed the closest IC50 value to gefitinib, a well-known EGFR inhibitor, with its noncompetitive inhibition mode. The Ki value of compound 6e was determined as 0.174 µM.

Renal cell carcinoma (RCC) is one of the most common tumors of high malignancy in the urological system. Sunitinib is commonly used to treat RCC, while drug resistance severely limited the therapeutic efficacy. Tumor-derived exosomes play important roles in facilitating cancer development. However, the role of drug-resistant tumor-derived exosomes in tumorigenesis and resistance of RCC has not been elucidated. Here we isolated sunitinib-sensitive/resistant RCC cells-derived exosomes, characterized by transmission electron microscopy (TEM) and western blot. Furthermore, co-culture experiments were performed and we found that sunitinib-resistant RCC cells-derived exosomes (R-exos) promoted cell proliferation and upregulated proliferation-related genes cyclin D1 (CCND1) and proliferating cell nuclear antigen (PCNA) expression, and inhibited apoptosis and the expression of Bax and Caspase-3 of sunitinib-resistant RCC (RCC/R) cells by delivering lncRNA small nuclear RNA host gene 16 (SNHG16). In resistant cell-derived xenograft (CDX-R) models, R-exos induced tumor growth in vivo, while knockdown of SNHG16 effectively diminished the tumorigenesis of RCC. Moreover, SNHG16 positively regulated the expression of trophinin associated protein (TROAP) by sponging miR-106a-5p in RCC cells, whereas inhibition of miR-106a-5p or overexpression of TROAP greatly reversed the suppression of tumorigenesis and sunitinib resistant by silencing SNHG16. R-exos lncRNA SNHG16 promoted sunitinib resistant and malignant progress by regulating the miR-106a-5p/TROAP axis, and targeting SNHG16/miR-106a-5p/TROAP axis may be a novel therapeutic approach for sunitinib-treated patients of RCC.

During or after chemotherapy, cognitive impairments characterized by forgetfulness, difficulty concentrating, and depressive and anxiety-like symptoms are observed. There is limited research examining the effects of rosuvastatin (RVS), an HMG-CoA reductase inhibitor, in the context of neuroinflammation-related cognitive disruption. Here, we aimed to investigate the neuroprotective potential of RVS against doxorubicin (DOX)-induced cognitive impairments. Experimental groups were planned as control (normal saline, intraperitoneal), DOX (total cumulative dose 10 mg/kg, intraperitoneal), RVS (10 mg/kg, oral, 20 days), and RVS + DOX. Efficacy was monitored by applying a battery of behavioral assessments, as well as biochemical, genetic, histopathological, and immunohistochemical examinations. Results from Morris water maze (MWM), passive avoidance, locomotion activity, and elevated plus maze (EPM) tests showed that DOX administration caused behavioral disorders. Moreover, DOX increased the levels of inducible nitric oxide synthase (iNOS), malondialdehyde (MDA), and tumor necrosis factor-α (TNF-α), while decreasing the levels of interleukin-10 (IL-10), glutathione (GSH), superoxide dismutase, catalase (SOD), endothelial nitric oxide (eNOS), and catalase (CAT). Co-treatment with RSV significantly attenuated DOX-induced behavioral changes and oxidative stress markers. In addition, similar to the immunohistochemical results, we determined that it increased the expression levels of extracellular signal-related kinases 1/2 (ERK1/2), cyclic adenosine monophosphate response element binding protein (CREB), and brain-derived neurotrophic factor (BDNF) and restored the histopathological structure of the brain. Therefore, these results indicated that RSV has a neuroprotective effect against DOX-induced cognitive impairment by reducing neurobehavioral impairments, exerting antioxidant and anti-inflammatory effects, and modulating brain growth factors.