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Background: Peripheral T-cell lymphoma (PTCL) is a heterogeneous disease with dismal outcomes. We conducted an open-label, phase 2 nonrandomised, externally controlled study to evaluate the efficacy and safety of targeted agents plus CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) (CHOPX) for PTCL in the front-line setting. Methods: Eligible patients were ≥18 years of age and newly diagnosed PTCL. Patients in the CHOPX group received standard CHOP at Cycle 1. Specific targeted agents were added from Cycle 2, decitabine if TP53 mut, azacytidine if TET2/KMT2D mut, tucidinostat if CREBBP/EP300 mut, and lenalidomide if without mutations above. Patients in the CHOP group received CHOP for 6 cycles. The primary endpoint was the complete response rate (CRR) at the end of treatment (EOT). Secondary endpoints included overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. The study was registered with ClinicalTrials.gov, NCT04480099. Findings: Between July 29, 2020, and Sep 22, 2022, 96 patients were enrolled and included for efficacy and safety analysis with 48 in each group. The study met its primary endpoint. CRR at EOT in the CHOPX group was superior to the CHOP group (64.6% vs. 33.3%, OR 0.27, 95%CI 0.12-0.64; p = 0.004). At a median follow-up of 24.3 months (IQR 12.0-26.7), improved median PFS was observed in the CHOPX group (25.5 vs. 9.0 months; HR 0.57, 95%CI 0.34-0.98; p = 0.041). The median OS was similar between two groups (not reached vs. 30.9 months; HR 0.55, 95%CI 0.28-1.10; p = 0.088). The most common grade 3-4 hematological and non-hematological adverse events in the CHOPX group were neutropenia (31, 65%) and infection (5, 10%). Interpretation: Targeted agents combined with CHOP demonstrated effective and safe as first-line treatment in PTCL. Biomarker-driven therapeutic strategy is feasible and may lead to promising efficacy specifically toward molecular features in PTCL. Funding: This study was supported by the National Key Research and Development Program (2022YFC2502600) and the General Program of the Shanghai Municipal Health Commission (202040400).
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This study explored the molecular mechanisms underlying the time-dependent autophagy and apoptosis induced by nutrient depletion in human multiple myeloma cell line RPMI8226 cells.RT-PCR and qRT-PCR were used to evaluate the transcriptional levels of Deptor,JNK1,JNK2,JNK3,Raf-1,p53,p21 and NFκB1 at 0,6,12,18,24 and 48 h after nutrient depletion in RPMI8226 cells.We found that transcriptional levels of Deptor were increased time-dependently at 0,6,12 and 18 h,and then decreased.Its alternation was consistent with autophagy.Transcriptional levels of Raf-1,JNK1,JNK2,p53 and p21 were increased time-dependently at 0,6,12,18,24 and 48 h accompanying with the increase of apoptosis.Transcriptional levels of NFκB 1 at 6,12,18,24 and 48 h were decreased as compared with 0 h.It was suggested that all the studied signaling molecules were involved in cellular response to nutrient depletion in RPMI8226 cells.Deptor contributed to autophagy in this process.Raf-1/JNK/p53/p21 pathway may be involved in apoptosis,and NFκB1 may play a possible role in inhibiting apoptosis.It remained to be studied whether Deptor was involved in both autophagy and apoptosis.
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Overexpression of human ether-a-go-go (eag) related gene (hERG) has been found in a broad range of human leukemia cell lines and primary human leukemia. The block of hERG protein might he a potential therapeutic strategy for leukemia. Gambogic acid (GA) has recently exhibited marked anti-tumor potency on solid tumors of various derivations. Here, we investigated the anti-leukemia effects of GA and its relation to the regulation of hERG in K562 leukemia cells in vitro.K562 cells were treated with various concentrations of GA (0.125-8.0 μmol/L) for 0-72 h. MTT assay was used to evaluate the inhibition effect of GA on the growth of K562 cells. Cell apoptosis was meas-ured through both Annexin-V FITC/PI double-labeled cytometry and transmission electron microscopy.Cell cycle regulation was studied by a propidium iodide method. RT-PCR and Western blot were applied to detect the expression level of hERG in K562 cells. GA presented striking growth inhibition and apoptosis induction potency on K562 cells in vitro in a time- and dose-dependent manner. The IC50 value of GA for 24 h was 2.637±0.208 μmol/L. Moreover, GA induced K562 cells arrested in G0/G1 phase, accordingly, cells in S phase decreased gradually, and no obvious changes were found in G2/M phase cells. Under the transmission electron microscopy, apoptotic bodies containing nuclear fragments were found in GA-treated K562 cells. After treatment with GA of 2.0μmol/L for 24 h, the percentage of apoptotic cells was increased from 4.09% to 18.47% (P<0.01), Overexpression of hERG channel was found in K562 cells, while GA could down-regulate it at both protein and mRNA levels (P<0.01). It was concluded that GA exhibited its anti-leukemia effects partially through down-regulating the expression level of hERG channel in K562 cells, suggesting that GA may be a potential agent against leukemia with a mechanism of blocking hERG channel.
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ssion of total Akt showed no change. It is concluded that wortmannin can inhibit the proliferation and induce apoptosis of K562 leukemia cells possibly by down-regulating the survival signaling pathways (PI3K/Akt and NF-κB channels).