JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY
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2024
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IF 3.9
Shao-Liang Jiang,Wang-Cai Chen,Yu-Ting Wu,Huan-Yu Sui,Dong Chen,Li Li,Tao Wu,Jie-Hua Shi
Ribociclib (RIB), a tyrosine kinase inhibitor, exhibits promising antitumor efficacy and controlled toxicity in HR+/HER2- breast cancer patients, which is closely related to the binding with plasma proteins. This study utilized a combination of spectroscopic techniques including UV spectroscopy, fluorescence spectroscopy, and circular dichroism (CD) as well as molecular docking and molecular dynamic simulation to clarify the binding mechanism between bovine serum albumin (BSA) and RIB. The findings demonstrated that RIB produced a 1:1 stoichiometric complex with BSA, which quenched BSA's fluorescence in the manner of the static quenching mechanism. Site labelling experiments pinpointed Site III on BSA as the primary binding site for RIB, a finding validated by molecular docking. Van der Waals forces and hydrogen bonding interactions as key drivers in the formation of RIB-BSA complexes, a conclusion supported by molecular docking. Molecular simulation studies suggested that the insertion of RIB into the hydrophobic cavity (Site III) of BSA induced subtle conformational changes in the BSA protein, and CD measurements confirmed alterations in BSA secondary structure content. Synchronous and three-dimensional fluorescence spectroscopy further demonstrated that RIB decreased the hydrophobicity of the microenvironment surrounding tyrosine and tryptophan residues. These findings offer valuable insights into the pharmacokinetics and structural modifications of RIB.
研究领域:
药理学
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生物化学
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计算生物学
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产品关联
DOI
PubMed
高影响因子
TOXICOLOGY AND APPLIED PHARMACOLOGY
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2025
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IF 3.4
Yueping Qiu,Jing Chen,Yu Zhang,Chang Shu,Yan Hu,Libin Pan,Wenxiu Xin,Haiying Ding,Shuanghui Lu,Luo Fang
Ribociclib, a cornerstone CDK4/6 inhibitor for advanced breast cancer, carries a risk of serious pulmonary toxicity, including rare but fatal interstitial lung disease. This study demonstrates that ribociclib directly induces alveolar epithelial cell apoptosis, driving lung injury in mice and human alveolar epithelial cells. Mechanistically, we identify an off-target activation of Mucolipin-1 (MCOLN1) as the critical event, which arrests autophagic flux by blocking autophagosome-lysosome fusion. Moreover, this autophagic impairment precedes and precipitates apoptosis independently of CDK4/6 inhibition. Crucially, we reveal the antidiabetic drug metformin as a potent therapeutic intervention. Metformin rescues ribociclib-induced toxicity both in vitro and in vivo by restoring autophagic flux through suppressing Mucolipin-1 expression to overcome the autophagosome-lysosome fusion blockade. This significantly attenuates epithelial apoptosis, inflammatory infiltration, and pathological damage in the lungs. Our work provides the first demonstration of Mucolipin-1-mediated autophagic arrest as the core mechanism underlying ribociclib's pulmonary toxicity and establishes metformin as a clinically actionable strategy for mitigation, highlighting autophagic flux restoration as a new paradigm for countering kinase inhibitor-related organ toxicities.
研究领域:
肿瘤学
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药理学
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细胞生物学
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毒理学
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呼吸医学
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产品关联
DOI
PubMed
高影响因子
CRYSTAL GROWTH & DESIGN
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2026
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IF 3.6
Zhiling Chen,Yue Feng,Can Wang,Xiaomin Han,Yangyang Song,Xingyu Yao,Guisen Zhang,Rongbin Wei,Tao Zhuang
Ribociclib (RBC), an antitumor drug, is categorized as a BCS Class IV drug with low solubility and permeability. Despite achieving clinically relevant bioavailability in its marketed malate salt form, the limited aqueous solubility of RBC still poses significant challenges for formulation development. In this work, three novel RBC salts with nonsteroidal anti-inflammatory drugs (diclofenac, DIC; ibuprofen, IBU; loxoprofen, LOX) were successfully synthesized and comprehensively characterized. Among them, compared with pure RBC, the multicomponent RBC-LOX salt showed 2.97-fold higher solubility and 1.90-fold faster dissolution rate in pH 7.4 buffer, and 1.73-fold stronger in vitro cytotoxicity against MDA-MB-231 breast cancer cells. Moreover, in vivo pharmacokinetic evaluations revealed that the RBC-LOX salt significantly improved the oral bioavailability of RBC (1.49-fold), demonstrating enhanced bioavailability. Overall, these findings highlight the potential of RBC-NSAID salts as a strategy to enhance the solubility, anticancer activity, and bioavailability of ribociclib, offering a promising approach for optimizing its therapeutic efficacy.
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DOI
高影响因子
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