I13 overrides resistance mediated by the T315I mutation in chronic myeloid leukemia by direct BCR-ABL inhibition

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm caused by a BCR-ABL fusion gene. Imatinib has significantly improved the treatment of CML as a first-generation tyrosine kinase inhibitor (TKIs). The T315I mutant form of BCR-ABL is the most common mutation that confers resistance to imatinib or the second-generation TKIs, resulting in poor clinical prognosis. In this work, we assessed the effect of a potent histone deacetylase (HDAC) inhibitor, I13, on the differentiation blockade in CML cells harboring T315I-mutated and wild-type BCR-ABL by MTT assay, flow cytometery, cell colony formation assay, mRNA Sequencing, Quantitative real-time PCR and Western blotting analysis. We found that I13 possessed highly potent activity against T315I-mutated BCR-ABL mutant-expressing cells and wild-type BCR-ABL-expressing cells. I13 induced cell differentiation and significantly suppressed the proliferation of these CML cells via the cell cycle G0/G1-phase accumulation. Moreover, it was revealed that I13 triggered the differentiation of BaF3-T315I cells, which was attributed to the block of the chronic myeloid leukemia signaling pathway via the depletion of BCR-ABL that was mediated by the inhibition of HDAC activity presented by the acetylation of histones H3 and H4. Taken together, I13 efficiently depleted BCR-ABL in CML cells expressing the BCR-ABL-T315I mutation, which blocked its function, serving as a scaffold protein that modulated the chronic myeloid leukemia signaling pathway mediating cell differentiation. The present findings demonstrate that I13 is a BCR-ABL modulator for the development of CML therapy that can override resistance caused by T315I-mutated BCR-ABL

On the Lab. II building site

425 special CDSs in PCN033 (XLSX 29 kb

Targeting Glucose Metabolism Enzymes in Cancer Treatment: Current and Emerging Strategies

Reprogramming of glucose metabolism provides sufficient energy and raw materials for the proliferation, metastasis, and immune escape of cancer cells, which is enabled by glucose metabolism-related enzymes that are abundantly expressed in a broad range of cancers. Therefore, targeting glucose metabolism enzymes has emerged as a promising strategy for anticancer drug development. Although several glucose metabolism modulators have been approved for cancer treatment in recent years, some limitations exist, such as a short half-life, poor solubility, and numerous adverse effects. With the rapid development of medicinal chemicals, more advanced and effective glucose metabolism enzyme-targeted anticancer drugs have been developed. Additionally, several studies have found that some natural products can suppress cancer progression by regulating glucose metabolism enzymes. In this review, we summarize the mechanisms underlying the reprogramming of glucose metabolism and present enzymes that could serve as therapeutic targets. In addition, we systematically review the existing drugs targeting glucose metabolism enzymes, including small-molecule modulators and natural products. Finally, the opportunities and challenges for glucose metabolism enzyme-targeted anticancer drugs are also discussed. In conclusion, combining glucose metabolism modulators with conventional anticancer drugs may be a promising cancer treatment strategy

Endoplasmic reticulum and mitochondrial double-targeted NIR photosensitizer synergistically promote tumor cell death

The excessive production of reactive oxygen species (ROS) can damage the mitochondrial membrane and induce apoptosis, causing endoplasmic reticulum stress and triggering immunogenic cell death. Therefore, the combination of apoptosis and immunogenic death by the dual-targeted ROS generator has great potential to address inefficient cancer treatment. A near-infrared photosensitizer was developed for efficient ROS production and dual-targeted cancer treatment. Due to the modulation of electron structure, the reduced transition energy barrier affords TCy5-I-3F the highest efficiency to produce ROS. TCy5-I-3F has excellent mitochondrial and endoplasmic reticulum targeting ability, causing cell apoptosis and stress of the endoplasmic reticulum for destroying cancer cells. In the dual-targeted mode, high expression of GRP780, activation of heat shock protein (HSP70), the outflow of high mobility group protein B1, efflux of Calreticulin, and massive efflux of adenosine triphosphate are evaluated in the pharmacological experiments. In vivo experiments, the maturation of dendritic cells (DC, CD80+, CD86+), CD8+ T cells and CD3+ T cells also highlights the effectiveness. The tumors of mice treated with TCy5-I-3F and near-infrared (NIR) light are significantly inhibited. The multifunctional targeting design and corresponding mechanisms prove a new insight for exploring efficient photodynamic therapy drugs

Additional file 2: Table S2. of Genome analysis and in vivo virulence of porcine extraintestinal pathogenic Escherichia coli strain PCN033

Core genome content used to construct phylogenetic tree (XLSX 225 kb

Additional file 1: Table S1. of Genome analysis and in vivo virulence of porcine extraintestinal pathogenic Escherichia coli strain PCN033

Genomes used for phylogenetic and Escherichia coli protein database construction (DOC 86 kb