COLLOIDS AND SURFACES B-BIOINTERFACES
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2024
·
IF 5.4
Xiaotong Yu,Mengying Xia,Yuanhong Li,Geyun Chen,Chenhao Yu,Qianming Chen,Qiang Peng
Developing the delivery systems with high therapeutic efficacy and low side effects is of great interest and significance for anticancer therapy. Compared to the high cost in synthesizing new chemotherapeutic drugs, exploring the anticancer potentials of existing chemicals is more convenient and efficient. Sodium bicarbonate (BC), a simple inorganic salt, has shown its tumor inhibition capacity via regulating the acidity of tumor microenvironment. However, the effects of intracytoplasmic BC on tumor growth and the potentials of BC to serve as an anticancer agent are still unknown. Herein, we developed a BC-loaded cationic liposome system (BC-CLP) to deliver BC into the cytosol of cancer cells. The in vitro studies showed that the BC-CLP containing 1% BC (w/v) had a size of 112.9 nm and a zeta potential of 19.1 mV, which reduced the viability of the model cancer cells (human oral squamous cell carcinoma HSC-3 cells) to 13.7%. In contrast, the neutral BC-LP caused less than 50% viability reduction. We further found that BC-CLP released BC directly into cytoplasm via membrane fusion pathway rather than endocytosis, leading to the remarkable increase of cytosolic pH, which may contribute to the anticancer effect of BC-CLP. Our findings indicate that BC-CLP is a potential system for high-efficiency cancer therapy without causing drug-related side effects or resistance.
研究领域:
药剂学
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肿瘤学
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药物递送系统
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产品关联
DOI
PubMed
高影响因子
Signal Transduction and Targeted Therapy
·
2024
·Vol. 9
·期 1
·1-25
·
IF 40.8
Chen Yu-jia-nan,Shi Rong-chen,Xiang Yuan-cai,Fan Li,Tang Hong,He Gang,Zhou Mei,Feng Xin-zhe,Tan Jin-dong,Huang Pan,Ye Xiao,Zhao Kun,Fu Wen-yu,Li Liu-li,Bian Xu-ting,Chen Huan,Wang Feng,Wang Teng,Zhang Chen-ke,Zhou Bing-hua,Chen Wan,Liang Tao-tao,Lv Jing-tong,Kang Xia,Shi You-xing,Kim Ellen,Qin Yin-hua,Hettinghouse Aubryanna,Wang Kai-di,Zhao Xiang-li,Yang Ming-yu,Tang Yu-zhen,Piao Hai-long,Guo Lin,Liu Chuan-ju,Miao Hong-ming,Tang Kang-lai
Metabolites can double as a signaling modality that initiates physiological adaptations. Metabolism, a chemical language encoding biological information, has been recognized as a powerful principle directing inflammatory responses. Cytosolic pH is a regulator of inflammatory response in macrophages. Here, we found that L-malate exerts anti-inflammatory effect via BiP-IRF2BP2 signaling, which is a sensor of cytosolic pH in macrophages. First, L-malate, a TCA intermediate upregulated in pro-inflammatory macrophages, was identified as a potent anti-inflammatory metabolite through initial screening. Subsequent screening with DARTS and MS led to the isolation of L-malate-BiP binding. Further screening through protein‒protein interaction microarrays identified a L-malate-restrained coupling of BiP with IRF2BP2, a known anti-inflammatory protein. Interestingly, pH reduction, which promotes carboxyl protonation of L-malate, facilitates L-malate and carboxylate analogues such as succinate to bind BiP, and disrupt BiP-IRF2BP2 interaction in a carboxyl-dependent manner. Both L-malate and acidification inhibit BiP-IRF2BP2 interaction, and protect IRF2BP2 from BiP-driven degradation in macrophages. Furthermore, both in vitro and in vivo, BiP-IRF2BP2 signal is required for effects of both L-malate and pH on inflammatory responses. These findings reveal a previously unrecognized, proton/carboxylate dual sensing pathway wherein pH and L-malate regulate inflammatory responses, indicating the role of certain carboxylate metabolites as adaptors in the proton biosensing by interactions between macromolecules.
研究领域:
免疫学
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细胞生物学
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代谢研究
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炎症研究
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DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）