Decreased HMGB1 expression contributed to cutaneous toxicity caused by lapatinib

Jiang, Liyu; Zeng, Yan; Ai, Leilei; Hao, Yan; Yang, Xiaochun; Luo, Peihua; Yang, Bo; Xu, Zhifei; He, Qiaojun

doi:10.1016/j.bcp.2022.115105

Cited by 4 publications

(2 citation statements)

References 47 publications

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“…COMET Assay: The COMET assay was performed as described previously. [50] First, a single-cell suspension was prepared at a density of ≈2 × 10 4 cells mL −1 in PBS. Next, preheated 0.5% normal-gellingtemperature agarose was placed onto a microscope slide.…”

Section: Methodsmentioning

confidence: 99%

Chloroquine Intervenes Nephrotoxicity of Nilotinib through Deubiquitinase USP13‐Mediated Stabilization of Bcl‐XL

et al. 2023

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Nephrotoxicity has become prominent due to the increase in the clinical use of nilotinib, a second‐generation BCR‐ABL1 inhibitor in the first‐line treatment of Philadelphia chromosome‐positive chronic myeloid leukemia. To date, the mechanism of nilotinib nephrotoxicity is still unknown, leading to a lack of clinical intervention strategies. Here, it is found that nilotinib could induce glomerular atrophy, renal tubular degeneration, and kidney fibrosis in an animal model. Mechanistically, nilotinib induces intrinsic apoptosis by specifically reducing the level of BCL2 like 1 (Bcl‐XL) in both vascular endothelial cells and renal tubular epithelial cells, as well as in vivo. It is confirmed that chloroquine (CQ) intervenes with nilotinib‐induced apoptosis and improves mitochondrial integrity, reactive oxygen species accumulation, and DNA damage by reversing the decreased Bcl‐XL. The intervention effect is dependent on the alleviation of the nilotinib‐induced reduction in ubiquitin specific peptidase 13 (USP13) and does not rely on autophagy inhibition. Additionally, it is found that USP13 abrogates cell apoptosis by preventing excessive ubiquitin‒proteasome degradation of Bcl‐XL. In conclusion, the research reveals the molecular mechanism of nilotinib's nephrotoxicity, highlighting USP13 as an important regulator of Bcl‐XL stability in determining cell fate, and provides CQ analogs as a clinical intervention strategy for nilotinib's nephrotoxicity.

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Section: Methodsmentioning

confidence: 99%

Chloroquine Intervenes Nephrotoxicity of Nilotinib through Deubiquitinase USP13‐Mediated Stabilization of Bcl‐XL

et al. 2023

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“…皮肤主要由表皮、真皮、皮下组织构成，皮疹是由于表皮或浅层真皮异常引起的皮肤疾病。由于真皮浅层中富含大量毛细血管，因此药物可以通过毛细血管转运最终直接作用于表皮深层细胞，而表皮深层细胞主要为角质形成细胞。角质形成细胞通过分化、向外迁移至表皮取代表皮脱落的细胞，同时也会分泌各种构成细胞紧密连接的基础角蛋白，对于维持表皮的正常生理功能至关重要［ 7 ］。诸多小分子激酶抑制剂可以通过影响角质形成细胞的命运来诱导皮肤毒性的发生，例如直接诱导细胞凋亡以及调节细胞的过度分化、迁移和角化不完全等［ 8 - 11 ］。现代医学发现，多种天然化合物可以通过调控氧化应激、炎症反应、免疫失调和DNA损伤等方式改善受损的皮肤［ 12 - 13 ］。如黄芪、瓜蒌、当归中提取到的活性成分芒柄花素对炎症性皮肤病具有保护作用［ 14 ］；丹参酮ⅡA抑制中波紫外线照射引起的人表皮形成细胞生长阻滞与DNA损伤基因的转录以及信号通路分子磷酸化，减少紫外线辐照造成的人皮肤角质形成细胞的损伤［ 15 ］；黄芪甲苷可以加速创面组织的恢复和血管生成，缓解糖尿病导致的皮肤缺损［ 16 ］；甘草素增强抗氧化能力保护长波紫外线诱导的人角质形成细胞氧化损伤［ 17 ］；对已经受损的皮肤，天然冰片可以通过诱导表皮细胞的增殖和分化，促进受伤部位皮肤的再生，从而达到修复皮肤屏障的作用［ 18 ］。基于此，文本聚焦于探索吉列替尼诱发皮肤毒性的机制以及天然化合物能否改善吉列替尼皮肤毒性展开研究，以期为临床解决吉列替尼皮肤毒性寻找一种安全有效的干预策略。…”

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Protective effect of borneol on the cutaneous toxicity of gilteritinib

ZHOU,

YIN,

HUANG

et al. 2023

J Zhejiang Univ (Med Sci)

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目的研究吉列替尼皮肤毒性的发生机制并寻找有效干预策略。方法对C57BL/6J雄性小鼠连续28 d灌胃给予吉列替尼，通过皮肤形态观察、苏木精-伊红染色、TUNEL检测、免疫组织化学法检测小鼠皮肤组织角质形成细胞损伤情况。对人角质形成细胞HaCaT给予吉列替尼，通过磺酰罗丹明B（SRB）染色法和显微镜观察法考察细胞死亡和形态学变化；蛋白质印迹法、流式细胞术结合碘化丙啶/Annexin Ⅴ双染法、免疫荧光技术考察吉列替尼作用下HaCaT细胞凋亡情况；流式细胞术结合2 ，7 -二氯荧光黄双乙酸盐（DCFH-DA）法考察细胞活性氧累积情况。采用SRB染色法筛选天然化合物库中能有效干预吉列替尼皮肤毒性的天然化合物。HaCaT细胞给予吉列替尼和/或冰片联合处理，考察冰片对吉列替尼皮肤毒性的体外干预效果。C57BL/6J雄性小鼠连续灌胃给予吉列替尼和/或冰片28 d，考察冰片对吉列替尼皮肤毒性的体内干预效果。结果体内研究中，组织病理学检查结果提示吉列替尼皮肤毒性造模成功，且模型组雄性小鼠皮肤发生病理性改变，棘层和颗粒层角质形成细胞发生凋亡。体外研究中，与正常对照组比较，吉列替尼模型组发生凋亡、切割型多腺苷二磷酸核糖聚合酶（c-PARP）和磷酸化组蛋白H2AX（γ-H2AX）水平显著上调，活性氧累积明显增多。在天然化合物库中筛选发现冰片对HaCaT细胞死亡显示出极好的干预效果。在体外，相较于吉列替尼对照组，冰片+吉列替尼组凋亡明显减少，细胞中c-PARP、γ-H2AX及活性氧水平显著下降。在体内，冰片可缓解吉列替尼诱导的雄性小鼠皮肤病理性改变和皮肤细胞凋亡。结论吉列替尼通过引起细胞内活性氧累积诱导角质形成细胞凋亡，导致皮肤毒性损伤。冰片可以通过减少活性氧累积和皮肤角质形成细胞凋亡，缓解吉列替尼的皮肤毒性作用。

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Dasatinib causes keratinocyte apoptosis via inhibiting high mobility group Box 1-mediated mitophagy

Gao

et al. 2023

Toxicology Letters

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Decreased HMGB1 expression contributed to cutaneous toxicity caused by lapatinib

Cited by 4 publications

References 47 publications

Chloroquine Intervenes Nephrotoxicity of Nilotinib through Deubiquitinase USP13‐Mediated Stabilization of Bcl‐XL

Chloroquine Intervenes Nephrotoxicity of Nilotinib through Deubiquitinase USP13‐Mediated Stabilization of Bcl‐XL

Protective effect of borneol on the cutaneous toxicity of gilteritinib

Dasatinib causes keratinocyte apoptosis via inhibiting high mobility group Box 1-mediated mitophagy

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