期刊
MOLECULAR AND CELLULAR BIOCHEMISTRY
卷 465, 期 1-2, 页码 175-185出版社
SPRINGER
DOI: 10.1007/s11010-019-03677-7
关键词
EGFR tyrosine kinase inhibitor erlotinib; Hypomagnesemia; Circulating substance P; Skin substance P receptors; progressive skin rash; hair loss; Neutrophil activation; Total plasma 8-isoprostane; Cardiac dysfunction; Substance P receptor blocker; aprepitant
类别
资金
- Hoth Biopharmaceutical Inc, Nevada, USA. [Contract] Funding Source: Medline
- GWU [George Washington University McCormick Genomic & Proteomic Center 2018] Funding Source: Medline
Cutaneous changes like rash and hair loss, as well as other neurogenic inflammation side effects, occur frequently during anticancer treatment with the epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), erlotinib. These adverse events may be so severe that they impair the patient's compliance with the treatment or even cause its discontinuation. In the current preclinical study, rats (9.2 weeks) were treated with erlotinib (10 mg/kg/day) +/- aprepitant (2 mg/kg/day) for 12 weeks. Visual changes in the development of facial skin lesions/hair loss and SP-receptor expression (immunohistochemically) in facial skin tissue were assessed; also changes in plasma magnesium, 8-isoprostane, substance P (SP), neutrophil superoxide production, and cardiac function (echocardiography) were measured. Erlotinib lowered plasma magnesium 14%, elevated SP 65%, caused 3.7-fold higher basal superoxide production, 2.5-fold higher 8-isoprostane levels, 11.6% lower cardiac systolic, and 10.9% lower diastolic function. Facial dermatological changes (alopecia, skin reddening, scabbing, nose crusting) occurred by 4 weeks (+/- + to ++) in erlotinib-treated rats, and progressively worsened (+/-++ to +++) by week 12. Facial skin SP-receptor upregulation (78% higher) occurred in epidermal and hair follicle cells. All adverse effects were substantially and significantly mitigated by aprepitant, including a 62% lowering of skin SP-receptors (p < 0.05). Elevated SP levels mediated the side effects of erlotinib treatment, but aprepitant's significant prevention of the systemic and cutaneous adverse events indicates a novel potential therapy against the side effects of this anticancer treatment.
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