Quantitative structure-activity relationship modeling for predication of inhibition potencies of imatinib derivatives using SMILES attributes.

Chronic myelogenous leukemia (CML) which is resulted from the BCR-ABL tyrosine kinase (TK) chimeric oncoprotein, is a malignant clonal disorder of hematopoietic stem cells. Imatinib is used as an inhibitor of BCR-ABL TK in the treatment of CML patients. The main object of the present manuscript is focused on constructing quantitative activity relationships (QSARs) models for the prediction of inhibition potencies of a large series of imatinib derivatives against BCR-ABL TK. Herren, the inbuilt Monte Carlo algorithm of CORAL software is employed to develop QSAR models. The SMILES notations of chemical structures are used to compute the descriptor of correlation weights (CWs). QSAR models are established using the balance of correlation method with the index of ideality of correlation (IIC). The data set of 306 molecules is randomly divided into three splits. In QSAR modeling, the numerical value of R2, Q2, and IIC for the validation set of splits 1 to 3 are in the range of 0.7180-0.7755, 0.6891-0.7561, and 0.4431-0.8611 respectively. The numerical result of [Formula: see text] > 0.5 for all three constructed models in the Y-randomization test validate the reliability of established models. The promoters of increase/decrease for pIC50 are recognized and used for the mechanistic interpretation of structural attributes.

Assessment of hyaluronic acid-modified imatinib mesylate cubosomes through CD44 targeted drug delivery in NDEA-induced hepatic carcinoma.

This study aimed at the development of hyaluronic acid-functionalised imatinib mesylate cubosomes (HA-IM-CBs) that might be useful in CD44 targeting against hepatic cancer. The HA-IM-CBs had a 130.7 ±â€¯2.92 nm particle size, -31.40 ±â€¯2.76 mV zeta potential, and 76.14 ±â€¯2.69% release. The architecture of HA-IM-CBs was confirmed using HR-TEM and AFM. When compared to plain IM and IM-CBs, in vitro experiments revealed that HA-IM-CBs outperformed by significantly reducing cell viability. DAPI staining and ROS corroborated the apoptotic effects. Biodistribution and Pharmacokinetics studies showedthat HA-IM-CBs exhibit a higher drug concentration in tumour tissue and better pharmacokinetic activity. This is the first study to show that HA-IM-CBs had CD44 targeting activity against HCC. CD44 regulates apoptosis via Bcl-2 family proteins and caspases, which interact with HA. Higher levels of e-NOS, BAD, BAX, and Cyt C and lower expressions of Bcl-xl, i-NOS, and Bcl-2 demonstrated the anti-HCC potential of HA-IM-CBs in qrt-PCR investigations. The remarkable therapeutic potential of HA-IM-CBs began with substantial stimulation of CD44 regulated caspase-mediated mitochondrial apoptotic pathway, accountable for their anti-HCC activity. The perturbed metabolites are restored to acceptable levels as indicated by metabolomic studies (1H NMR). Interestingly, the antineoplastic effect of HA-IM-CBs was proven to be potentially valuable against HCC.

Ex vivo platelet morphology assessment of chronic myeloid leukemia patients before and after Imatinib treatment.

Chronic myeloid leukemia (CML) is a myeloproliferative disease and the first line treatment is through the administration of Imatinib, a first generation tyrosine kinase inhibitor. Thrombocytosis and bleeding irregularities are common in CML, however, the morphological variations in CML patients' platelets are not well documented. In this study, ex vivo platelet morphology of control participants, as well as CML patients were assessed before and after Imatinib treatment. The topographical and structural morphology of platelets were determined via scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Qualitative data of SEM and TEM revealed that CML patient's platelets were prone to aggregation and coagulation at time of diagnosis; the samples that were not aggregated at time of diagnosis showed typical discoid shaped platelets, which was comparable to control participants' platelets. TEM results of CML patients' platelets at diagnosis showed that internal granular constituents including dense bodies were decreased in comparison to control participants. In all CML patients, platelets appeared activated after 6 months of treatment with Imatinib with membrane structure abnormalities and constituent variations. Research to date has primarily focused on the effects of CML on leukocyte populations, however, the results of the current study implicate the impact of CML pathogenesis on platelets, seemingly as a result of alterations in normal hematopoiesis. In addition, the impact of Imatinib treatment on platelet morphology was also established, indicating an increase in platelet activation. Recognizing and understanding the impact of CML disease progression on platelets is of importance to aid improved patient treatment. RESEARCH HIGHLIGHTS: In the study, results from SEM and TEM indicated that CML patient's platelets were prone to aggregation at time of diagnosis, and activation after Imatnib treatment. Platelet samples that did not aggregate had decreased internal granular constituents.

Assessment of azithromycin as an anticancer agent for treatment of imatinib sensitive and resistant CML cells.

INTRODUCTION: Chronic Myeloid Leukemia (CML) is a hematological disease which is characterized by the presence of BCR-ABL fusion protein. Imatinib (IMA), a tyrosine kinase inhibitor of BCR-ABL, is used as a frontline treatment.Although IMA aids in killing a majority of leukemia cells, it may not kill CML stem cells which are the primary roots of disease and therapy resistance. Recently, antimicrobial drugs have been gaining attention because of their selective targeting of cancer cells. Therefore, we now ask if combinational therapy of IMA with a targeted antimicrobial drug Azithromycin (AZT) can enhance the treatment efficiency in IMA resistant CML. METHODS: K562S (IMA sensitive) and K562R (IMA resistant) cells were treated with increasing concentrations of AZT to determine its effects on cell proliferation and apoptosis. Cell viability, apoptosis, caspase3/7 activity and P-glycoprotein (Pgp) function were investigated with spectrophotometric MTT assay and flow cytometric Annexin V staining, caspase 3/7 activity, and Rhodamine123 staining assays respectively. The expression levels of pro-apoptotic (BAX, BAD and BIM), anti- apoptotic (BCL-XL and BCL-2) and drug transporter (MDR-1 and MRP-1) genes were assessed with qRT-PCR. RESULTS: AZT treatment alone inhibited cell viability, induced apoptosis and enhanced caspase 3/7 activity in both K562S and high MDR-1 (Pgp) expressing K562R cells. Moreover, combination of AZT/IMA suppressed cell viability, induced apoptosis and caspase3/7 activity more effectively and significantly compared to K562R cells treated with only IMA or AZT. Furthermore, AZT and AZT/IMA combination decreased Pgp function in K562R cells in comparison with their controls. Based on qRT-PCR data, single AZT and combined AZT/IMA treatment also induced BAX/BCL-2 ratio significantly in both K562S and K562R cells. CONCLUSION: Single AZT and AZT/IMA combinational treatment can be proposed as a promising and effective treatment strategy for CML. One of the mechanisms underlying the potent anticancer effect of combined AZT/IMA could be its ability to inhibit Pgp function and increase intracellular accumulation of IMA which leads to the induction of apoptosis in K562R cells.

Cost-effectiveness Analysis of Genetic Testing and Tailored First-Line Therapy for Patients With Metastatic Gastrointestinal Stromal Tumors.

Importance: Gastrointestinal stromal tumor (GIST) is frequently driven by oncogenic KIT variations. Imatinib targeting of KIT marked a new era in GIST treatment and ushered in precision oncological treatment for all solid malignant neoplasms. However, studies on the molecular biological traits of GIST have found that tumors respond differentially to imatinib dosage based on the KIT exon with variation. Despite this knowledge, few patients undergo genetic testing at diagnosis, and empirical imatinib therapy remains routine. Barriers to genetic profiling include concerns about the cost and utility of testing. Objective: To determine whether targeted gene testing (TGT) is a cost-effective diagnostic for patients with metastatic GIST from the US payer perspective. Design, Setting, and Participants: This economic evaluation developed a Markov model to compare the cost-effectiveness of TGT and tailored first-line therapy compared with empirical imatinib therapy among patients with a new diagnosis of metastatic GIST. The main health outcome, quality-adjusted life years (QALYs), and costs were obtained from the literature, and transitional probabilities were modeled from disease progression and survival estimates from randomized clinical trials of patients with metastatic GIST. Data analyses were conducted October 2019 to January 2020. Exposure: TGT and tailored first-line therapy. Main Outcomes and Measures: The primary outcome was QALYs and cost. Cost-effectiveness was defined using an incremental cost-effectiveness ratio, with an incremental cost-effectiveness ratio less than $100 000/QALY considered cost-effective. One-way and probabilistic sensitivity analyses were conducted to assess model stability. Results: Therapy directed by TGT was associated with an increase of 0.10 QALYs at a cost of $9513 compared with the empirical imatinib approach, leading to an incremental cost-effectiveness ratio of $92 100. These findings were sensitive to the costs of TGT, drugs, and health utility model inputs. Therapy directed by TGT remained cost-effective for genetic testing costs up to $3730. Probabilistic sensitivity analysis found that TGT-directed therapy was considered cost-effective 70% of the time. Conclusions and Relevance: These findings suggest that using genetic testing to match treatment of KIT variations to imatinib dosing is a cost-effective approach compared with empirical imatinib.

The impact assessment of anticancer drug imatinib on the feeding behavior of rotifers with an integrated perspective: Exposure, post-exposure and re-exposure.

The anticancer drugs are getting increasing attention as an emerging contaminant in the aquatic environments. In the present study, feeding behavior of the rotifer Brachionus calyciflorus under the impact of anticancer drug imatinib was evaluated. Traditional toxicological studies usually focus on dose-effect relationship at a given exposure time, while ignore the possible impact after the exposure. Thus, how the impact varied in the post-exposure and re-exposure was also considered in the present study. The feeding depression of the rotifers was attributed to the increased concentration of imatinib. Although the filtration and ingestion rate of the rotifers recovered to a certain extent after the exposure, the significant feeding inhibition still persisted even if the exposure was ended. In the re-exposure period, the feeding behavior was less depressed than those of the exposure period, which implied that rotifers might develop a tolerance to the same toxics. The activities of acetylcholine esterase (AchE) and the levels of reactive oxygen species (ROS) in rotifers were also detected. Imatinib inhibited the activities of AchE in the exposure and re-exposure while ROS levels increased significantly in the re-exposure period. Our present study provided an integrated assessment the potential environmental risks of imatinib at a new perspective.

The anti-leukemic and lipid lowering effects of imatinib are not hindered by statins in CML: a retrospective clinical study and in vitro assessment of lipid-genes transcription.

Imatinib, which has revolutionized chronic myeloid leukemia (CML) treatment, was suggested to improve lipid profile. Statins, a dyslipidemia drug, were reported to potentiate imatinib's antileukemic effect. However, analysis of imatinib combined with statins is lacking. We have retrospectively analyzed the normalization period of bcr-abl, blood counts, and lipids in 40 CML patients, 19 of which co-treated with statins, during short (<12 months) and prolonged (>12 months) imatinib treatment. Prior statins treatment did not hinder nor sensitized imatinib's anti-leukemic and lipid-lowering effects. CML cells (K562) treated with 1µM imatinib (24-96 h) were further assessed for the expression of central lipid-related genes by real-time PCR. HMGCoAR, LDL-R, and apobec1 expressions were significantly increased while CETP declined after 48-96 h. To conclude, imatinib produces an independent favorable lipid profile, which is not hindered by statins and is partly mediated via transcription regulation of genes involved in the clearance of plasma lipids.