Anticancer Research Articles

Nme8 is essential for protection against chemotherapy drug cisplatin-induced male reproductive toxicity in mice.

Cisplatin (CP), a chemotherapy drug commonly used in cancers treatment, causes serious reproductive toxicity. With younger cancer patients and increasing survival rates, it is important to preserve their reproductive capacity. NME8 is highly expressed in testis and contains thioredoxin and NDPK domains, suggesting it may be a target against the CP-induced reproductive toxicity. We deleted exons 6-7 of the Nme8 in mice based on human mutation sites and observed impaired transcript splicing. In mice, Nme8 was not essential for spermatogenesis, possibly due to functional compensation by its paralog, Nme5. Nme8 expression was elevated and translocated to the nucleus in response to two weeks of CP treatment. Under CP treatment, Nme8 deficiency further impaired antioxidant capacity, induced lipid peroxidation and increased ROS level, and failed to activate autophagy, resulting in aggravated DNA damage in testes and sperm. Consequently, the proliferation and differentiation of spermatogonia and the meiosis of spermatocyte were almost completely halted, and sperm motility was impaired. Our research indicates that NME8 protects against CP-induced testis and sperm damage. This may provide new insights into the physiological functions of the Nme family and potential targets for preserving fertility in young male cancer patients.

Scoping review of anticancer drug utilization in lung cancer patients at the end of life.

This scoping review aims to deepen the understanding of end-of-life anticancer drug use in lung cancer patients, a disease marked by high mortality and symptom burden. Insight into unique end-of-life treatment patterns is crucial for improving the appropriateness of cancer care for these patients. Comprehensive searches were carried out in Medline and Embase to find articles on the utilization of anticancer drugs in the end of life of lung cancer patients. We identified 68 publications, highlighting the methodological characteristics of studies including the timing of the research, disease condition, treatment regimen, type of treatment, and features of the treatment. We outlined the frequency of anticancer drug use throughout different end-of-life periods. This review provides a comprehensive overview of primary studies exploring end-of-life treatments in lung cancer patients. Methodological inconsistencies pose many challenges, revealing a notable proportion of patients experiencing potential overtreatment, warranting more standardized research methods for robust evaluations.

The EXO1/Polη/Polι axis as a promising target for miR-3163-mediated attenuation of cancer stem-like cells in non-small cell lung carcinoma.

Cancer stem-like cells (CSLCs) drive tumour progression and chemoresistance. The concerted efforts of EXO1 and TLS polymerases safeguard DNA integrity against chemotherapeutic drugs. In absence of potential drug targets, non-small cell lung carcinoma (NSCLC) patients have few therapeutic options. In current scenario, microRNAs offer a potential avenue for eradicating CSLCs. EXO1 downregulation impact on CSLCs expansion was assessed via flow cytometry. Co-localisation of EXO1, Polη and Polι was validated through co-immunoprecipitation and confocal-imaging. The effects of co-downregulation of Polη and Polι on CSLC survival, repair synthesis, and mutagenesis were evaluated using flow cytometry and immunohistochemistry in cell lines and xenografts. MicroRNA targeting EXO1 was studied for its role in CSLCs regulation. EXO1 downregulation in NSCLC CSLCs induces DNA lesions, triggering apoptosis and enhances cisplatin sensitivity. It collaborates with Polη and Polι in DNA repair, contributing to cisplatin resistance in CSLCs. Absence of Polη and Polι impairs repair and reduces cisplatin-induced mutagenesis. Co-downregulation of Polη and Polι in xenografts reduces tumour proliferation significantly. MiR-3163 overexpression sensitises CSLCs to cisplatin via targeting EXO1/Polη/Polι axis, as shown in mechanistic studies. This study unveils a novel regulatory pathway involving EXO1/Polη/Polι axis and miR-3163, providing insights into CSLCs regulation in NSCLC. EXO1/Polη/Polι axistargeted by miR-3163, resulting in the inhibition of cell growth and induction of apoptosis inNSCLC CSLCs.

Enhanced Synergistic Efficacy Against Breast Cancer Cells Promoted by Co-Encapsulation of Piplartine and Paclitaxel in Acetalated Dextran Nanoparticles.

Malignant breast tumors constitute the most frequent cancer diagnosis among women. Notwithstanding the progress in treatments, this condition persists as a major public health issue. Paclitaxel (PTX) is a first-line classical chemotherapeutic drug used as a single active pharmaceutical ingredient (API) or in combination therapy for breast cancer (BC) treatment. Adverse effects, poor water solubility, and inevitable susceptibility to drug resistance seriously limit its therapeutic efficacy in the clinic. Piplartine (PPT), an alkaloid extracted from Piper longum L., has been shown to inhibit cancer cell proliferation in several cell lines due to its pro-oxidant activity. However, PPT has low water solubility and bioavailability in vivo, and new strategies should be developed to optimize its use as a chemotherapeutic agent. In this context, the present study aimed to synthesize a series of acetalated dextran nanoparticles (Ac-Dex NPs) encapsulating PPT and PTX to overcome the limitations of PPT and PTX, maximizing their therapeutic efficacy and achieving prolonged and targeted codelivery of these anticancer compounds into BC cells. Biodegradable, pH-responsive, and biocompatible Ac-Dex NPs with diameters of 100-200 nm and spherical morphologies were formulated using a single emulsion method. Selected Ac-Dex NPs containing only PPT or PTX as well as those coloaded with PPT and PTX achieved excellent drug-loading capabilities (PPT, ca. 11-33%; PTX, ca. 2-14%) and high encapsulation efficiencies (PPT, ∼57-98%; PTX, ∼80-97%). Under physiological conditions (pH 7.4), these NPs exhibited excellent colloidal stability and were capable of protecting drug release, while under acidic conditions (pH 5.5) they showed structural collapse, releasing the therapeutics in an extended manner. Cytotoxicity results demonstrated that the encapsulation in Ac-Dex NPs had a positive effect on the activities of both PPT and PTX against the MCF-7 human breast cancer cell line after 48 h of treatment, as well as toward MDA-MB-231 triple-negative BC cells. PPT/PTX@Ac-Dex NPs were significantly more cytotoxic (IC50/PPT = 0.25-1.77 μM and IC50/PTX = 0.07-0.75 μM) and selective (SI = 2.9-6.7) against MCF-7 cells than all the control therapeutic agents: free PPT (IC50 = 4.57 μM; SI = 1.2), free PTX (IC50 = 0.97 μM; SI = 1.0), the single-drug-loaded Ac-Dex NPs, and the physical mixture of both free drugs. All combinations of PPT and PTX resulted in pronounced synergistic antiproliferative effects in MCF-7 cells, with an optimal molar ratio of PPT to PTX of 2.3:1. PPT/PTX-2@Ac-Dex NPs notably promoted apoptosis, cell cycle arrest at the G2/M, accumulation of intracellular reactive oxygen species (ROS), and combined effects from both PPT and PTX on the microtubule network of MCF-7 cells. Overall, the combination of PTX and PPT in pH-responsive Ac-Dex NPs may offer great potential to improve the therapeutic efficacy, overcome the limitations, and provide effective simultaneous delivery of these therapeutics for BC treatment.

Intra-arterial chemotherapy combined with BCG immunotherapy is more effective than intra-arterial chemotherapy plus intravesical chemotherapy or standard BCG immunotherapy in preventing the recurrence and progression of high-risk non–muscle-invasive bladder cancer

BackgroundUp to 45% of patients with high-risk non–muscle-invasive bladder cancer (NMIBC) will not benefit from adjuvant intravesical instillation. We aimed to introduce intra-arterial chemotherapy (IAC) to existing intravesical treatment and evaluate its feasibility and safety. Materials and methodsWe collected data from 170 patients who had been diagnosed with high-risk NMIBC and underwent transurethral resection of bladder tumor (TURBT) over the last 5 years. Twenty-seven patients were excluded according to specific exclusion criteria. The remaining 143 patients were divided into 3 groups according to their treatment: intravesical instillation of Bacillus Calmette – Guerin (BCG), BCG+ intra-arterial chemotherapy (IAC), and intravesical chemotherapy (IVC)+IAC groups. All groups received standard intravesical instillation of BCG or chemotherapeutic agents. In contrast, both the BCG+IAC and IVC+IAC groups received four courses of IAC (injection of cisplatin [60 mg/m2] and epirubicin [50 mg/m2] in the internal iliac arteries via Seldinger's percutaneous technique). ResultsThe median follow-up time was 47 months, ranging from 20 to 60 months. The restricted mean survival time (RMST), which represents the recurrence and progression rate of the BCG+IAC group, differed significantly when compared with the BCG group (P = 0.029 and 0.004, respectively) and the IVC+IAC group (P = 0.004 and 0.006, respectively). Kaplan-Meier plots revealed that the recurrence and progression-free survival of the BCG+IAC group were significantly higher than the BCG and IVC+IAC groups (P = 0.033 and 0.028, respectively). In contrast, the BCG and IVC+IAC groups showed similar RMST (P = 0.156 and 0.935, respectively), recurrence (P = 0.627), and progression-free (P = 0.931) survival. A small proportion of patients (20%) suffered from the adverse effects of IAC while 65% suffered from adverse reactions to intravesical instillation. Most adverse effects were ranked as grade I or II according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. ConclusionAnalysis showed that tumor recurrence and progression rate in the BCG+IAC group was lower than the BCG and IVC+IAC groups while patients in the IVC+IAC group suffered from milder adverse effects in cystitis and flu-like symptoms. Our findings may provide a new perspective for urologists when treating patients with high-risk NMIBC.

Idarubicin-loaded drug-eluting microspheres transarterial chemoembolization for intermediate stage hepatocellular carcinoma: safety, efficacy, and pharmacokinetics.

Transarterial chemoembolization (TACE) is the treatment of choice for the intermediate stage hepatocellular carcinoma (HCC). Doxorubicin remains the most used chemotherapeutic agent in TACE, although in vitro screening has demonstrated that idarubicin exhibits greater cytotoxicity against HCC. This study aimed to evaluate safety, efficacy, and pharmacokinetics of idarubicin-loaded drug-eluting microspheres TACE (DEMIDA-TACE) in intermediate stage HCC patients. Between September 2019 and December 2021, 31 consecutive intermediate stage HCC patients (96.8% cirrhotic) were included to this study. 2 mL of LifePearl™ microspheres (100 μm) loaded with 10 mg of 1 mg/mL idarubicin were used for treatment. The adverse events, objective response rate (ORR), progression free survival (PFS), time to TACE untreatable progression (TTUP), median overall survival (mOS), and pharmacokinetics were evaluated. There were 68 TACE procedures performed. Adverse events grade ≥ 3 were noted after 29.4% procedures. The ORR was 83.9%, median PFS and TTUP were 10.5 months (95% CI: 6.8-14.3 months) and 24.6 months (95% CI: 11.6-37.6 months), respectively. Median OS was 36.0 months (95% CI: 21.1-50.9 months). Significant differences between patients achieving objective response (OR) and those with progressive disease were observed regarding idarubicinol and combined idarubicin-idarubicinol plasma concentrations at 72 hours post-procedure, higher plasma concentrations were observed in patients achieving OR (p = 0.014 and 0.014; cut-off values 1.2 and 1.29 ng/mL, respectively). DEMIDA-TACE emerges as a safe and effective method of treatment for the intermediate stage HCC with low rates of adverse events alongside high tumor response, favourable disease control and overall survival. Idarubicinol and combined idarubicin-idarubicinol plasma concentrations at 72 hours post-procedure may serve as prognostic factors for achieving OR.

Exploring 5-Nitro-N-phenyl-3-(phenylamino)-1H-indazole-1-carboxamide (5-NPIC) Derivatives as Anticancer Agents: Synthesis, Docking, and Molecular Dynamics Insights

Exploring 5-Nitro-N-phenyl-3-(phenylamino)-1<i>H</i>-indazole-1-carboxamide (5-NPIC) Derivatives as Anticancer Agents: Synthesis, Docking, and Molecular Dynamics Insights

A comparison of the renal function biomarkers serum creatinine, pro-enkephalin and cystatin C to predict clearance of pemetrexed.

For drugs with a narrow therapeutic window, there is a delicate balance between efficacy and toxicity, thus it is pivotal to administer the right dose from the first administration onwards. Exposure of pemetrexed, a cytotoxic drug used in lung cancer treatment, is dictated by kidney function. To facilitate optimized dosing of pemetrexed, accurate prediction of drug clearance is pivotal. Therefore, the aim of this study was to investigate the performance of the kidney function biomarkers serum creatinine, cystatin C and pro-enkephalin in terms of predicting the elimination of pemetrexed. We performed a population pharmacokinetic analysis using a dataset from two clinical trials containing pharmacokinetic data of pemetrexed and measurements of all three biomarkers. A three-compartment model without covariates was fitted to the data and the obtained individual empirical Bayes estimates for pemetrexed clearance were considered the "true" values (Cltrue). Subsequently, the following algorithms were tested as covariates for pemetrexed clearance: the Chronic Kidney Disease Epidemiology Collaboration equation using creatinine (CKD-EPICR), cystatin C (CKD-EPICYS), a combination of both (CKD-EPICR-CYS), pro-enkephalin as an absolute valueor in a combined algorithm with age and serum creatinine, and lastly, a combination of pro-enkephalin with cystatin C. The dataset consisted of 66 subjects with paired observations for all three kidney function biomarkers. Inclusion of CKD-EPICR-CYS as a covariate on pemetrexed clearance resulted in the best model fit, with the largest decrease in objective function (p < 0.00001) and explaining 35% of the total inter-individual variability in clearance. The predictive performance of the model to containing CKD-EPICR-CYS to predict pemetrexed clearance was good with a normalized root mean squared error and mean prediction error of 19.9% and 1.2%, respectively. In conclusion, this study showed that the combined CKD-EPICR-CYS performs best in terms predicting pharmacokinetics of pemetrexed. Despite the hypothesized disadvantages, creatinine remains to be a suitable and readily available marker to predict pemetrexed clearance in clinical practice.

Identification of honokiol-based scaffold to design tankyrase 1/2 inhibitors by in silico and in vitro studies.

Recently, we identified magnolol bioinspired derivatives as new Tankyrase 1/2 (TNKS1/2) inhibitors by our Inverse Virtual Screening protocol. Based on these findings, in the present contribution, we enlarged our investigation of neolignans to the natural product honokiol (1) and a group of its analogues (2-8). By integrating in silico analysis and Surface Plasmon Resonance experiments, we demonstrated the binding of 1 (honokiol), 2, 6 and 7 towards TNKS2. Furthermore, we also proved the binding specificity of 1 and 7 against TNKS2, while 2 and 6 were found to be also TNSK1 binders, along with 4. Promising antiproliferative activity in A549 cancer cell line were observed for 1 and 6, with honokiol (1) presenting a higher potency than the well-known TNKS2 inhibitor XAV939. Collectively, these outcomes suggest that the honokiol-based scaffold can be employed to design novel anti-cancer therapeutic agents.

High loading and sustained-release system of doxorubicin-carbon dots as nanocarriers for cancer therapeutics

Nanocarriers for drugs have been investigated for decades, yet it is still challenging to achieve sustained release from nanomaterials due to drug loading inefficiency and burst release. In this study, we developed novel functional carbon dots (CDs) and investigated the therapeutic efficacy by studying the loading efficiency and release behavior of the anticancer drug doxorubicin (DOX). CDs were successfully synthesized using a one-step pyrolysis method with varying concentrations of citric acid (CA) and thiourea (TU). Functional groups, morphology, particle size, and zeta potential of synthesized CT-CDs and DOX loaded CT-CDs were investigated by UV-visible, Fluorescence, dynamic light scattering, Zeta Potential measurements, FTIR, and transmission electron microscopy. The zeta potential data revealed DOX loading onto CT-CDs by charge difference, i.e. -24.6 ± 0.44 mV (CT-CDs) and 20.57 ± 0.55 mV (DOX-CT-CDs). DOX was loaded on CDs with a loading efficiency of 88.67 ± 0.36%.In vitrodrug release studies confirmed pH-dependent biphasic drug release, with an initial burst effect and sustained release of DOX was found to be 21.42 ± 0.28% (pH 5), 13.30 ± 0.03% (pH 7.4), and 13.95 ± 0.18% (pH 9) even after 144 h at 37 °C. The CT-CDs were non-toxic and biocompatible with L929 Fibroblasts cells. The cytotoxic effect of DOX-CT-CDs showed a concentration-dependent effect after 48 h with Glioblastoma U251 cells. Flow cytometry was used to examine the cellular uptake of CT-CDs and DOX-CT-CDs in L929 and U251 cells. It was observed that the maximum CT-CDs uptake was around 75% at the end of 24 h. This study showed that the synthesized fluorescent CT-CDs demonstrated a high drug loading capacity, pH-dependent sustained release of DOX, and high cellular uptake by mammalian cells. We believe this work provides practical and biocompatible CDs for chemotherapeutic drug delivery that can be applied to other drugs for certain therapeutic aims.

Quantum Insights into Partially Molecular Imprinted Microspheres for Anticancer Therapeutics: Experimental and Theoretical Studies.

Drug solubility is a determining factor for controlled release, and solubility-dependent release kinetics can be modified by changing the drug's state in the polymer matrix through partial molecular imprinting (PMI), although research in this area remains limited. This novel PMI approach creates nanocavities within the polymer by partially retaining the imprinting molecule and trapping the drug. Such a method holds promise for developing advanced biomaterial-based drug delivery systems for anticancer therapies. In this study, we developed microspheres designed for anticancer drug delivery utilizing PMI to enhance controlled release properties. Poly(vinyl alcohol) (PVA) microspheres were partially imprinted with aspirin (ASP) to create nanocavities for gemcitabine (GEM) molecules, inducing a polymorphic shift of GEM within the polymer matrix. This novel PMI approach enhanced drug release properties by enabling control over the drug crystallinity and release rate. The PVA-ASP-GEM complex showed zero-order release kinetics, releasing 21.6% of GEM over 48 h, maintaining steady state release profile. In contrast, nonimprinted PVA-GEM microspheres exhibited first-order kinetics with a faster release of 46.85% in the same period. Quantum insights from density functional theory (DFT) calculations revealed the superior stability of the PVA-ASP-GEM complex, with a binding free energy of -56.03 kcal/mol, compared to -29.07 kcal/mol for PVA-GEM. Molecular dynamics (MD) simulations demonstrated that ASP's presence created nanocavities that restricted GEM's movement, further contributing to the controlled release. Experimental validation through differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), X-ray diffraction (XRD), and Raman spectroscopy confirmed the polymorphic transitions within the PVA-ASP-GEM complex. This PMI-based approach offers a promising method for modulating drug release kinetics and improving the stability of anticancer therapeutics, paving the way for innovative biomaterial-based drug delivery systems.

Loss of heterozygosity of CYP2D6 enhances the sensitivity of hepatocellular carcinomas to talazoparib

Loss of heterozygosity (LOH) diminishes genetic diversity within cancer genomes. A tumour arising in an individual heterozygous for a functional and a loss-of-function (LoF) allele of a gene occasionally retain only the LoF allele. This can result in deficiency of specific protein activities in cancer cells, creating unique differences between tumour cells and normal cells of the individual. Such differences may constitute vulnerabilities that can be exploited through allele-specific therapies. To discover frequently lost genes with prevalent LoF alleles, we mined the 1000 Genomes dataset for SNVs causing protein truncation through base substitution, indels or splice site disruptions, resulting in 60 LoF variants in 60 genes. From these, the variant rs3892097 in the liver enzyme CYP2D6 was selected because it is located within a genomic region that frequently undergoes LOH in several tumor types including hepatocellular cancers. To evaluate the relationship between CYP2D6 activity and the toxicities of anticancer agents, we screened 525 compounds currently in clinical use or undergoing clinical trials using cell model systems with or without CYP2D6 activity. We identified 12 compounds, AZD-3463, CYC-116, etoposide, everolimus, GDC-0349, lenvatinib, MK-8776, PHA-680632, talazoparib, tyrphostin 9, VX-702, and WZ-3146, using an engineered HEK293T cell model. Of these, talazoparib and MK-8776 demonstrated consistently heightened cytotoxic effects against cells with compromised CYP2D6 activity in engineered hepatocellular cancer cell models. Moreover, talazoparib displayed CYP2D6 genotype dependent effects on primary hepatocellular carcinoma organoids. Exploiting the loss of drug-metabolizing enzyme gene activity in tumor cells following loss of heterozygosity could present a promising therapeutic strategy for targeted cancer treatment. This work was funded by Barncancerfonden (T.S, PR2022-0099 and PR2020-0171, X.Z, TJ2021-0111), Cancerfonden (T.S, 211719Pj and D.G, 222449Pj), Vetenskapsrådet (T.S, 2020-02371 and D.G, 2020-04707), and the Erling Persson Foundation (T.S, 2020-0037 and T.S, 2023-0113).

Action Mechanism of Bioactive Compounds from Plants and Spices Mixture as promising Anticancer agents: In Silico Drug Design predictions targeting Cancer Cell proliferation through Cell Cycle Arrest Pathway

Action Mechanism of Bioactive Compounds from Plants and Spices Mixture as promising Anticancer agents: In Silico Drug Design predictions targeting Cancer Cell proliferation through Cell Cycle Arrest Pathway

Thioredoxin-interacting protein (TXNIP) is a substrate of the NEDD4-like E3 ubiquitin-protein ligase WWP1 in cellular redox state regulation of acute myeloid leukemia cells.

The HECT-type E3 ubiquitin WWP1 (also known as NEDD4-like E3 ubiquitin-protein ligase WWP1) acts as an oncogenic factor in acute myeloid leukemia (AML) cells. WWP1 overexpression in AML confers a proliferative advantage to leukemic blasts (abnormal immature white bloodcells) and counteracts apoptotic cell death and differentiation. In aneffort to elucidate the molecular basis of WWP1 oncogenic activities, we identified WWP1 as a previously unknown negative regulator of thioredoxin-interacting protein (TXNIP)-mediated reactive oxygen species (ROS) production in AML cells. TXNIP inhibits the disulfide reductase enzymatic activity of thioredoxin (Trx), impairing its antioxidant function and, ultimately, leading to the disruption of cellular redox homeostasis. In addition, TXNIP restricts cell growth and survival by blocking glucose uptake and metabolism. Here, we found that WWP1 directly interacts with TXNIP, thus promoting its ubiquitin-dependent proteasomal proteolysis. As a result, accumulation of TXNIP in response to WWP1 inactivation inAML blasts reduces Trx activity and increases ROS production, henceinducing cellular oxidative stress. Increased ROS generation in WWP1-depleted cells culminates in DNA strand breaks and subsequent apoptosis. Coherently with TXNIP stabilization following WWP1 inactivation, we also observed an impairment of both glucose up-take and consumption. Hence, a contribution to the increased cell death observed in WWP1-depleted cells also possibly arises from the attenuation of glucose up-take and glycolytic flux resulting from TXNIP accumulation. Future studies are needed to establish whether TXNIP-dependent deregulation of redox homeostasis in WWP1-overexpressing blasts may affect the response of leukemic cells to chemotherapeutic drugs.

Ironing Out the Kinks: Arming Natural Killer Cells against Ovarian Cancer.

Ameliorating the tumor immune microenvironment is a key strategy to improve the therapeutic outcomes of patients with cancer. Sandoval and colleagues demonstrate that iron chelation enhances type I IFN production, promotes NK cell tumor trafficking and activation, and synergizes with chemotherapy drug cisplatin to reduce metastatic ovarian cancer progression in murine models. See related article by Sandoval et al., p. 1901.

Engineered Extracellular Vesicles for Combinatorial TNBC Therapy: SR-SIM-Guided Design Achieves Substantial Drug Dosage Reduction.

Triple negative breast cancer is an aggressive subtype of breast cancer that has no therapeutic targets, relies on chemotherapeutics for treatment, and is in dire need of novel therapeutic approaches for improved patient outcomes. Extracellular vesicles serve as intercellular communicators and have been proposed as ideal drug delivery vehicles. Here, extracellular vesicles were engineered with RNA nanotechnology to develop Triple negative breast cancer tumor inhibitors. Utilizing Super Resolved-Structured Illumination Microscopy, extracellular vesicles were optimized for precise Survivin siRNA conjugated to chemotherapeutics loading and CD44 aptamer ligand decoration, thereby enhancing specificity towards triple negative breast cancer cells. Conventional treatments typically employ chemotherapy drugs Gemcitabine and Paclitaxel at dosages on the order of mg/kg respectively, per injection (IV) in mice. In contrast, engineered extracellular vesicles encapsulating these drugs saw functional tumor growth inhibition at significantly reduced concentrations: 2.2 μg/kg for Gemcitabine or 5.6 μg/kg for Paclitaxel, in combination with 21.5 μg/kg Survivin-siRNA in mice. The result is a substantial decrease of chemotherapeutic dose required, by orders of magnitude, compared to standard regimens. In vivo and in vitro evaluations in a triple negative breast cancer orthotopic xenograft mouse model demonstrated the efficacy of this reduced dosage strategy, indicating potential for decreased chemotherapy-associated toxicity.

Investigation of 5-fluorouracil cardiotoxicity in combinational therapy: Influence of risk factors and demographics in a Pakistani population.

5-Fluorouracil (5-FU) is a chemotherapeutic agent used to treat various types of cancers. Although widely used, it has consistently been attributed to cardiotoxicities after administration. The purpose of this study was to assess the parameters and predictors of cardiotoxicities associated with various 5-FU-based chemotherapeutic protocols in patients with GI/colorectal cancer, as well as the correlation of these cardiotoxic events with age, sex, cumulative dose, and risk factors such as obesity, hypertension, and family history of cardiac diseases. A prospective study consisting of 396 patients of both sexes was conducted in the oncology ward of Nishtar Hospital in Multan, Pakistan. Patients were grouped according to the therapeutic protocol they received (5-FU monotherapy or in combination, with different dosing regimens). Electrocardiography and serum troponin levels were used to assess 5-FU-induced cardiotoxicity. In cases where cardiotoxicity was detected, 5-FU treatment was interrupted; nitroglycerin, nitrates, and calcium channel blockers were administered; and cardiac monitoring was initiated. 5-FU was discontinued in all cases of acute myocardial infarction. Of the 396 patients, 28.5% reported different cardiotoxic symptoms after receiving various 5-FU-containing protocols. 35% had anginal pain, 13% suffered a myocardial infarction, 11% developed hypertension, and 10% presented heart failure. Patients receiving 5-FU combination therapy showed cardiotoxic events that were significantly different from those on 5-FU monotherapy. Based on the ECG results, only the QTc-d interval increased significantly (p < 0.001) after therapy. 68% of the patients had troponin levels > 2 ng/mL at the end of treatment. Pre-existing cardiac diseases, treatment duration, smoking, and obesity were found to be influential components in the development of cardiotoxicity, and patients with cancer should be closely monitored during 5-FU chemotherapy.

Resistance to the platinum‑based chemotherapeutic drugs in oral cancer: Focus on the role of p22phox (Review)

Resistance to the platinum‑based chemotherapeutic drugs in oral cancer: Focus on the role of p22phox (Review)

Cisplatin vestibulotoxicity: a current review

Cisplatin, a commonly used chemotherapy drug, is well-established for its ototoxic effects, primarily attributed to the damage it inflicts on cochlear hair cells. However, its impact on the vestibular system remains inadequately understood. Here, we provide a comprehensive review of existing literature concerning cisplatin-induced vestibulotoxicity. Animal studies have shown that cisplatin induces a vestibular hair cell loss that is dose-dependent, with the severity of damage also varying according to the route of administration. Notably, intratympanic and systemic injections in animal models have manifested significant damage primarily to utricular hair cells, with a lesser degree of damage observed for the other vestibular end organs. The underlying mechanisms of cisplatin induced vestibular hair cell loss include apoptosis, oxidative stress, and inflammatory cytokines. Several protective agents, such as Pifithrin-α, DAPT, Ginkgolide B, and heat shock proteins, have demonstrated efficacy in inhibiting cisplatin-induced vestibular damage in preclinical studies. Human clinical findings indicate that cisplatin treatment can cause vestibular dysfunction, characterized by symptoms ranging from transient dizziness to persistent vertigo. Challenges in diagnosis, including the limited utilization of comprehensive vestibular testing for many patients, contribute to the variability in reported outcomes. Cisplatin-induced vestibulotoxicity is a significant complication of chemotherapy, necessitating further research to understand its mechanisms and to improve diagnosis and management, ultimately aiming to enhance the quality of life for cancer patients undergoing cisplatin therapy.

Thionin Production in Elicited Plant Cell Suspension and its Application as Antibacterial, Anticancer and Anti-Inflammatory Agent

Thionin Production in Elicited Plant Cell Suspension and its Application as Antibacterial, Anticancer and Anti-Inflammatory Agent