Targeting mitochondrial bioenergetics by combination treatment with imatinib and dichloroacetate in human erythroleukemic K­562 and colorectal HCT­116 cancer cells.

Tumor malignant cells are characterized by dysregulation of mitochondrial bioenergetics due to the 'Warburg effect'. In the present study, this metabolic imbalance was explored as a potential target for novel cancer chemotherapy. Imatinib (IM) downregulates the expression levels of SCΟ2 and FRATAXIN (FXN) genes involved in the heme­dependent cytochrome c oxidase biosynthesis and assembly pathway in human erythroleukemic IM­sensitive K­562 chronic myeloid leukemia cells (K­562). In the present study, it was investigated whether the treatment of cancer cells with IM (an inhibitor of oxidative phosphorylation) separately, or together with dichloroacetate (DCA) (an inhibitor of glycolysis), can inhibit cell proliferation or cause death. Human K­562 and IM­chemoresistant K­562 chronic myeloid leukemia cells (K­562R), as well as human colorectal carcinoma cells HCT­116 (+/+p53) and (­/­p53, with double TP53 knock-in disruptions), were employed. Treatments of these cells with either IM (1 or 2 µM) and/or DCA (4 mΜ) were also assessed for the levels of several process biomarkers including SCO2, FXN, lactate dehydrogenase A, glyceraldehyde­3­phosphate dehydrogenase, pyruvate kinase M2, hypoxia inducing factor­1a, heme oxygenase­1, NF­κB, stem cell factor and vascular endothelial growth factor via western blot analysis. Computational network biology models were also applied to reveal the connections between the ten proteins examined. Combination treatment of IM with DCA caused extensive cell death (>75%) in K­562 and considerable (>45%) in HCT­116 (+/+p53) cultures, but less in K­562R and HCT­116 (­/­p53), with the latter deficient in full length p53 protein. Such treatment, markedly reduced reactive oxygen species levels, as measured by flow­cytometry, in K­562 cells and affected the oxidative phosphorylation and glycolytic biomarkers in all lines examined. These findings indicated, that targeting of cancer mitochondrial bioenergetics with such a combination treatment was very effective, although chemoresistance to IM in leukemia and the absence of a full length p53 in colorectal cells affected its impact.

KIT-SNAP-tag/cell membrane chromatography model coupled with liquid chromatography-mass spectrometry for anti-GIST compound screening from Evodia rutaecarpa.

Gastrointestinal mesenchymal tumors, as the most common mesenchymal tumors in the gastrointestinal tract, are adjuvantly treated with multi-targeted tyrosine kinase inhibitors, such as imatinib and sunitinib, but there are problems of drug resistance and complex methods of monitoring therapeutic agents. The pathogenesis of this disease is related to mutations in tyrosine kinase (KIT) or platelet-derived growth factor receptor α, an important target for drug therapy. In recent years, the screening of relevant tyrosine kinase inhibitors from traditional Chinese medicine has become a hotspot in antitumor drug research. In the current study, the KIT-SNAP-tag cell membrane chromatography (KIT-SNAP-tag/CMC) column was prepared with satisfying specificity, selectivity, and reproducibility by chemically bonding high KIT expression cell membranes to the silica gel surface using the SNAP-tag technology. The KIT-SNAP-tag/CMC-HPLC-MS two-dimensional coupling system was investigated using the positive drug imatinib, and the results showed that the system was a reliable model for screening potential antitumor compounds from complex systems. This system screened and identified three potential active compounds of evodiamine (EVO), rutaecarpin (RUT), and dehydroevodiamine (DEVO), which possibly target the KIT receptor, from the alcoholic extract of the traditional Chinese medicine Evodia rutaecarpa. Then, the KD values of the interaction of EVO, RUT, and DEVO with KIT receptors measured using nonlinear chromatography were 7.75 (±4.93) × 10-6, 1.42 (±0.71) × 10-6, and 2.34 (±1.86) × 10-6 mol/L, respectively. In addition, the methyl thiazolyl tetrazolium assay validated the active effects of EVO and RUT in inhibiting the proliferation of high KIT-expressing cells in the ranges of 0.1-10 µmol/L and 0.1-50 µmol/L, respectively. In conclusion, the KIT-SNAP-tag/CMC could be a reliable model for screening antitumor components from complex systems.

Long-Term Efficacy of High-Dose Imatinib in Hispanic Patients Without Access to Second-Generation Tyrosine Kinase Inhibitors Treated in LATAM Centers.

BACKGROUND: While second-generation tyrosine kinase inhibitors (TKI) revolutionized treatment for patients with chronic myeloid leukemia (CML) who developed a suboptimal response to imatinib, many patients in developing countries are fixed to the latter due to socioeconomic barriers. Despite this scenario, scarce information is available to evaluate the clinical prognosis of these patients. METHODS: We conducted a retrospective cohort analysis to compare the overall mortality of patients with CML who developed a suboptimal response to a standard dose of imatinib and were treated with either high-dose imatinib or a second-generation TKI. We created a marginal structural model with inverse probability weighting and stabilized weights. Our primary outcome was overall survival (OS) at 150 months. Our secondary outcomes were disease-free survival (DFS) at 150 months and adverse events. RESULTS: The cohort included 148 patients, of which 32 received high-dose imatinib and 116 a second-generation TKI. No difference was found in the 150-month overall survival risk (RR: 95% CI 0.91, 0.55-1.95, P-value = .77; RD: -0.04, -0.3 to 0.21, P-value = .78) and disease-free survival (RR: 1.02, 95% CI 0.53-2.71, P-value = .96; RD: 0.01, -0.26 to 0.22, P-value = .96). There was also no difference in the incidence of adverse events in either group. CONCLUSION: Ideally, patients who develop a suboptimal response to imatinib should be switched to a second-generation TKI. If impossible, however, our findings suggest that patients treated with high-dose imatinib have a similar overall survival and disease-free survival prognosis to patients receiving a second-generation TKI.

Safety and efficacy of Vitamin D3 supplementation with Imatinib in Chronic Phase- Chronic Myeloid Leukaemia: an Exploratory Randomized Controlled Trial.

OBJECTIVES: The study aimed to compare early molecular response (EMR) rates at 3 months of imatinib therapy with and without vitamin D3 supplementation in patients newly diagnosed with chronic-phase chronic myeloid leukaemia (CML-CP). The secondary objective was to assess the effects of vitamin D3 on complete haematological response (CHR) and its safety. DESIGN: Double-blind, placebo-controlled, exploratory randomised trial. SETTING: Tertiary care hospital in northern India. PARTICIPANTS: Treatment-naive patients with chronic phase chronic myeloid leukaemia (n=62) aged >12 years were recruited from January 2020 to January 2021. Patients with progressive disease, pregnancy and hypercalcaemia were excluded. INTERVENTION: Oral vitamin D3 supplementation (60 000 IU) or matched placebo was given once weekly for an initial 8 weeks along with imatinib after randomisation with 1:1 allocation ratio. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was to compare EMR (defined as BCR-ABL1 transcript level ≤10%, international scale) at 3 months. The secondary outcomes were to compare effect of the intervention on CHR, correlation of 25(OH)2D3 levels with treatment response and safety according to Common Terminology Criteria for Adverse Events (CTCAE) version 5. RESULTS: At baseline, 14.5% of the patients had normal vitamin D3 levels. EMR at 3 months was attained in 24 patients (82.7%) of the vitamin D3 group and 21 (75%) of the placebo group (OR 1.6, 95% CI 0.37 to 7.37, p=0.4). A significant difference in vitamin D3 levels from baseline to the end of study was observed. Patients with vitamin D3 supplementation did not achieve higher CHR in comparison with placebo (OR 1.3, 95% CI 0.25 to 7.23, p=1.0). Vitamin D3 levels were not significantly correlated with BCR-ABL1 levels. No dose-limiting toxicities were observed. CONCLUSION: Vitamin D3 levels were low among patients with CML-CP in this study. Vitamin D3 supplementation with imatinib therapy did not have significant effect on EMR or CHR. Further clinical trials could be undertaken to assess the effective dosage and duration of vitamin D3 supplementation in these patients. TRIAL REGISTRATION NUMBER: CTRI/2019/09/021164.

System analysis of Huang-Lian-Jie-Du-Tang and their key active ingredients for overcoming CML resistance by suppression of leukemia stem cells.

BACKGROUND: BCR-ABL1-based resistance to imatinib, mainly resulting from BCR-ABL1 mutations, is largely solved after second- and third-generation tyrosine kinase inhibitors (TKIs) are discovered. Nonetheless, imatinib resistance without BCR-ABL1 mutations, including intrinsic resistance induced by stem cells within chronic myeloid leukemia (CML), remains the major clinical challenge for many patients. PURPOSE: To study the key active ingredients and corresponding target proteins in Huang-Lian-Jie-Du-Tang (HLJDT) against BCR-ABL1-independent CML resistance to therapeutics, and then explore its mechanism of against CML drug resistance. METHODS: Cytotoxicity of HLJDT and its active ingredients in BCR-ABL1-independent imatinib resistance cells was analyzed through MTT assay. The cloning ability was measured through soft agar assay. Monitoring therapeutic effect on Xenografted mice CML model by in vivo imaging technology and mice survival time. Predicting the potential target protein binding sites by the technology of photocrosslinking sensor chip, molecular space simulation docking, and use Surface Plasmon Resonance (SPR) technology . Flow cytometry to detect the ratio of stem progenitor cells (CD34+). Constructing bone marrow transplantation mice CML leukemia model, detect the effects on leukemia stem cells LSK (Lin-\ Sca-1+ \C-kit+) self-renewal. RESULTS: Treatment with HLJDT, berberine and baicalein inhibited cell viability and colony formation of BCR-ABL1-independent imatinib-resistant cells in vitro while prolonging survival in mouse with CML xenografts and transplatation CML-like mouse models in vivo. JAK2 and MCL1were identified as targets of berberine and baicalein. JAK2 and MCL1 are involved in multi-leukemia stem cell-related pathways. Moreover, the ratio of CD34+ cells in resistant CML cells is higher than in treatment-sensitive CML cells. Treatment with BBR or baicalein partially suppressed CML leukemic stem cells (LSCs) self-renewal in vitro and in vivo. CONCLUSION: From the above, we concluded that HLJDT and its key active ingredients (BBR and baicalein) allowed to overcome imatinib resistance with BCR-ABL1 independent by eradication of LSCs by targeting the JAK2 and MCL1 protein levels. Our results lay the foundation for applying HLJDT in patients with TKI-resistant CML.

Acute kidney injury and delayed methotrexate clearance in an adult patient with Philadelphia chromosome-positive acute lymphoblastic leukaemia treated with imatinib.

A female patient in her early 30s was treated with imatinib and high-dose methotrexate (HD-MTX) for Philadelphia chromosome-positive acute lymphoblastic leukaemia. The patient developed delayed MTX clearance and grade 3 acute kidney injury characterised by elevated creatinine (114% increase from baseline). After intensified calcium folinate rescue therapy and hydration, the MTX serum level was appropriately decreased 72 hours after the start of MTX infusion, and renal function returned to normal. Medication analysis by a clinical pharmacist suggested that the concomitant treatment with imatinib likely contributed to the delayed MTX clearance and caused the acute kidney injury.

A meta-analysis of the efficacy and toxicity of tyrosine kinase inhibitors in treating patients with different types of thyroid cancer: how to choose drugs appropriately?

PURPOSE OF REVIEW: Because the high risk of death and poor prognosis of patients with refractory thyroid cancer (TC), studies related to tyrosine kinase inhibitors (TKIs) in treating different types of refractory TC have gradually attracted attention. Thus, we conducted a meta-analysis of published randomized controlled trials and single-arm trials to evaluate tyrosine kinase inhibitors' efficacy and safety profile treatment in TC patients. RECENT FINDINGS: The studies of 29 in 287 met the criteria, 9 were randomized controlled trials and 20 were single-arm trials, involving 11 TKIs (Apatinib, Anlotinib, Cabozantinib, Imatinib, Lenvatinib, Motesanib, Pazopanib, Sorafenib, Sunitinib, Vandetanib, Vemurafenib). Treatment with TKIs significantly improved progression-free survival [hazard ratio [HR] 0.34 (95% confidence interval [CI]: 0.24, 0.48), P < 0.00001] and overall survival [OS] [HR 0.76, (95% CI: 0.64, 0.91), P = 0.003] in randomized controlled trials, but adverse events (AEs) were higher than those in the control group (P < 0.00001). The result of the objective response rate (ORR) in single-arm trials was statistically significant [odds ratio [OR] 0.49 (95% CI: 0.32, 0.75), P = 0.001]. SUMMARY: TKIs significantly prolonged progression-free survival and OS or improved ORR in patients with different types of TC (P < 0.01). Our recommendation is to select appropriate TKIs to treat different types of TC patients, and to prevent and manage drug-related AEs after using TKIs.

Piperlongumine overcomes imatinib resistance by inducing proteasome inhibition in chronic myelogenous leukemia cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Piper longum L., an herbal medicine used in India and other Asian countries, is prescribed routinely for a range of diseases, including tumor. Piperlongumine, a natural product isolated from Piper longum L., has received widespread attention due to its various pharmacological activities, such as anti-inflammatory, antimicrobial, and antitumor effects. AIM OF THE STUDY: Chronic myelogenous leukemia (CML) is a hematopoietic disease caused by Bcr-Abl fusion gene, with an incidence of 15% in adult leukemias. Targeting Bcr-Abl by imatinib provides a successful treatment approach for CML. However, imatinib resistance is an inevitable issue for CML treatment. In particular, T315I mutant is the most stubborn of the Bcr-Abl point mutants associated with imatinib resistance. Therefore, it is urgent to find an alternative approach to conquer imatinib resistance. This study investigated the role of a natural product piperlongumine in overcoming imatinib resistance in CML. MATERIALS AND METHODS: Cell viability and apoptosis were evaluated by MTS assay and Annexin V/propidium iodide counterstaining assay, respectively. Levels of intracellular signaling proteins were assessed by Western blots. Mitochondrial membrane potential was reflected by the fluorescence intensity of rhodamine-123. The function of proteasome was detected using 20S proteasomal activity assay, proteasomal deubiquitinase activity assay, and deubiquitinase active-site-directed labeling. The antitumor effects of piperlongumine were assessed with mice xenografts. RESULTS: We demonstrate that (i) Piperlongumine inhibits proteasome function by targeting 20S proteasomal peptidases and 19S proteasomal deubiquitinases (USP14 and UCHL5) in Bcr-Abl-WT and Bcr-Abl-T315I CML cells; (ii) Piperlongumine inhibits the cell viability of CML cell lines and primary CML cells; (iii) Proteasome inhibition by piperlongumine leads to cell apoptosis and downregulation of Bcr-Abl; (iv) Piperlongumine suppresses the tumor growth of CML xenografts. CONCLUSIONS: These results support that blockade of proteasome activity by piperlongumine provides a new therapeutic strategy for treating imatinib-resistant CML.

Effects of Imatinib Combined With Everolimus on Mouse Pituitary Tumor Cell AtT-20.

Context: Pituitary adenoma is a clinical syndrome in which excessive production of pituitary corticotropin (ACTH). For ACTH tumor cells, researchers know little about the influence of the cell-cycle process on ACTH production and cell proliferation. Some research has shown that imatinib can induce apoptosis of tumor cells. Objective: The study intended to explore the effects and molecular mechanisms of imatinib combined with everolimus on AtT-20 cells in AtT-20 mouse pituitary tumors. Design: The research team performed a laboratory study using murine corticotropin tumor AtT-20 cells. Setting: The study took place at the Department of Neurosurgery at Renmin Hospital of the Hubei University of Medicine in Shiyan, Hubei, China. Intervention: The research team cultured the cells in AtT-20-cell-specific medium containing 100 µg/mL of streptomycin, 100 U/mL of penicillin, and 10% fetal bovine serum at 37°C and 5% CO2. The team divided the cells into a control group, a normal culture without the drug, and an intervention group, incubated for 24 hours with 1 µM of imatinib and 3 µM of everolimus when the cells grew to 40% confluence. Outcome Measures: The research team: (1) determined the effects of the combined drugs on cell viability using a methyl thiazolyl tetrazolium (MTT) assay; (2) detected the cell's mitochondrial membrane potential and LDH leakage using "sytox blue, 5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolylcarbocyanine iodide," CBIC2(3) or JC-1, and lactate dehydrogenase (LDH) assay kits, respectively; (3) detected AtT-20 cell apoptosis using a "terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick-end labeling" (TUNEL) kit; (4) analyzed the expression of protein kinase B (p-Akt), cAMP-response element binding protein (p-CREB), p27, p53, and cyclin E using a Western blot test; (5) detected the mRNA expression of opioid melanin procorticotropin (POMC)), caspase-3, and pituitary tumor transforming gene 1 (PTTG1) using reverse transcription-polymerase chain reaction (RT-PCR); (6) measure the concentration of adreno-cortico-tropic-hormone (ACTH) in the supernatant using an enzyme-linked immunoassay (ELISA) kit; and (7) assessed the cell cycle distribution using flow cytometry. Results: No differences existed in cell viability between the groups at the baseline (0 h) of the culture period (P > .05). Compared to the control group, the intervention group's: (1) cell viability was significantly lower at 4, 8, and 12 hours and postintervention at 16 hours (P < .001); (2) LDH concentration was significantly higher (P < .001); (3) mitochondrial membrane potential was significantly lower (P < .001); (4) apoptosis rate of TUNEL was significantly higher (P < .001 ); (5) expression of p-Akt, p-CREB phosphorylation, and cyclin E was significantly lower (P < .001), (6) expression of p27 and p53 protein was significantly higher (P < .001); (7) mRNA expression of POMC and PTTG1 were significantly lower (P < .001); (8) mRNA expression of caspase-3 was significantly higher (P < .001); (9) concentration of ACTH was lower (P < .001); and (10) percentage of cells in the G0/G1 phase was significantly higher, while the percentage of cells in the S phase was significantly lower (P < .05). Conclusions: Imatinib combined with everolimus can affect the AtT-20 cell cycle through the signaling pathway of the phosphatidylin-ositol-3-kinase (PI3K)/Akt/ protein kinase A (PKA) system and can inhibit cell proliferation and induce cell apoptosis. Therefore, Imatinib and everolimus may be an effective combination of candidates for drugs for mouse pituitary tumor.

Comparative efficacy and safety of pharmacological interventions for severe COVID-19 patients: An updated network meta-analysis of 48 randomized controlled trials.

BACKGROUND: To date, there has been little agreement on what drug is the "best" drug for treating severe COVID-19 patients. This study aimed to assess the efficacy and safety of different medications available at present for severe COVID-19. METHODS: We searched databases for randomized controlled trials (RCTs) published up to February 28, 2022, with no language restrictions, of medications recommended for patients (aged 16 years or older) with severe COVID-19 infection. We extracted data on trials and patient characteristics, and the following primary outcomes: all-cause mortality (ACM), and treatment-emergent adverse events (TEAEs). RESULTS: We identified 4021 abstracts and of these included 48 RCTs comprising 9147 participants through database searches and other sources. For decrease in ACM, we found that ivermectin/doxycycline, C-IVIG (i.e., a hyperimmune anti-COVID-19 intravenous immunoglobulin), methylprednisolone, interferon-beta/standard-of-care (SOC), interferon-beta-1b, convalescent plasma, remdesivir, lopinavir/ritonavir, immunoglobulin gamma, high dosage sarilumab (HS), auxora, and imatinib were effective when compared with placebo or SOC group. We found that colchicine and interferon-beta/SOC were only associated with the TEAEs of severe COVID-19 patients. CONCLUSION: This study suggested that ivermectin/doxycycline, C-IVIG, methylprednisolone, interferon-beta/SOC, interferon-beta-1b, convalescent plasma (CP), remdesivir, lopinavir/ritonavir, immunoglobulin gamma, HS, auxora, and imatinib were efficacious for treating severe COVID-19 patients. We found that most medications were safe in treating severe COVID-19. More large-scale RCTs are still needed to confirm the results of this study.

A clinician perspective on the treatment of chronic myeloid leukemia in the chronic phase.

Tyrosine kinase inhibitors (TKIs) have vastly improved long-term outcomes for patients with chronic myeloid leukemia (CML). After imatinib (a first-generation TKI), second- and third-generation TKIs were developed. With five TKIs (imatinib, dasatinib, bosutinib, nilotinib, and ponatinib) targeting BCR::ABL approved in most countries, and with the recent approval of asciminib in the USA, treatment decisions are complex and require assessment of patient-specific factors. Optimal treatment strategies for CML continue to evolve, with an increased focus on achieving deep molecular responses. Using clinically relevant case studies developed by the authors of this review, we discuss three major scenarios from the perspective of international experts. Firstly, this review explores patient-specific characteristics that affect decision-making between first- and second-generation TKIs upon initial diagnosis of CML, including patient comorbidities. Secondly, a thorough assessment of therapeutic options in the event of first-line treatment failure (as defined by National Comprehensive Cancer Network and European LeukemiaNet guidelines) is discussed along with real-world considerations for monitoring optimal responses to TKI therapy. Thirdly, this review illustrates the considerations and importance of achieving treatment-free remission as a treatment goal. Due to the timing of the writing, this review addresses global challenges commonly faced by hematologists treating patients with CML during the COVID-19 pandemic. Lastly, as new treatment approaches continue to be explored in CML, this review also discusses the advent of newer therapies such as asciminib. This article may be a useful reference for physicians treating patients with CML with second-generation TKIs and, as it is focused on the physicians' international and personal experiences, may give insight into alternative approaches not previously considered.

A Ten-Year Experience of Treating Chronic Myeloid Leukemia in Rural Rwanda: Outcomes and Insights for a Changing Landscape.

PURPOSE: In describing our ten-year experience with treating chronic myeloid leukemia (CML) as part of the Glivec Patient Assistance Program (GIPAP) in rural Rwanda, we evaluate (1) patient characteristics and treatment outcomes, (2) resource-adapted management strategies, and (3) the impact of diagnostic capacity development. METHODS: We retrospectively reviewed all patients with BCR-ABL-positive CML enrolled in this GIPAP program between 2009 and 2018. Clinical data were analyzed using descriptive statistics, Kaplan-Meier methods, proportional hazards regression, and the Kruskal-Wallis test. RESULTS: One hundred twenty-four patients were included. The median age at diagnosis was 34 (range 8-81) years. On imatinib, 91% achieved complete hematologic response (CHR) after a median of 49 days. Seven (6%) and 12 (11%) patients had primary and secondary imatinib resistance, respectively. The 3-year overall survival was 80% (95% CI, 72 to 87) for the cohort, with superior survival in imatinib responders compared with those with primary and secondary resistance. The median time from imatinib initiation to CHR was 59 versus 38 days (P = .040) before and after in-country diagnostic testing, whereas the median time to diagnosis (P = .056) and imatinib initiation (P = .170) was not significantly different. CONCLUSION: Coupling molecular diagnostics with affordable access to imatinib within a comprehensive cancer care delivery program is a successful long-term strategy to treat CML in resource-constrained settings. Our patients are younger and have higher rates of imatinib resistance compared with historic cohorts in high-income countries. High imatinib resistance rates highlight the need for access to molecular monitoring, resistance testing, and second-generation tyrosine kinase inhibitors, as well as systems to support drug adherence. Hematologic response is an accurate resource-adapted predictor of survival in this setting. Local diagnostic capacity development has allowed for continuous, timely CML care delivery in Rwanda.

Itrifal-e-Aftimoon potentiates imatinib-induced anti-leukemic effect by influencing FAK/STAT/Akt/ERK signalling pathways against chronic myeloid leukaemia in vitro.

OBJECTIVES: Limited treatment options are available for advanced stages of chronic myeloid leukaemia (CML). Moreover, patients' relapse after a short remission period, which prompts them to identify a potent drug with the least toxicity. An Unani herbal formulation, Itrifal-e-Aftimoon (IEA) is used for certain neurological disorders, however, its antitumor potential has not been reported yet in any malignancy, including CML. METHODS: The aqueous extract of IEA was characterized by HPLC/LC-MS and used alone or in combination with standard drug, imatinib in CML cell lines (K562, KU812) in vitro to assess its effect on cancer-associated parameters such as cytotoxicity, cell cycle, apoptosis, oxidative stress, inflammation, angiogenesis, and certain signalling pathways. RESULTS: LC-MS characterization of IEA showed the presence of antitumor compounds including catechin and caffeic acid. Treatment with IEA caused cytotoxicity and arrested cells in the sub-G0/G1 phase. Subsequent assays confirmed apoptosis-mediated cell death with mitochondrial membrane depolarization and alleviation of oxidative stress. IEA abrogates IL-6, VEGF, angiopoietin-2, and alters Th1/Th2 cytokines. IEA potentiated the effect of imatinib even at lower doses by affecting FAK/STAT/Akt/ERK pathways. CONCLUSION: IEA possesses antitumor potential against CML and increases the efficacy of imatinib when used in combination, suggesting utilization of IEA as an adjuvant therapy for better management of CML in the future.

Setting up criteria for drug-induced autoimmune-like hepatitis through a systematic analysis of published reports.

Nitrofurantoin, minocycline, methyldopa and infliximab, have been found to induce autoimmune-like hepatitis (DI-AILH). Evidence for other drugs and herbal and dietary supplements (HDS) is unclear. The aims of the study were to establish criteria to define and review the published evidence of suspected DI-AILH. Search was undertaken in Pubmed using search terms "drug-induced liver injury," "autoimmune hepatitis," and "drug-induced autoimmune hepatitis." DI-AILH was defined as (1) drug as a potential trigger of liver injury with autoimmune features and histological findings compatible with AIH; (2) no or incomplete recovery or worsening of liver tests after discontinuation of the drug; (3) corticosteroids requirement or spontaneous recovery; (4) follow-up without immunosuppression (IS) and no relapse of AIH at least 6 months after discontinuation of IS; and (5) drugs potentially inducing AILH with a chronic course. Cases fulfilling the first four criteria were considered probable DI-AILH with three possible DI-AILH. A total of 186 case reports were identified for conventional drugs (n = 148; females 79%; latency 2.6 months) and HDS (n = 38; females 50%). The most commonly reported agents of DI-AILH were interferons (n = 37), statins (n = 24), methylprednisolone (MPS) (n = 16), adalimumab (n = 10), imatinib (n = 8), and diclofenac (n = 7). Tinospora cordifolia and Khat were the only HDS with probable DI-AILH cases. No relapses of AIH were observed when IS was stopped after interferons, imatinib, diclofenac, and methylprednisolone. Conclusion: Beyond well-recognized nitrofurantoin, methyldopa, hydralazine, minocycline, and infliximab as causes of DI-AILH, interferons, imatinib, adalimumab, and MPS were the best-documented agents leading to probable DI-AILH. Khat and Tinospora cordifolia were the only HDS found to be able to induce DI-AILH. Long-term immunosuppression appears to be rarely required in patients with DI-AILH due to these drugs.

In-vitro pH-responsive release of imatinib from iron-supplement coated anatase TiO2 nanoparticles.

Targeted drug delivery is one such precision method of delivering medication inside the human body which can vanquish all the limitations of the conventional chemotherapeutic techniques. In the present study, two types of nanoparticles (NPs) were chosen for the in-vitro pH-responsive release study of the drug, Imatinib, namely anatase Titanium Dioxide nanoparticles (TiO2 NPs) and iron-capped TiO2 NPs, designated as Fe@TiO2 NPs. The novelty of this work lies behind the use of commercially available iron supplement 'Autrin' meant for human consumption, as the material to coat the TiO2 NPs to synthesize Fe@TiO2 NPs. The synthesized NPs were analyzed by XRD, HR-TEM, SAED, EDX and VSM. UV-Vis spectroscopy was performed for absorption studies. Fe@TiO2 NPs showed superparamagnetic behavior and thus they are able to ensure the facile transfer of Imatinib via external magnetic fields. The results obtained from in-vitro drug release studies depicted that both TiO2 NPs and Fe@TiO2 NPs showed a controlled pH-sensitive delivery of the loaded Imatinib molecules. Moreover, both types of NPs do not result in the formation of ROS under human physiological conditions. These results can lay the foundation to the development of efficacious targeted drug delivery systems in the healthcare sector.

Anticancer Activity and Molecular Mechanism of Momordica cochinchinensis Seed Extract in Chronic Myeloid Leukemia Cells.

Targeting Bcr-Abl is the key to the treatment of chronic myeloid leukemia. Despite great progress in the treatment of patients with chronic CML, advanced CML patients are still unable to obtain effective and safe drugs. Momordica cochinchinensis seed is the dried ripe seed of Momordica cochinchinensis, which is a kind of fruit and consumed for dietary as well as medicinal uses. This study aimed to investigate the anticancer activity of Momordica cochinchinensis seed extract (MCSE) in CML cells. CML cells (KBM5 and KBM5-T315I) were treated with MCSE and analyzed for growth, apoptosis, and signal transduction. Nude mouse xenograft model was used to evaluate the antitumor activity of MCSE In Vivo. MCSE significantly reduced the cell viability of CML cells, triggered G0/G1 phase arrest in KBM5 cells and S phase arrest in KBM5-T315I cells. Concurrently, MCSE caused the activation of caspase-3, -8, -9, PARP and the degradation of Mcl-1, ultimately triggering endogenous and exogenous cell apoptosis. Meanwhile, MCSE downregulated Bcr-Abl levels and its downstream signaling pathways. Additionally, MCSE inhibited the growth of CML cells in nude mouse xenografts. Taken together, this study demonstrated the anticancer mechanism of MCSE, namely blocking Bcr-Abl and downregulating Mcl-1, and finally induced apoptosis of CML cells.

Antimetabolic cooperativity with the clinically approved l-asparaginase and tyrosine kinase inhibitors to eradicate CML stem cells.

OBJECTIVE: Long-term treatment with tyrosine kinase inhibitors (TKI) represents an effective cure for chronic myeloid leukemia (CML) patients and discontinuation of TKI therapy is now proposed to patient with deep molecular responses. However, evidence demonstrating that TKI are unable to fully eradicate dormant leukemic stem cells (LSC) indicate that new therapeutic strategies are needed to control LSC and to prevent relapse. In this study we investigated the metabolic pathways responsible for CML surviving to imatinib exposure and its potential therapeutic utility to improve the efficacy of TKI against stem-like CML cells. METHODS: Using complementary cell-based techniques, metabolism was characterized in a large panel of BCR-ABL+ cell lines as well as primary CD34+ stem-like cells from CML patients exposed to TKI and L-Asparaginases. Colony forming cell (CFC) assay and flow cytometry were used to identify CML progenitor and stem like-cells. Preclinical models of leukemia dormancy were used to test the effect of treatments. RESULTS: Although TKI suppressed glycolysis, compensatory glutamine-dependent mitochondrial oxidation supported ATP synthesis and CML cell survival. Glutamine metabolism was inhibited by L-asparaginases such as Kidrolase or Erwinase without inducing predominant CML cell death. However, clinically relevant concentrations of TKI render CML cells susceptible to Kidrolase. The combination of TKI with Lasparaginase reactivates the intinsic apoptotic pathway leading to efficient CML cell death. CONCLUSION: Targeting glutamine metabolism with the FDA-approved drug, Kidrolase in combination with TKI that suppress glycolysis represents an effective and widely applicable therapeutic strategy for eradicating stem-like CML cells.

Eficacia y seguridad de dasatinib en pacientes adultos con leucemia linfoblástica aguda philadelphia positivo resistente o intolerante a quimioterapia más imatinib / Efficacy and safety of dasatinib in adult patients with philadelphia-positive acute lymphoblastic leukemia resistant or intolerant to chemotherapy plus imatinib

ANTECEDENTES : El presente dictamen expone la evaluación de la eficacia y seguridad de dasatinib con o sin quimioterapia, comparado con quimioterapia, en pacientes adultos con leucemia linfoblástica aguda, philadelphia positivo, resistente o intolerante a quimioterapia más imatinib. En la literatura se señala que, la leucemia linfoblástica aguda (LLA) cromosoma Philadelphia positivo (Ph+) representa entre el 20.0 al 30 % de los casos de LLA. En el Perú, no se conoce el número de casos de LLA Ph+; sin embargo, se conoce que, en el 2019, la tasa de incidencia de LLA en personas mayores de 20 años fue de 1.04 casos por cada 100,000 personas y la tasa de mortalidad fue de 0.79 muertes por cada 100,000 personas.  Luego de la terapia de inducción con un inhibidor de la tirosina quinasa (TKI, por sus siglas en inglés), entre el 10 y 20 % de los pacientes desarrolla LLA resistente. Debido a la aparición de casos de resistencia o intolerancia a los TKI de primera generación (imatinib), se han desarrollado otros TKI, como dasatinib. En EsSalud, se cuentan con varias opciones de medicamentos que pueden ser empleados en diferentes esquemas de quimioterapia en este grupo de pacientes con resistencia o intolerancia a TKI. Actualmente, dasatinib se encuentra disponible en EsSalud para el tratamiento de pacientes con leucemia mieloide crónica (LMC), Ph+ resistente o intolerante a tratamientos previos a dosis altas a imatinib y sin mutación T315l. No obstante, algunos especialistas de EsSalud solicitan que se amplíe el uso de dasatinib a pacientes adultos con LLA Ph+ resistente o intolerante, aduciendo que dasatinib (con o sin quimioterapia) podría mejorar la sobrevida libre de progresión (SLP) del paciente. Así, el presente dictamen preliminar expone la evaluación de la eficacia y seguridad de dasatinib, con o sin quimioterapia, en pacientes adultos con LLA Ph+ resistente o intolerante a quimioterapia más imatinib. METODOLOGÍA: Tras la búsqueda de la literatura científica, se identificaron dos guías de práctica clínicas (GPC) elaboradas por The National Comprehensive Cancer Network (NCCN) y The European Society for Medical Oncology (ESMO), y dos evaluaciones de tecnologías sanitarias (ETS) elaboradas por The Scottish Medicines Consortium (SMC) y Comissão Nacional de Incorporação de Tecnologías no Sistema Único de Saúde (CONITEC). Además, se encontraron dos estudios de fase II; sin grupo de comparación, el estudio START-L (Ottman et al., 2007), empleado para sustentar la aprobación acelerada de uso de dasatinib por parte de la Food and Drug Administration (FDA) y la aprobación de la European Medicines Agency (EMA) en pacientes con LLA Ph+ y resistencia o intolerancia a una terapia previa, y el estudio de Sakamaki et al., 2009. RESULTADOS: Se describe la evidencia disponible según el tipo de publicación, siguiendo lo indicado en los criterios de elegibilidad. CONCLUSIONES: En el presente documento, se evaluó la mejor evidencia científica disponible hasta la actualidad, sobre la eficacia y seguridad de dasatinib con o sin quimioterapia, comparado con quimioterapia, en pacientes adultos con LLA Ph+y resistencia o intolerancia a la quimioterapia más imatinib. La búsqueda sistemática de la evidencia culminó con la selección de dos GPC (NCCN 2021; Hoelzer et al. 2016), dos ETS (CONITEC 2020; SMC 2007), el estudio de fase II START-L, pivotal de dasatinib (Ottmann et al. 2007), y el estudio de fase II de Sakamaki et al. (Sakamaki et al. 2009). Las GPC del NCCN y ESMO coinciden en señalar que la evidencia disponible sobre el uso de dasatinib para el tratamiento de los pacientes con LLA Ph+ y resistencia o recaída no es de calidad. Por ello, la ESMO resalta que no hay una terapia estándar de reinducción y el NCCN recomienda, especialmente, la participación en un ensayo clínico. Las ETS del SMC y del CONITEC coinciden en dar una recomendación en contra del uso de dasatinib en pacientes con LLA Ph+ con resistencia/recaída a una terapia previa o al mesilato de imatinib. La SMC basó en que la terapia con dasatinib no sería costo-efectiva en este grupo de pacientes; y la CONITEC, en la alta incidencia de EAS, y las altas tasas de abandono del tratamiento y de reducción de dosis observadas en la evidencia analizada. Los estudios START-L y de Sakamaki et al., de fase II, presentaron limitaciones (e.g. falta de un grupo de comparación, pequeño tamaño de la muestra y la falta de acceso al protocolo del estudio) que afectan la validez de sus resultados. Aun así, sus resultados sugieren que el perfil de seguridad de dasatinib no puede ser considerado como favorable para los pacientes (altas tasas de eventos adversos, reducción de dosis de dasatinib y descontinuación del tratamiento). Actualmente, en EsSalud, se cuentan con varias opciones de medicamentos que pueden ser empleados en diferentes esquemas de quimioterapia para pacientes con LLA Ph+ resistente o intolerante a quimioterapia más imatinib. Por lo expuesto, el IETSI no aprueba el uso de dasatinib con o sin quimioterapia en pacientes adultos con LLA Ph+ resistente o intolerante a quimioterapia más imatinib.

Eficacia y seguridad de bosutinib en pacientes con leucemia mieloide crónica con el gen de fusion bcr-abl, con mutación T315I negativo y con falla y/o intolerancia a imatinib, dasatinib y nilotinib / Efficacy and safety of bosutinib in patients with chronic myeloid leukemia with the bcr-abl fusion gene, negative T315I mutation and with failure and/or intolerance to imatinib, dasatinib and nilotinib

INTRODUCCIÓN: El presente dictamen preliminar expone la evaluación de la eficacia y seguridad de bosutinib, comparado con la mejor terapia de soporte, para el tratamiento de pacientes con leucemia mieloide crónica con el gen de fusión BCR-ABL, con mutación T315I negativo y con falla y/o intolerancia a imatinib, dasatinib y nilotinib. La leucemia mieloide crónica (LMC) es una neoplasia mieloproliferativa y de baja frecuencia; no obstante, es la sexta causa de muerte por cáncer en Perú. El gen de fusión BCR-ABL, presente en más del 90 % de los casos, produce una proteína con alta actividad catalítica de tirosina quinasa, implicada en la patogénesis de la LMC. Esta enfermedad consta de tres fases: crónica, acelerada y de crisis blástica. Si bien el trasplante alogénico de células hematopoyéticas (TACMH) es potencialmente curativo, algunos pacientes no son candidatos a recibir un TACMH o no es posible encontrar un donante compatible. En estos casos, los pacientes pueden recibir inhibidores de la tirosina quinasa (ITQ), los cuales actúan de manera específica sobre la proliferación celular inducida por el gen de fusión BCR-ABL. En EsSalud se cuenta con tres ITQ (imatinib, dasatinib y nilotinib) que pueden ser utilizados hasta una tercera línea de tratamiento. Sin embargo, existen pacientes, con la mutación T315I negativo, no respondedores a los tres ITQ por falla o intolerancia, para quienes los médicos especialistas de la institución sugieren el uso de bosutinib, un ITQ de segunda generación, como cuarta línea de tratamiento. METODOLOGÍA: Se llevó a cabo una búsqueda sistemática de la literatura con el objetivo de identificar la mejor evidencia sobre la eficacia y seguridad de bosutinib, en comparación con la mejor terapia de soporte, para el tratamiento de pacientes con LMC con el gen de fusión BCR-ABL, con mutación T315I negativo y con falla y/o intolerancia a imatinib, dasatinib y nilotinib. La búsqueda se realizó en las bases de datos: PubMed, The Cochrane Library y LILACS. Adicionalmente, se realizó una búsqueda manual dentro de las páginas web pertenecientes a grupos que realizan evaluación de tecnologías sanitarias (ETS) y guías de práctica clínica (GPC) incluyendo: el National Institute for Health and Care Excellence (NICE), la Canadian Agency for Drugs and Technologies in Health (CADTH), el Scottish Medicines Consortium (SMC), el Scottish Intercollegiate Guidelines Network (SIGN), el Institute for Clinical and Economic Review (ICER), el Institute for Quality and Efficiency in Healthcare (IQWiG por sus siglas en alemán), la Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas (BRISA), la OMS, el Ministerio de Salud del Perú (MINSA), el Instituto de Evaluación de Tecnologías en Salud e Investigación (IETSI), la National Comprehensive Cancer Network (NCCN), la British Society for Haematology (BSH) y la European Society for Medical Oncology (ESMO). Finalmente, se realizó una búsqueda manual en la página web de registro de ensayos clínicos (EC) de ClinicalTrials.gov para identificar EC en curso o con resultados que no hayan sido publicados. RESULTADOS: La presente sinopsis describe la evidencia científica sobre el uso de bosutinib como tratamiento de pacientes con LMC con el gen de fusión BCR-ABL, con mutación T315I negativo y con falla y/o intolerancia a imatinib, dasatinib y nilotinib, según el tipo de publicación. CONCLUSIONES: El objetivo del presente dictamen fue evaluar la mejor evidencia disponible sobre la eficacia y seguridad de bosutinib comparado con la mejor terapia de soporte (hidroxiurea) para el tratamiento de pacientes con LMC con el gen de fusión BCR-ABL (cromosoma Ph positivo), con mutación T315I negativo y con falla y/o intolerancia a imatinib, dasatinib y nilotinib. La población de interés (pacientes con LMC con cromosoma Ph positivo, con mutación T315I negativo y con falla y/o intolerancia imatinib, dasatinib y nilotinib) no cuenta con una alternativa de tratamiento contra la LMC (vacío terapéutico), ante el vacío terapéutico estos pacientes progresarían a etapas más avanzadas con mayor riesgo de muerte. Luego de la búsqueda de la literatura se identificó una GPC desarrollada por BSH; cuatro ETS desarrolladas por el SMC, la CADTH, el NICE y el IQWiG; un EC de fase I/II (estudio pivotal) publicado por Khoury et al.; un EC de fase IV (fase de post comercialización) publicado por Hochhaus et al. y un estudio observacional retrospectivo publicado por García-Gutiérrez et al. Debido a las limitaciones del los ECA de fase II y IV y el estudio observacional (todos sin grupo de comparación), la eficacia y seguridad de bosutinib y su beneficio neto en la calidad de vida son inciertos puesto que no se puede establecer una relación causal entre los resultados reportados y el tratamiento con bosutinib. No obstante, cabe precisar que datos descriptivos muestran que la mortalidad a los dos años con el uso bosutinib es menor al 5 %, mientras que con el uso de hidroxiurea sería entre 20 % y 47.5 %. La guía recomienda usar ITQ en el contexto de cuarta línea en pacientes con intolerancia a ITQ recibidos previamente. No obstante, no se especifica la evidencia de soporte. Las ETS de NICE, SMC y CADTH optaron por recomendar el uso de bosutinib en pacientes adultos con LMC con cromosoma Ph positivo, que previamente han recibido ITQ y para quienes imatinib, dasatinib y nilotinib no son apropiados, dicha recomendación fue condicionada a un descuento confidencial sobre el precio de lista de bosutinib. Las tres ETS emplearon como evidencia de soporte el estudio clínico fase I/II, el cual incluyó solo tres pacientes que recibieron bosutinib en cuarta línea. La ETS de IQWiG concluye que no es posible determinar el beneficio del tratamiento con bosutinib frente a otro ITQ. La principal limitación para ello fue que el EC de fase I/II no evalúa bosutinib frente a los comparadores de interés para IQWiG, los cuales fueron diferentes a los establecidos en la PICO del presente dictamen. El uso prolongado de la terapia de soporte con hidroxiurea podría generar similares incidencias de EA que con bosutinib (toxicidad gastrointestinal, neutropenia, anemia, trombocitopenia); pero, adicionalmente podría generar otros problemas como ulceras graves, neoplasias malignas, toxicidad pulmonar, mielosupresión grave, entre otros. Existe plausibilidad biológica; ya que no todas las mutaciones que confieren resistencia a imatinib, dasatinib o nilotinib, confieren resistencia a bosutinib; y aún existe la posibilidad de que bosutinib sí sea eficaz. Por lo expuesto, el Instituto de Evaluación de Tecnologías en Salud e Investigación aprueba el uso de bosutinib para el tratamiento de pacientes con LMC con el gen de fusión BCR-ABL (cromosoma Ph positivo), con mutación T315I negativo, con falla y/o intolerancia a tres inhibidores de la tirosina quinasa (imatinib, dasatinib y nilotinib), según lo establecido en el Anexo N°1. La vigencia del presente dictamen preliminar es de un año a partir de la fecha de publicación. Así, la continuación de dicha aprobación estará sujeta a la evaluación de los resultados obtenidos y de mayor evidencia que pueda surgir en el tiempo.