Ferroptosis ; Piperazines/pharmacology* ; Cell Line, Tumor

The mutation rate of anaplastic lymphoma kinase (ALK) in patients with non-small cell lung cancer is 3% to 7%. Due to its low mutation rate and better long-term survival compared with epidermal growth factor receptor-positive non-small cell lung cancer patients, therefore, it's called "diamond mutation". At present, there are three generations of ALK tyrosine kinase inhibitor (TKI) drugs in the world. The first-generation ALK-TKI drug approved in China is crizotinib, and the second-generation drugs are alectinib, ceritinib and ensartinib. Among them, ensartinib is an ALK-TKI domestically developed, and its efficacy is similar to that of alectinib. The main adverse event is transient rash, and compliance to ensartinib is better from the perspective of long-term survival of patients. The manifestation of rash caused by ensartinib is different from that of other ALK-TKI drugs. In order to facilitate clinical application and provide patients with more treatment options, under the guidance of the Committee of Cancer Rehabilitation and Palliative Care of China Anti-Cancer Association, this article collects and summarizes the common adverse reactions of ensartinib. Based on the clinical practice, a clear adverse classification and specific treatment plan are formulated, in order to provide a corresponding reference for clinicians to make more comprehensive clinical decisions.
Anaplastic Lymphoma Kinase ; Carbazoles/adverse effects* ; Carcinoma, Non-Small-Cell Lung/pathology* ; Consensus ; Exanthema/drug therapy* ; Humans ; Lung Neoplasms/pathology* ; Piperazines ; Protein Kinase Inhibitors/adverse effects* ; Pyridazines

Abivertinib, a third-generation tyrosine kinase inhibitor, is originally designed to target epidermal growth factor receptor (EGFR)-activating mutations. Previous studies have shown that abivertinib has promising antitumor activity and a well-tolerated safety profile in patients with non-small-cell lung cancer. However, abivertinib also exhibited high inhibitory activity against Bruton's tyrosine kinase and Janus kinase 3. Given that these kinases play some roles in the progression of megakaryopoiesis, we speculate that abivertinib can affect megakaryocyte (MK) differentiation and platelet biogenesis. We treated cord blood CD34⁺ hematopoietic stem cells, Meg-01 cells, and C57BL/6 mice with abivertinib and observed megakaryopoiesis to determine the biological effect of abivertinib on MK differentiation and platelet biogenesis. Our in vitro results showed that abivertinib impaired the CFU-MK formation, proliferation of CD34⁺ HSC-derived MK progenitor cells, and differentiation and functions of MKs and inhibited Meg-01-derived MK differentiation. These results suggested that megakaryopoiesis was inhibited by abivertinib. We also demonstrated in vivo that abivertinib decreased the number of MKs in bone marrow and platelet counts in mice, which suggested that thrombopoiesis was also inhibited. Thus, these preclinical data collectively suggested that abivertinib could inhibit MK differentiation and platelet biogenesis and might be an agent for thrombocythemia.
Acrylamides/pharmacology* ; Animals ; Blood Platelets/drug effects* ; Cell Differentiation ; Megakaryocytes/drug effects* ; Mice ; Mice, Inbred C57BL ; Piperazines/pharmacology* ; Pyrimidines/pharmacology*

OBJECTIVE: To explore the mechanism by which berberine inhibits ferroptosis of mouse hippocampal neuronal cells (HT22). METHODS: Cultured HT22 cells were pretreated with 30 or 60 μmol/L berberine for 2 h before exposure to 0.5 μmol/L erastin for 8 h, and the cell proliferation, intracellular ferric iron level, changes in intracellular reactive oxygen species (ROS) and cell apoptosis were detected using CCK-8, Fe²⁺ fluorescent probe, fluorescent dye (DAPI) and fluorescent probe (H2DCFH-DA). RT-qPCR and Western blotting were used to detect the mRNA and protein expressions of Nrf2, HO-1 and GPX4 in the cells. We further tested the effects of treatments with 2 μmol/L ML385 (a Nrf2 inhibitor), 60 μmol/L berberine and erastin in the cells to explore the protective mechanism of berberine against erastin-induced ferroptosis in the neuronal cells. RESULTS: Treatment with 0.5 μmol/L erastin significantly lowered the viability of HT22 cells (P < 0.05) and increased the production of ROS, cell apoptosis rate and ferric iron level (P < 0.05). Pretreatment with 30 and 60 μmol/L berberine both significantly increased the vitality of erastin-exposed cells (P < 0.05) and lowered the levels of intracellular ROS and ferric iron content (P < 0.05). RT-qPCR and Western blotting showed that berberine obviously promoted the expressions of Nrf2, HO-1 and GPX4 in the cells (P < 0.05), and treatment with ML385 significantly inhibited the Nrf2-HO-1/GPX4 pathway, increased intracellular ROS and ferric iron contents and mitigated the protective effect of berberine against erastin-induced ferroptosis (P < 0.05). CONCLUSION Berberine can inhibit erastin-induced ferroptosis in HT22 cells possibly by activating the Nrf2-HO-1/ GPX4 pathway.
Animals ; Berberine/pharmacology* ; Ferroptosis ; Fluorescent Dyes ; Hippocampus/metabolism* ; Iron/metabolism* ; Mice ; NF-E2-Related Factor 2/metabolism* ; Piperazines ; Reactive Oxygen Species/metabolism*

OBJECTIVE: To evaluate the clinical efficacy and safety of domestic imatinib (made in China) in patients with newly diagnosed chronic myeloid leukemia chronic phase(CML-CP). METHODS: Fifty-seven newly diagnosed CML-CP patients who did not receive any other anti-CML treatment were treated by domestic imatinib 400 mg once a day. The hematological, cytogenetic and molecular reactions and safety were observed and evaluated after 3, 6 and 12 months of treatment. RESULTS: Fifty-six patients were treated for ≥3 and 6 months, among which 50 patients were treated for ≥12 months. After 3 months of treatment, 49 patients underwent hematological examination, 47 patients (95.9%) achieved complete hematological response (CHR), 49 patients underwent cytogenetic examination, 39 patients (79.6%) achieved major cytogenetic response (MCyR), and 12 patients (24.5%) achieved complete cytogenetic response (CCyR). 49 patients underwent the level of BCR-ABL test, including 41 patients (83.7%) with BCR-ABL CONCLUSION In the real world, Domestics imatinib mesylate is effective and safe in the treatment of newly diagnosed CML-CP patients, but long-term follow-up data are still necessary to verify its long-term efficacy.
Antineoplastic Agents/therapeutic use* ; Benzamides/therapeutic use* ; China ; Fusion Proteins, bcr-abl/genetics* ; Humans ; Imatinib Mesylate/therapeutic use* ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy* ; Piperazines ; Pyrimidines/therapeutic use* ; Treatment Outcome

OBJECTIVE: To investigate the regulatory effects of Olaparib on natural killer cell activating receptor (NKG2D) ligands expression on human acute myeloid leukemia (AML) cell line HL-60, and to explore the molecular mechanism of Olaparib on HL-60 cells. METHODS: After HL-60 cells in logarithmic growth phase were treated with Olaparib at different concentrations for different times (24, 48 h), the expression of NKG2D ligand on the surface of HL-60 cells was detected by flow cytometry. Western blot was used to dectect the expression of ERK expression in HL-60 cells. The killing effect of NK cells to HL-60 cells was detected by CFSE/PI method. RESULTS: 10 μmol/L Olaparib could upregulate the expression of NKG2D ligand on the surface of HL-60 cell at 24 and 48 hours, while 5 μmol/L Olaparib could induce up-regulation of the expression of ULBP-2 and ULBP-3 at 48 hours. Western blot analysis showed that ERK phosphorylation of HL-60 cells was enhanced after treating with Olaparib. The killing effect of NK cells to HL-60 cells could be enhanced by Olaparib, however, ERK inhibitor could suppress the killing effect of NK cells to HL-60 cells. CONCLUSION Olaparib can upregulate NKG2D ligands expression on the surface of HL-60 cells and enhance the cytotoxicity of NK cell to HL-60 cells. The mechanism may be related to Olaparib promoting ERK phosphorylation expression.
Cell Line, Tumor ; Cytotoxicity, Immunologic ; HL-60 Cells ; Histocompatibility Antigens Class I ; Humans ; Ligands ; NK Cell Lectin-Like Receptor Subfamily K ; Phthalazines ; Piperazines ; Poly(ADP-ribose) Polymerase Inhibitors

OBJECTIVE: To evaluate the clinical effect of filiform fire needling on moderate and severe pain in advanced cancer. METHODS: A total of 66 patients with moderate and severe pain in advanced cancer were randomly divided into an observation group (34 cases, 4 cases dropped off) and a control group (32 cases, 2 cases dropped off). The two groups were treated with oral analgesics continuously for 4 weeks. The moderate pain patients was given bucinnazine hydrochloride tablets (starting at 30 mg, once every 6 hours, increasing by 30%-50% until the titration volume was reached), and the severe pain patients were given oxycodone hydrochloride sustained-release tablets (starting at 20 mg every 12 hours and increasing by 25%-50% until the titration volume was reached). The observation group was cooperated with filiform fire needling at point, Zusanli (ST 36), Liangqiu (ST 34), Qihai (CV 6), Guanyuan(CV 4), Quchi (LI 11) and Waiguan (TE 5) once every other day for 4 weeks. The changes of numerical rating scales (NRS) scores were observed in both groups before and after treatment, and the amount of analgesics and the incidence of adverse reactions were recorded. The clinical effects in the two groups were evaluated. RESULTS: The effective rate was 90.0% (27/30) in the observation group, which was higher than 66.7% (20/30) in the control group (<0.05). After treatment, the NRS scores of both groups were lower than those before treatment (<0.05), and the reducing degree in the observation group was larger than that in the control group (<0.05). The average dosage of bunarizine hydrochloride tablets and oxycodone hydrochloride sustained release tablets to titration volume in the observation group was less than that in the control group (<0.05). The incidence of adverse reactions was 23.3% (28/120) in the observation group, which was lower than 44.2% (53/120) in the control group (<0.05). CONCLUSION Filiform fire needling can alleviate pain symptoms of patients with moderate and severe pain in advanced cancer, reduce the amount of analgesics, and decrease the incidence of adverse reactions.
Acupuncture Points ; Acupuncture Therapy ; Analgesics ; therapeutic use ; Cancer Pain ; therapy ; Humans ; Neoplasms ; complications ; therapy ; Oxycodone ; therapeutic use ; Pain Management ; Piperazines ; therapeutic use ; Treatment Outcome

OBJECTIVE: To investigate the effects of blocking the activation of ERK pathway on the expression of matrix metalloproteinase-9 (MMP-9) and the formation of cerebral edema in SD rats after brain injury. METHODS: Ninety SD rats were randomly divided into 3 equal groups, including a sham-operated group, modified Feeney's traumatic brain injury model group, and ERK inhibition group where the ERK inhibitor SCH772984 (500 μg/kg) was injected via the femoral vein 15 min before brain trauma. At 2 h and 2 days after brain trauma, the permeability of blood-brain barrier was assessed by Evans blue method, the water content of the brain tissue was determined, and the phosphorylation level of ERK and the expression level of MMP-9 mRNA and protein were measured by RT-PCR and Western blotting. RESULTS: Compared with the sham-operated group, the rats with brain trauma exhibited significantly increased level of ERK phosphorylation at 2 h and significantly increased expression of MMP-9 mRNA and protein 2 days after the injury ( < 0.01). Treatment with the ERK inhibitor significantly decreased the phosphorylation level of ERK after the injury ( < 0.01), suppressed over-expression of MMP-9 mRNA and protein 2 days after the injury ( < 0.01). The permeability of blood-brain barrier increased significantly 2 h after brain trauma ( < 0.05) and increased further at 2 days ( < 0.01); the water content of the brain did not change significantly at 2 h ( > 0.05) but increased significantly 2 d after the injury ( < 0.01). Treatment with the ERK inhibitor significantly lowered the permeability of blood-brain barrier and brain water content after brain trauma ( < 0.01). CONCLUSIONS Blocking the activation of ERK pathway significantly reduced the over-expression of MMP-9 and alleviates the damage of blood-brain barrier and traumatic brain edema, suggesting that ERK signaling pathway plays an important role in traumatic brain edema by regulating the expression of MMP-9.
Animals ; Brain Edema ; drug therapy ; etiology ; Brain Injuries, Traumatic ; complications ; drug therapy ; Gene Expression Regulation, Enzymologic ; drug effects ; Indazoles ; pharmacology ; therapeutic use ; MAP Kinase Signaling System ; drug effects ; Matrix Metalloproteinase 9 ; genetics ; Piperazines ; pharmacology ; therapeutic use ; Protein Kinase Inhibitors ; pharmacology ; therapeutic use ; Random Allocation ; Rats ; Rats, Sprague-Dawley

OBJECTIVE: To investigate the effect of palbociclib on cell cycle progression and proliferation of human renal tubular epithelial cells. METHODS: Human renal tubular epithelial cell line HK-2 was treated with 1, 5, 10, and 20 μmol/L of palbociclib, and the changes in cell proliferation and viability were examined by cell counting and CCK8 assay. EDU staining was used to assess the proliferation of HK-2 cells following palbiciclib treatment at different concentrations for 5 days. The effect of palbociclib on cell cycle distribution of HK-2 cells was evaluated using flow cytometry. SA-β-Gal staining and C12FDG senescence staining were used to detect senescence phenotypes of HK-2 cells after palbociclib treatment at different concentrations for 5 days. The relative mRNA expression levels of P16, P21, and P53 and the genes associated with senescence-related secretion phenotypes were detected by RT-PCR, and the protein expressions of P16, P21 and P53 were detected by Western blotting. RESULTS: Palbociclib inhibited HK-2 cell proliferation and induced cell cycle arrest in G1 phase. Compared with the control cells, HK-2 cells treated with high-dose (10 μmol/L) palbociclib exhibited significantly suppressed cell proliferation activity, and the inhibitory effect was the most obvious on day 5 ( CONCLUSIONS Palbociclib induces HK-2 cell senescence by causing cell growth arrest and delaying cell cycle progression.
Cell Cycle ; Cell Cycle Checkpoints ; Cellular Senescence ; Epithelial Cells ; Humans ; Piperazines/pharmacology* ; Pyridines/pharmacology* ; Tumor Suppressor Protein p53/genetics*

OBJECTIVE: To investigate the effect of BAX gene deletion on the sensitivity of BCR-ABL-induced B-ALL cells of mice to imatinib and the related mechanism. METHODS: The target gene-knock out (BAX) mice were used as bone marrow cell donors; the wild type bone marrow cells(B6BM) and BAX bone marrow cells(B6BM-BAX) of mice were transfected by using reverse transcription virus, then the BCR-ABL transfected B6BM cells and B6BM-BAX cells were treated with imatinib at different concentration (0,0.5, 1.0 and 2.0 μmol/L) for 48 hours. The number of viable cells was detected by trypan blue, the flow cytometry was used to detect the cell apoptosis, the Western blot was used to detect the changes of BAX, Caspase expression. RESULTS: In BCR-ABL transfected bone marrow cells treated with imatinib, the numbers of viable cells of BAX deletion group was significantly higher than that of wild type groups with statristcal difference(P<0.05), and effect- and dose-dependency(r=-0.9533 for BAX deletion group, and r=-0.9812 for wild type group). The flow cytometry showed that the cell apoptosis in BAX deletion group signifincantly decreased, compared with wild type group(P<0.05). The Western blot showed that the expression of apoptotic protein Caspase 3 in BAX deletion group was significantly higher than that in wild type group(P<0.05). CONCLUSION BAX deletion can reduce the sensitivity of BCR-ABL-induced B-ALL cells to imatinib.
Animals ; Apoptosis ; Drug Resistance, Neoplasm ; Fusion Proteins, bcr-abl ; Gene Deletion ; Imatinib Mesylate ; Mice ; Piperazines ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma ; genetics ; bcl-2-Associated X Protein