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


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.

This is a preview of subscription content, log in to check access.

Access options

Buy single article

Instant unlimited access to the full article PDF.

US$ 39.95

Price includes VAT for USA

Subscribe to journal

Immediate online access to all issues from 2019. Subscription will auto renew annually.

US$ 199

This is the net price. Taxes to be calculated in checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7


  1. 1.

    Schettino C, Bareschino MA, Ricci V, Ciardiello F (2008) Erlotinib: an EGF receptor tyrosine kinase inhibitor in non-small-cell lung cancer treatment. Expert Rev Respir Med 2:167–178

  2. 2.

    Tejpar S, Piessevaux H, Claes K, Piront P, Hoenderop JGJ, Verslype C, Van Cutsem E (2007) Magnesium wasting associated with epidermal-growth-factor receptor-targeting antibodies in colorectal cancer: a prospective study. Lancet Oncol 8:387–394

  3. 3.

    Petrelli F, Borgonovo K, Cabiddu M, Ghilardi M, Barni S (2012) Risk of anti-EGFR monoclonal antibody-related hypomagnesemia: systematic review and pooled analysis of randomized studies. Expert Opin Drug Saf 11(S1):S9–S19

  4. 4.

    Mak IT, Kramer JH, Chmielinska JJ, Spurney CF, Weglicki WB (2015) EGFR-TKI, erlotinib, causes hypomagnesemia, oxidative stress, and cardiac dysfunction: attenuation by NK-1 receptor blockade. J Cardiovasc Pharmacol 65(1):54–61

  5. 5.

    Liu H, Mantyh PW, Basbaum AI (1997) NMDA-receptor regulation of substance P release from primary afferent nociceptors. Nature 386:721–724

  6. 6.

    Mishina M, Mori H, Araki K, Kushiya E, Meguro H, Kutsuwada T, Kashiwabuchi N, Ikeda K, Nagasawa M, Yamazaki M, Masaki H, Yamakura T, Morita T, Sakimura K (1993) Molecular and functional diversity of the NMDA receptor channel. Ann N Y Acad Sci 707:136–152

  7. 7.

    Masu M, Nakajima Y, Moriyoshi K, Ishii T, Akazawa C, Nakanashi S (1993) Molecular characterization of NMDA and metabotropic glutamate receptors. Ann N Y Acad Sci 707:153–164

  8. 8.

    Petrelli F, Ghidini M, Lonati V, Tomasello G, Borgonovo K, Ghilardi M, Cabiddu M, Barni S (2017) Efficacy of lapatinib and capcitabine in HER-2 positive breast cancer with brain metastases: a systemic review and pooled analyses. Eur J Cancer 84:141–148

  9. 9.

    Lee HL, Kim EJ et al (2010) Electrophysiological effects of the anti-cancer drug lapatinib on cardiac repolarization. Basic Clin Pharmacol Toxicol 107:614–618

  10. 10.

    Kiyohara Y, Yamazaki MD et al (2013) Erlotinib-related skin toxicities: treatment strategies in patients with metastatic non-small cell lung cancer. J Am Acad Dermatol 69:463–472

  11. 11.

    Jacouture M, Sibaud V (2018) Toxic side effects of targeted therapies and immunotherapies affecting skin, oral mucosa, hair and nails. Am J Clin Dermatol 19(Suppl 1):531–539

  12. 12.

    Weglicki WB, Kramer JH, Spurney CF, Chmielinska JJ, Mak IT (2012) The EGFR tyrosine kinase inhibitor tyrphostin AG-1478 causes hypomagnesemia and cardiac dysfunction. Can J Physiol Pharmacol 90:1145–1149

  13. 13.

    Mak IT, Kramer JH, Chen X, Chmielinska JJ, Spurney CF, Weglicki WB (2013) Mg-supplementation attenuates ritonavir-induced hyperlipidemia, oxidative stress and cardiac dysfunction in rats. Am J Physiol Regul Integr Comp Physiol 305:R1102–R1111

  14. 14.

    Kramer JH, Spurney CF, Iantorno M, Tziros C, Chmielinska JJ, Mak I-T, Weglicki WB (2012) D-propranolol protects against oxidative stress and progressive cardiac dysfunction in Fe-overloaded rats. Can J Physiol Pharmacol 90(9):1257–1268

  15. 15.

    Kramer JH, Spurney C, Iantorno M, Tziros C, Mak IT, Tejero-Taldo MI, Chmielinska JJ, Komarov AM, Weglicki WB (2009) Neurogenic inflammation and cardiac dysfunction due to hypomagnesemia. Am J Med Sci 338:22–27

  16. 16.

    Mak IT, Chmielinska JJ, Kramer JH, Weglicki WB (2009) AZT-Induced cardiovascular toxicity—attenuation by Mg-supplementation. Cardiovasc Toxicol 9:78–85

  17. 17.

    Weglicki WB, Chmielinska JJ, Tejero-Taldo MI, Kramer JH, Spurney C, Viswalingham K, Lu B, Mak IT (2009) Neutral endopeptidase inhibition enhances substance P mediated inflammation due to hypomagnesemia. Magnes Res 22(3):167S–173S

  18. 18.

    Weglicki WB, Mak IT, Chmielinska JJ, Tejero-Taldo MI, Komarov A, Kramer JH (2012) The role of magnesium deficiency in cardiovascular and intestinal inflammation. Magnes Res 23:S199–206

  19. 19.

    Mak IT, Chmielinska JJ, Spurney CF, Weglicki WB, Kramer JH (2018) Combination ART-induced oxidative/nitrosative stress, neurogenic inflammation and cardiac dysfunction in HIV-1 transgenic (Tg) rats: protection by Mg-supplementation. Int J Mol Sci 19(8):2409–2426

  20. 20.

    Mak IT, Chmielinska JJ, Kramer JH, Spurney CF, Weglicki WB (2011) Loss of neutral endopeptidase activity contributes to neutrophil activation and cardiac dysfunction during chronic hypomagnesemia: protection by substance P receptor blockade. Exp Clin Cardiol 16:121–124

  21. 21.

    Pérez-Soler R, Delord JP, Halpern A, Kelly K, Krueger J, Sureda BM, von Pawel J, Temel J, Siena S, Soulières D, Saltz L, Leyden J (2005) HER1/EGFR inhibitor-associated rash: future directions for management and investigation outcomes from the HER1/EGFR inhibitor rash management forum. Oncologist 10(5):345–356

  22. 22.

    Brown AP, Dunstan RW, Courtney CL, Criswell KA, Graziano MJ (2008) Cutaneous lesions in the rat following administration of an irreversible inhibitor of erbB receptors, including the epidermal growth factor receptor. Toxicol Pathol 36:410–419

  23. 23.

    Sawyers C (2004) Targeted cancer therapy. Nature 432:294–297

  24. 24.

    Imai K, Takaoka A (2006) Comparing antibody and small-molecule therapies for cancer. Nat Rev Cancer 6:714–727

  25. 25.

    Dong J, Chen L (2018) Cardiotoxicity of anticancer therapeutics. Front Cardiovasc Med 5:1–8

  26. 26.

    Chen Z, Ai D (2016) Cardiotoxicity associated with targeted cancer therapies. Mol Clin Oncol 4:675–681

  27. 27.

    Choi JE, Di Nardo AD (2018) Skin neurogenic inflammation. Semin Immunopathol 40:249–259

  28. 28.

    Tejero-Taldo MI, Kramer JH, Mak I-T, Komarov AM, Chmielinska JJ, Weglicki WB (2006) The nerve-heart connection in the pro-oxidant response to Mg-deficiency. Heart Fail Rev 11:35–44

  29. 29.

    Muñoz M, Rosso M (2010) The NK-1 receptor antagonist aprepitant as a broad spectrum antitumor drug. Invest New Drugs 28:187–193

  30. 30.

    He A, Alhariri JM, Sweren RJ, Kwatra MM, Kwatra SG (2017) Aprepitant for the treatment of chronic refractory pruritus. Biomed Res Int 2017:4790810

  31. 31.

    Pojawa-Gołab M, Jaworecka K, Reich A (2019) NK-1 receptor antagonists and pruritus: review of current literature. Dermatol Ther (Heidelb) 9:391–405

Download references


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.

Ethics declarations

Conflict of interest

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.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation


  • 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