In vitro evaluation of the selective cytotoxicity and genotoxicity of three synthetic ortho-nitrobenzyl derivatives in human cancer cell lines, with and without metabolic activation.

Although the presence of nitro groups in chemicals can be recognized as structural alerts for mutagenicity and carcinogenicity, nitroaromatic compounds have attracted considerable interest as a class of agents that can serve as source of potential new anticancer agents. In the present study, the in vitro cytotoxicity, genotoxicity, and mutagenicity of three synthetic ortho-nitrobenzyl derivatives (named ON-1, ON-2 and ON-3) were evaluated by employing human breast and ovarian cancer cell lines. A series of biological assays was carried out with and without metabolic activation. Complementarily, computational predictions of the pharmacokinetic properties and druglikeness of the compounds were performed in the Swiss ADME platform. The MTT assay showed that the compounds selectively affected selectively the cell viability of cancer cells in comparison with a nontumoral cell line. Additionally, the metabolic activation enhanced cytotoxicity, and the compounds affected cell survival, as demonstrated by the clonogenic assay. The comet assay, the cytokinesis-block micronucleus assay, and the immunofluorescence of the γ-H2AX foci formation assay have that the compounds caused chromosomal damage to the cancer cells, with and without metabolic activation. The results obtained in the present study showed that the compounds assessed were genotoxic and mutagenic, inducing double-strand breaks in the DNA structure. The high selectivity indices observed for the compounds ON-2 and ON-3, especially after metabolic activation with the S9 fraction, must be highlighted. These experimental biological results, as well as the theoretical properties predicted for the compounds have shown that they are promising anticancer candidates to be exploited in additional studies.

An epidermal growth factor receptor-targeting immunotoxin based on IgG shows potent antitumor activity against head and neck cancer.

The epidermal growth factor receptor (EGFR) is an important target for cancer therapies. Many head and neck cancer (HNC) cells have been reported to overexpress EGFR; therefore, anti-EGFR therapies have been attempted in patients with HNC. However, its clinical efficacy is limited owing to the development of drug resistance. In this study, we developed an EGFR-targeting immunotoxin consisting of a clinically proven anti-EGFR IgG (cetuximab; CTX) and a toxin fragment (LR-LO10) derived from Pseudomonas exotoxin A (PE) using a novel site-specific conjugation technology (peptide-directed photo-crosslinking reaction), as an alternative option. The immunotoxin (CTX-LR-LO10) showed specific binding to EGFR and properties of a typical IgG, such as stability, interactions with receptors of immune cells, and pharmacokinetics, and inhibited protein synthesis via modification of elongation factor-2. Treatment of EGFR-positive HNC cells with the immunotoxin resulted in apoptotic cell death and the inhibition of cell migration and invasion. The efficacy of CTX-LR-LO10 was evaluated in xenograft mouse models, and the immunotoxin exhibited much stronger tumor suppression than CTX or LR-LO10. Transcriptome analyses revealed that the immunotoxins elicited immune responses and altered the expression of genes related to its mechanisms of action. These results support the notion that CTX-LR-LO10 may serve as a new therapeutic agent targeting EGFR-positive cancers.

Sevoflurane inhibits the malignant behavior of nasopharyngeal carcinoma cells by regulating mitochondrial membrane potential.

This study aims to determine the effect of sevoflurane (Sev) on nasopharyngeal carcinoma (NPC) in malignant behavior and mitochondrial membrane potential (MMP). NPC cells (5-8F and CNE2) were exposed to Sev at different concentrations and then tested for proliferation by CCK-8 and colony formation assays, apoptosis by flow cytometry, and invasion and migration by Transwell assays. In addition, the Warburg effect was examined by measurements of glucose consumption, lactic acid production, and adenosine triphosphate (ATP). Mitochondrial function was evaluated by reactive oxygen species (ROS) production, oxidative stress-related indexes, and mitochondrial membrane potential. Sev suppressed 5-8F and CNE2 cell proliferation, invasion, and migration, and enhanced apoptosis. Moreover, Sev dampened the Warburg effect by reducing glucose consumption, lactic acid production, and ATP, as well as decreasing hexokinase 2 and pyruvate kinases type M2 protein expressions. Also, Sev induced ROS production and malondialdehyde content and reduced superoxide and glutathione peroxidase levels. Finally, Sev caused damage to mitochondrial homeostasis through induction of cleaved caspase-3, cleaved caspase-9, and cytochrome c protein expression and reduction of MMP. Sev inhibits the malignant behavior of NPC cells by regulating MMP.

Erlotinib or Gefitinib for Treating Advanced Epidermal Growth Factor Receptor Mutation-Positive Lung Cancer in Aotearoa New Zealand: Protocol for a National Whole-of-Patient-Population Retrospective Cohort Study and Results of a Validation Substudy.

BACKGROUND: Starting in 2010, the epidermal growth factor receptor (EGFR) kinase inhibitors erlotinib and gefitinib were introduced into routine use in Aotearoa New Zealand (NZ) for treating advanced lung cancer, but their impact in this setting is unknown. OBJECTIVE: The study described in this protocol aims to understand the effectiveness and safety of these new personalized lung cancer treatments and the contributions made by concomitant medicines and other factors to adverse outcomes in the general NZ patient population. A substudy aimed to validate national electronic health databases as the data source and the methods for determining patient eligibility and identifying outcomes and variables. METHODS: This study will include all NZ patients with advanced EGFR mutation-positive lung cancer who were first dispensed erlotinib or gefitinib before October 1, 2020, and followed until death or for at least 1 year. Routinely collected health administrative and clinical data will be collated from national electronic cancer registration, hospital discharge, mortality registration, and pharmaceutical dispensing databases by deterministic data linkage using National Health Index numbers. The primary effectiveness and safety outcomes will be time to treatment discontinuation and serious adverse events, respectively. The primary variable will be high-risk concomitant medicines use with erlotinib or gefitinib. For the validation substudy (n=100), data from clinical records were compared to those from national electronic health databases and analyzed by agreement analysis for categorical data and by paired 2-tailed t tests for numerical data. RESULTS: In the validation substudy, national electronic health databases and clinical records agreed in determining patient eligibility and for identifying serious adverse events, high-risk concomitant medicines use, and other categorical data with overall agreement and κ statistic of >90% and >0.8000, respectively; for example, for the determination of patient eligibility, the comparison of proxy and standard eligibility criteria applied to national electronic health databases and clinical records, respectively, showed overall agreement and κ statistic of 96% and 0.8936, respectively. Dates for estimating time to treatment discontinuation and other numerical variables and outcomes showed small differences, mostly with nonsignificant P values and 95% CIs overlapping with zero difference; for example, for the dates of the first dispensing of erlotinib or gefitinib, national electronic health databases and clinical records differed on average by approximately 4 days with a nonsignificant P value of .33 and 95% CIs overlapping with zero difference. As of May 2024, the main study is ongoing. CONCLUSIONS: A protocol is presented for a national whole-of-patient-population retrospective cohort study designed to describe the safety and effectiveness of erlotinib and gefitinib during their first decade of routine use in NZ for treating EGFR mutation-positive lung cancer. The validation substudy demonstrated the feasibility and validity of using national electronic health databases and the methods for determining patient eligibility and identifying the study outcomes and variables proposed in the study protocol. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12615000998549; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=368928. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/51381.

Efficacy of cryotherapy in the prevention of chemotherapy-induced peripheral neuropathy: A systematic review and meta-analysis.

PURPOSE: The study investigates cryotherapy's efficacy in mitigating Chemotherapy-induced peripheral neuropathy (CIPN), an adverse effect of chemotherapy that often leads to dosage reduction or treatment discontinuation. METHOD: The study was registered with PROSPERO (CRD42023428936). A literature search was conducted using the PubMed, Embase, and Cochrane Library databases. Randomized and nonrandomized controlled trials that investigated the effects of cryotherapy on CIPN were included for systematic review and meta-analysis. The primary outcome for prevention was the incidence of CIPN. RESULTS: We identified 17 trials involving 2,851 patients. In total, 11 trials compared the incidence of CIPN between cryotherapy and control groups. Significant differences in the incidence of CIPN at the midpoint and end of chemotherapy were observed, with risk ratios (RRs) of 0.23 (95% confidence interval [CI] = 0.13 to 0.43) and 0.54 (95% CI = 0.33 to 0.88), respectively. Cryotherapy also significantly reduced the incidence of sensory CIPN, with an RR of 0.67 (95% CI = 0.49 to 0.92). Additionally, cryotherapy demonstrated a significant reduction in the incidence of CIPN in patients with gynecological cancers (RR = 0.24, 95% CI = 0.14 to 0.41). Significantly favorable global quality of life scores following chemotherapy (standardized mean difference = 1.43; 95% CI = 0.50 to 2.36) and relieved neuropathic symptoms were found with cryotherapy. CONCLUSIONS: Cryotherapy demonstrates a pronounced preventive effect against the development of CIPN, providing substantial symptomatic relief and quality of life improvements for patients undergoing chemotherapy. The administration of cryotherapy through the use of frozen gloves and socks, or continuous-flow cooling systems, optimally initiated 15 min prior to and concluded 15 min following chemotherapy, is recommended for achieving maximum therapeutic efficacy.

Strengthening access to cancer medicines for children in East Africa: policy options to enhance medicine procurement, forecasting, and regulations.

Gaps in access to quality essential medicines remain a major impediment to the effective care of children with cancer in low-and middle-income countries (LMICs). The World Health Organization reports that less than 30% of LMICs have consistent availability of childhood cancer medicines, compared to over 95% in high-income countries. Information provided within this policy brief is drawn from a review of the literature and a mixed-methods study published in the Lancet Oncology that analyzed determinants of cancer medicine access for children in Kenya, Tanzania, Uganda, and Rwanda. Three key policy options are presented to guide strategic policy direction and critical health system planning for strengthening access to cancer medicines for children: pooled procurement, evidence-based forecasting, and regional harmonization of regulatory processes. Enhancing regional pooled procurement to address fragmented markets and improve medicine supply, investing in health information systems for improved forecasting and planning of childhood cancer medicine needs, and promoting regulatory harmonization to streamline medicine approval and quality assurance across East Africa are recommended. This policy brief is intended for policymakers, clinicians, and health-system planners involved in the procurement, supply chain management, policy and financing of childhood cancer medicines.

Investigating the potential of monocyclic B9N9 and C18 rings for the electrochemical sensing, and adsorption of carbazole-based anti-cancer drug derivatives: DFT-based first-principle study.

CONTEXT: For the first time, the use of monocyclic rings C18 and B9N9 as sensors for the sensing of carbazole-based anti-cancer drugs, such as tetrahydrocarbazole (THC), mukonal (MKN), murrayanine (MRY), and ellipticine (EPT), is described using DFT simulations and computational characterization. The geometries, electronic properties, stability studies, sensitivity, and adsorption capabilities of C18 and B9N9 counterparts towards the selected compounds confirm that the analytes interact through active cavities of the C18 and B9N9 rings of the complexes. METHODS: Based on the interaction energies, the sensitivity of surfaces towards EPT, MKN, MRY, and THC analytes is observed. The interaction energy of EPT@B9N9, MKN@B9N9, MRY@B9N9, and THC@B9N9 complexes are observed - 20.40, - 19.49, - 20.07, and - 18.27 kcal/mol respectively which is more exothermic than EPT@C18, MKN@C18, MRY@C18, and THC@C18 complexes are - 16.37, - 13.97, - 13.96, and - 11.39 kcal/mol respectively. According to findings from the quantum theory of atoms in molecules (QTAIM) and the reduced density gradient (RDG), dispersion forces play a significant role in maintaining the stability of these complexes. The electronic properties including FMOs, density of states (DOS), natural bond orbitals (NBO), charge transfer, and absorption studies are carried out. In comparison of B9N9 and C18, the analyte recovery time for C18 is much shorter (9.91 × 10-11 for THC@C18) than that for B9N9 shorter recovery time value of 3.75 × 10-9 for EPT@B9N9. These results suggest that our reported sensors B9N9 and C18 make it faster to detect adsorbed molecules at room temperature. The sensor response is more prominent in B9N9 due to its fine energy gap and high adsorption energy. Consequently, it is possible to think of these monocyclic systems as a potential material for sensor applications.

Recent Update on Nanocarrier(s) as the Targeted Therapy for Breast Cancer.

Despite ongoing advances in cancer therapy, the results for the treatment of breast cancer are not satisfactory. The advent of nanotechnology promises to be an essential tool to improve drug delivery effectiveness in cancer therapy. Nanotechnology provides an opportunity to enhance the treatment modality by preventing degradation, improving tumour targeting, and controlling drug release. Recent advances have revealed several strategies to prevent cancer metastasis using nano-drug delivery systems (NDDS). These strategies include the design of appropriate nanocarriers loaded with anti-cancer drugs that target the optimization of physicochemical properties, modulate the tumour microenvironment, and target biomimetic techniques. Nanocarriers have emerged as a preferential approach in the chemotropic treatment for breast cancer due to their pivotal role in safeguarding the therapeutic agents against degradation. They facilitate efficient drug concentration in targeted cells, surmount the resistance of drugs, and possess a small size. Nevertheless, these nanocarrier(s) have some limitations, such as less permeability across the barrier and low bioavailability of loaded drugs. To overcome these challenges, integrating external stimuli has been employed, encompassing infrared light, thermal stimulation, microwaves, and X-rays. Among these stimuli, ultrasound-triggered nanocarriers have gained significant attention due to their cost-effectiveness, non-invasive nature, specificity, ability to penetrate tissues, and capacity to deliver elevated drug concentrations to intended targets. This article comprehensively reviews recent advancements in different nanocarriers for breast cancer chemotherapy. It also delves into the associated hurdles and offers valuable insights into the prospective directions for this innovative field.

Preliminary evaluation of antiproliferative and apoptotic activities of novel indolin-2-one derivatives.

Indole-based agents are frequently used in targeted or supportive therapy of several cancers. In this study, we investigated the anticancer properties of originally synthesized novel indolin-2-one derivatives (6a-d) against Malignant Mesothelioma, Breast cancer, and Colon Cancer cells. Our results revealed that all derivatives were effectively delayed cell proliferation by inhibiting the ERK1/2, AKT, and STAT3 signaling pathways in a concentration-dependent manner. Additionally, these variants induced cell cycle arrest in the S phase, accompanied by elevated levels of p21 and p27 expressions. Derivatives also initiated mitochondrial apoptosis through the upregulation of Bax and downregulation of Bcl-2 proteins, leading to the activation of caspase 3 and PARP cleavage in exposed cells. Remarkably, three of the indolin-2-one derivatives displayed significant selectivity towards Breast and Colon Cancer cells, with compound 6d promising as the most potent and wide spectral one for all cancer cell lines.

Antitumor activity of anlotinib in malignant melanoma: modulation of angiogenesis and vasculogenic mimicry.

Malignant melanoma presents a formidable challenge due to its aggressive metastatic behavior and limited response to current treatments. To address this, our study delves into the impact of anlotinib on angiogenesis and vasculogenic mimicry using malignant melanoma cells and human umbilical vein endothelial cells. Evaluating tubular structure formation, cell proliferation, migration, invasion, and key signaling molecules in angiogenesis, we demonstrated that anlotinib exerts a dose-dependent inhibition on tubular structures and effectively suppresses cell growth and invasion in both cell types. Furthermore, in a mouse xenograft model, anlotinib treatment resulted in reduced tumor growth and vascular density. Notably, the downregulation of VEGFR-2, FGFR-1, PDGFR-ß, and PI3K underscored the multitargeted antitumor activity of anlotinib. Our findings emphasize the therapeutic potential of anlotinib in targeting angiogenesis and vasculogenic mimicry, contributing to the development of novel strategies for combating malignant melanoma.

Improved efficacy of cisplatin delivery by peanut agglutinin­modified liposomes in non­small cell lung cancer.

Globally, non­small cell lung cancer (NSCLC) is a significant threat to human health, and constitutes >80% of lung cancer cases. Cisplatin (CDDP), a commonly used drug in clinical treatment, has been the focus of research aiming to mitigate its potent toxicity through encapsulation within liposomes. However, challenges, such as a reduced drug loading efficiency and nonspecific release, have emerged as obstacles. The present study aimed to improve the encapsulation efficiency of CDDP within liposomes by pre­preparation of CDDP and modifying the liposome surface through the incorporation of peanut agglutinin (PNA) as a ligand [CDDP­loaded PNA­modified liposomes (CDDP­PNA­Lip)]. This strategy was designed to enhance the delivery of CDDP to tumour tissues, thereby reducing associated side effects. The effect of CDDP­PNA­Lip on the proliferation and migration of NSCLC cell lines with high MUC1 expression was elucidated through in vitro studies. Additionally, the capacity of PNA modification to augment the targeted anti­tumour efficacy of liposomes was assessed through xenograft tumour experiments. The results indicated that in an in vitro uptake assay Rhodamine B (RhB)­loaded PNA­modified liposomes were taken up by cells with ~50% higher efficiency compared with free RhB. In addition, CDDP­PNA­Lip resulted in a 2.65­fold enhancement of tumour suppression in vivo compared with free CDDP. These findings suggested that the encapsulation of CDDP within ligand­modified liposomes may significantly improve its tumour­targeting capabilities, providing valuable insights for clinical drug development.

Additive antitumor effect of arsenic trioxide with exposure to ionizing radiation to human acute promyelocytic leukemia HL­60 cells.

Arsenic trioxide (ATO) is expected to be a chemical drug with antitumor activity against acute promyelocytic leukemia (APL), a type of acute myeloid leukemia. In Japan, its antitumor effects were confirmed in clinical trials for APL, and it has been approved in various countries around the world. However, there have been no reports on ATO's antitumor effects on radioresistant leukemia cells, which can be developed during radiotherapy and in combination with therapeutic radiation beams. The present study sought to clarify the antitumor effect of ATO on APL cells with radiation resistance and determine its efficacy when combined with ionizing radiation (IR). The radiation­resistant HL60 (Res­HL60) cell line was generated by subjecting the native cells to 4­Gy irradiation every week for 4 weeks. The half­maximal inhibitory concentration (IC50) for cell proliferation by ATO on native cell was 0.87 µM (R2=0.67), while the IC50 for cell proliferation by ATO on Res­HL60 was 2.24 µM (R2=0.91). IR exposure increased the sub­G1 and G2/M phase ratios in both cell lines. The addition of ATO resulted in a higher population of G2/M after 24 h rather than 48 h. When the rate of change in the sub­G1 phase was examined in greater detail, the sub­G1 phase in both control cells without ATO significantly increased by exposure to IR at 24 h, but only under the condition of 2 Gy irradiation, it had continued to increase at 48 h. Res­HL60 supplemented with ATO showed a higher rate of sub­G1 change at 24 h; however, 2 Gy irradiation resulted in a decrease compared with the control. There was a significant increase in the ratio of the G2/M phase in cells after incubation with ATO for 24 h, and exposure to 2 Gy irradiation caused an even greater increase. To determine whether the inhibition of cell proliferation and cell cycle disruptions is related to reactive oxygen species (ROS) activity, intracellular ROS levels were measured with a flow cytometric assay. Although the ROS levels of Res­HL60 were higher than those of native cells in the absence of irradiation, they did not change after 0.5 or 2 Gy irradiation. Furthermore, adding ATO to Res­HL60 reduced intracellular ROS levels. These findings provide important information that radioresistant leukemia cells respond differently to the antitumor effect of ATO and the combined effect of IR.

Associations of three differential white blood cell counts, platelet counts, and their derived inflammatory indices with cancer-related fatigue in patients with breast cancer undergoing chemotherapy.

PURPOSE: Inflammation is thought to be a vital element in the etiology of cancer-related fatigue (CRF), and circulating blood cell parameters could be important markers of inflammatory response. However, the associations of several major blood cell counts and their derived inflammatory indices with CRF are not well described. The present study aimed to establish whether a relationship exists between the counts of three white blood cell (WBC) types, platelets, and CRF and investigate whether several systemic inflammatory indices were associated with CRF in patients with breast cancer (BC). METHODS: A cross-sectional survey was conducted with a sample of 824 patients with BC undergoing chemotherapy. The cancer fatigue scale was administered to assess CRF. Hematological indicators, including neutrophils, lymphocytes, monocytes, and platelets, were retrieved from routine blood test. Network analyses were used to examine the associations among them. RESULTS: Among 824 participants, the mean score of CRF was (27 ± 10), ranging from 0 to 57. The results of network models indicated that physical fatigue was negatively linked to lymphocyte counts (weight = - 0.161), and affective fatigue was positively associated with neutrophil counts (weight = 0.070). Additionally, physical fatigue was positively linked to the platelet-to-lymphocyte ratio (PLR) (weight = 0.049). CONCLUSION: There were preliminary associations of counts of three WBC types, platelet counts, and systemic inflammatory indices, with distinct dimensions of CRF in patients with BC. Findings provide empirical support for the cellular basis of fatigue-associated inflammatory states.

Novel 1,3,4-oxadiazole derivatives of naproxen targeting EGFR: Synthesis, molecular docking studies, and cytotoxic evaluation.

The close association between inflammation and cancer inspired the synthesis of a series of 1,3,4-oxadiazole derivatives (compounds H4-A-F) of 6-methoxynaphtalene. The chemical structures of the new compounds were validated utilizing Fourier-transform infrared, proton nuclear magnetic resonance, and carbon-13 nuclear magnetic resonance spectroscopic techniques and CHN analysis. Computer-aided drug design methods were used to predict the compounds biological target, ADMET properties, toxicity, and to evaluate the molecular similarities between the design compounds and erlotinib, a standard epidermal growth factor receptor (EGFR) inhibitor. The antiproliferative effects of the new compounds were evaluated by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay, cell cycle analysis, apoptosis detection by microscopy, quantitative reverse transcription-polymerase chain reaction, and immunoblotting, and EGFR enzyme inhibition assay. In silico analysis of the new oxadiazole derivatives indicated that these compounds target EGFR, and that compounds H4-A, H4-B, H4-C, and H4-E show similar molecular properties to erlotinib. Additionally, the results indicated that none of the synthesized compounds are carcinogenic, and that compounds H4-A, H4-C, and H4-F are nontoxic. Compound H4-A showed the best-fit score against EGFR pharmacophore model, however, the in vitro studies indicated that compound H4-C was the most cytotoxic. Compound H4-C caused cytotoxicity in HCT-116 colorectal cancer cells by inducing both apoptosis and necrosis. Furthermore, compounds H4-D, H4-C, and H4-B had potent inhibitory effect on EGFR tyrosine kinase that was comparable to erlotinib. The findings of this inquiry offer a basis for further investigation into the differences between the synthesized compounds and erlotinib. However, additional testing will be needed to assess all of these differences and to identify the most promising compound for further research.

Serum androgen dynamics in young women aged 18-40 treated with chemotherapy for breast cancer: an observational, multicentric, prospective study in France.

Although the deleterious impact of chemotherapy regimen used to treat women of reproductive age with breast cancer on ovarian reserve has been extensively studied, hardly anything has been reported on the effect of these protocols on theca cell function and ovarian androgen secretion. The aim of this prospective multicentric cohort study was to describe serum levels of total testosterone and androstenedione during chemotherapy and 24-month follow-up in 250 patients <40 years treated for breast cancer. Mean basal levels of androstenedione and total testosterone at diagnosis were 1.68 ng/mL and 0.20 ng/mL respectively. No correlation with age was found. Serum levels of androstenedione and total testosterone rapidly decreased after chemotherapy completion, before slowly increasing and almost returning to basal levels in all patients during 2-year follow-up. In conclusion our study demonstrates a chemotherapy-induced alteration of ovarian thecal function, resulting in a significant decrease in serum androgen levels. This alteration of theca cell function adds to the well-known alteration of granulosa cell function, resulting in a global, but partly transient, ovarian failure in young women treated for breast cancer. These data bring new insight into ovarian physiology and emphasize the need for pre and post-treatment ovarian follow-up. Trial registration: ClinicalTrial.gov identifier NCT01114464.

Alkynyl nicotinamides show antileukemic activity in drug-resistant acute myeloid leukemia.

Activating mutations of FLT3 contribute to deregulated hematopoietic stem and progenitor cell (HSC/Ps) growth and survival in patients with acute myeloid leukemia (AML), leading to poor overall survival. AML patients treated with investigational drugs targeting mutant FLT3, including Quizartinib and Crenolanib, develop resistance to these drugs. Development of resistance is largely due to acquisition of cooccurring mutations and activation of additional survival pathways, as well as emergence of additional FLT3 mutations. Despite the high prevalence of FLT3 mutations and their clinical significance in AML, there are few targeted therapeutic options available. We have identified 2 novel nicotinamide-based FLT3 inhibitors (HSN608 and HSN748) that target FLT3 mutations at subnanomolar concentrations and are potently effective against drug-resistant secondary mutations of FLT3. These compounds show antileukemic activity against FLT3ITD in drug-resistant AML, relapsed/refractory AML, and in AML bearing a combination of epigenetic mutations of TET2 along with FLT3ITD. We demonstrate that HSN748 outperformed the FDA-approved FLT3 inhibitor Gilteritinib in terms of inhibitory activity against FLT3ITD in vivo.

Role of drug-eluting bead bronchial arterial chemoembolisation in the treatment of non-small cell lung cancer: protocol for a meta-analysis.

BACKGROUND: Non-small cell lung cancer (NSCLC) has a poor prognosis. Transvascular intervention is an important approach for treating NSCLC. Drug-eluting bead bronchial artery chemoembolisation (DEB-BACE) is a technique of using DEBs loaded with chemotherapeutic drugs for BACE. This study aims to conduct a meta-analysis to comprehensively assess the effectiveness and safety of DEB-BACE in treating NSCLC and investigate a novel therapeutic strategy for NSCLC. METHODS AND ANALYSIS: Wanfang, China National Knowledge Infrastructure, Medline (via PubMed), Cochrane Library, Scopus and Embase databases will be searched in November 2024. A meta-analysis will be conducted to assess the effectiveness and safety of DEB-BACE in the treatment of NSCLC. The following keywords will be applied: "Carcinoma, Non-Small-Cell Lung", "Non-Small Cell Lung Cancer", "Drug-Eluting Bead Bronchial Arterial Chemoembolization" and "drug-eluting beads". Reports in Chinese or English comparing the efficacy of DEB-BACE with other NSCLC treatment options will be included. Case reports, single-arm studies, conference papers, abstracts without full text and reports published in languages other than English and Chinese will not be considered. The Cochrane Handbook for Systematic Reviews of Interventions will be used to independently assess the risk of bias for each included study. In case of significant heterogeneity between studies, possible sources of heterogeneity will be explored through subgroup and sensitivity analysis. For the statistical analysis of the data, RevMan V.5.3 will be used. ETHICS AND DISSEMINATION: This meta-analysis will seek publication in a peer-reviewed journal on completion. Ethical approval is not required for this study as it is a database-based study. PROSPERO REGISTRATION NUMBER: CRD42023411392.

CRISPR screens reveal convergent targeting strategies against evolutionarily distinct chemoresistance in cancer.

Resistance to chemotherapy has been a major hurdle that limits therapeutic benefits for many types of cancer. Here we systematically identify genetic drivers underlying chemoresistance by performing 30 genome-scale CRISPR knockout screens for seven chemotherapeutic agents in multiple cancer cells. Chemoresistance genes vary between conditions primarily due to distinct genetic background and mechanism of action of drugs, manifesting heterogeneous and multiplexed routes towards chemoresistance. By focusing on oxaliplatin and irinotecan resistance in colorectal cancer, we unravel that evolutionarily distinct chemoresistance can share consensus vulnerabilities identified by 26 second-round CRISPR screens with druggable gene library. We further pinpoint PLK4 as a therapeutic target to overcome oxaliplatin resistance in various models via genetic ablation or pharmacological inhibition, highlighting a single-agent strategy to antagonize evolutionarily distinct chemoresistance. Our study not only provides resources and insights into the molecular basis of chemoresistance, but also proposes potential biomarkers and therapeutic strategies against such resistance.

Accumulation of liposomes in metastatic tumor sites is not necessary for anti-cancer drug efficacy.

BACKGROUND: The tumor microenvironment is profoundly heterogeneous particularly when comparing sites of metastases. Establishing the extent of this heterogeneity may provide guidance on how best to design lipid-based drug delivery systems to treat metastatic disease. Building on our previous research, the current study employs a murine model of metastatic cancer to explore the distribution of ~ 100 nm liposomes. METHODS: Female NCr nude mice were inoculated with a fluorescently labeled, Her2/neu-positive, trastuzumab-resistant breast cancer cell line, JIMT-1mkate, either in the mammary fat pad to create an orthotopic tumor (OT), or via intracardiac injection (IC) to establish tumors throughout the body. Animals were dosed with fluorescent and radio-labeled liposomes. In vivo and ex vivo fluorescent imaging was used to track liposome distribution over a period of 48 h. Liposome distribution in orthotopic tumors was compared to sites of tumor growth that arose following IC injection. RESULTS: A significant amount of inter-vessel heterogeneity for DiR distribution was observed, with most tumor blood vessels showing little to no presence of the DiR-labelled liposomes. Further, there was limited extravascular distribution of DiR liposomes in the perivascular regions around DiR-positive vessels. While all OT tumors contained at least some DiR-positive vessels, many metastases had very little or none. Despite the apparent limited distribution of liposomes within metastases, two liposomal drug formulations, Irinophore C and Doxil, showed similar efficacy for both the OT and IC JIMT-1mkate models. CONCLUSION: These findings suggest that liposomal formulations achieve therapeutic benefits through mechanisms that extend beyond the enhanced permeability and retention effect.