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Substance P receptor blocker, aprepitant, inhibited cutaneous and other neurogenic inflammation side effects of the EGFR1-TKI, erlotinib

Abstract

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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Acknowledgements

The studies were funded in part by a grant from The George Washington University McCormick Genomic & Proteomic Center, and a contract from Hoth Biopharmaceutical Inc., Nevada, USA.

Author information

ITM, JHK, and WBW conception and design of research; JJC, JHK, ITM, and CFS performed experiments; JJC, JHK, and ITM analyzed data; JJC, JHK, ITM, and WBW interpreted results of experiments; JJC, JHK, and ITM prepared figures; JJC, JHK, and ITM drafted manuscript as co-first authors; JJC, JHK, ITM, CFS, and WBW edited and revised manuscript; JJC, JHK, ITM, CFS, and WBW approved final version of manuscript.

Correspondence to Joanna J. Chmielinska or Jay H. Kramer or I-Tong Mak.

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The authors declare no conflict of interest; the sponsors had no role in the design of the study, in the collection, analyses, or interpretation of data, in the writing of the manuscript, and in the decision to publish the results.

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Chmielinska, J.J., Kramer, J.H., Mak, I. et al. Substance P receptor blocker, aprepitant, inhibited cutaneous and other neurogenic inflammation side effects of the EGFR1-TKI, erlotinib. Mol Cell Biochem 465, 175–185 (2020) doi:10.1007/s11010-019-03677-7

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Keywords

  • 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