Bisdemethoxycurcumin alleviates vandetanib-induced cutaneous toxicity in vivo and in vitro through autophagy activation

Jin, Ying; Chen, Xueqin; Gao, Zizheng; Shen, Xiaofei; Fu, Huangxi; Pan, Zezheng; Hao, Yan; Yang, Bo; He, Qiaojun; Xu, Zhifei; Luo, Peihua

doi:10.1016/j.biopha.2021.112297

Cited by 6 publications

(2 citation statements)

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“…The epidermal tissue of skin is mainly composed of keratinocytes, and studies have shown that keratinocytes are essential for maintaining the normal physiological function of the epidermal tissue (Simpson, Patel & Green, 2011). As described in previous studies reported by our and other teams, small molecule kinase inhibitors (SMKIs) could induce cutaneous toxicity by affecting keratinocyte fate, such as promoting cell death directly, regulating cell hyperdifferentiation, migration and incomplete keratinization (Chen et al, 2017;Jin et al, 2021;Luo et al, 2020). More importantly, keratinocyte apoptosis has been determined to be involved in the pathological process of various skin diseases such as skin injury, erythema, dermatitis and alopecia (Fabbrocini, Panariello, Caro & Cacciapuoti, 2015;Tang et al, 2018).…”

Section: Introductionmentioning

confidence: 94%

Reduced HMGB1 expression contributed to lapatinib-induced cutaneous injury

Jiang

Zeng

et al. 2022

Preprint

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Background and Purpose Lapatinib, a widely-used dual inhibitor of EGFR/ERBB1 and HER2/ERBB2 effectively targeting HER2 positive breast cancer, has been seriously limited due to cutaneous toxicity. However, the specific mechanism of lapatinib-induced cutaneous toxicity has not been clarified, leading to a lack of effective strategy targets to improve clinical safety. Here, we aimed to identify molecular mechanism occurs in this process and strive for effective intervention strategies against lapatinib-induced cutaneous side effects. Experimental and Approach C57BL/6 mice were subjected to lapatinib via intragastric administration, serum was used for ELISA assay, skin tissue was collected and performed with histopathological analysis. Apoptotic assay was analyzed in HaCaT and NHEK cell lines, comet assay was conducted to measure the damage of DNA, real-time PCR was used to assess the level of HMGB and inflammatory factors. Key Results We found that lapatinib could induce mitochondrial dysfunction, lead to DNA damage and finally cause apoptosis of keratinocytes. In addition, we found that lapatinib could induce aberrant immune response and promote the release of inflammatory factors in vitro and in vivo. Mechanistically, downregulated expression of HMGB1 played a critical role in these toxic reaction processes. Delightfully, we found that saikosaponin A could significantly rescue the reduced HMGB1 transcription, which could alleviate lapatinib-induced DNA damage, inhibit keratinocyte apoptosis and further prevent toxicity of lapatinib in mice. Conclusion and Implications Our study provided molecular mechanism of lapatinib-induced cutaneous toxicity, and shed new light on the prevention of cutaneous adverse drug reactions induced by EGFR inhibitors.

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Section: Introductionmentioning

confidence: 94%

Reduced HMGB1 expression contributed to lapatinib-induced cutaneous injury

Jiang

Zeng

et al. 2022

Preprint

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“…近年来，有研究发现天然化合物具有防治TKI所致皮肤毒性的作用［ 10 ］。本研究在体外模型中对天然化合物库进行筛选发现，冰片可以显著逆转吉列替尼引起的角质形成细胞死亡，表明其干预吉列替尼皮肤毒性的潜力。冰片是一种提取自樟科植物龙脑樟枝叶的天然产物，在中医药治疗中常作为佐使药，以加强主药的药效或减弱主药毒性，进而起到相辅相成、相得益彰的功效［ 29 ］。本文资料显示，冰片能改善吉列替尼诱导的角质形成细胞活性氧过度累积和凋亡，且其本身对角质形成细胞没有杀伤作用。为了验证冰片在临床上应用的可能性，本研究采用小鼠体内模型验证了冰片对吉列替尼皮肤毒性的干预作用，结果表明冰片与吉列替尼的合用可以有效地抑制吉列替尼引起的皮疹，改善表皮增厚、角质形成细胞凋亡等毒性表型。此外，仅给予冰片的小鼠未产生明显的毒性症状，证明了冰片临床应用的安全性。…”

Section: 讨论unclassified

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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Decreased HMGB1 expression contributed to cutaneous toxicity caused by lapatinib

Jiang

Zeng

et al. 2022

Biochemical Pharmacology

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Bisdemethoxycurcumin alleviates vandetanib-induced cutaneous toxicity in vivo and in vitro through autophagy activation

Cited by 6 publications

References 55 publications

Reduced HMGB1 expression contributed to lapatinib-induced cutaneous injury

Reduced HMGB1 expression contributed to lapatinib-induced cutaneous injury

Protective effect of borneol on the cutaneous toxicity of gilteritinib

Decreased HMGB1 expression contributed to cutaneous toxicity caused by lapatinib

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