DOI: https://doi.org/10.14710/dmj.v14i5.49108

PROPOSED MECHANISM OF ERLOTINIB-INDUCED RASH FORMATION IN RATS BASED ON THE SKIN EXPRESSION OF CINC1 AND TTP mRNAs

*Iqbal Julian orcid  -  Department of Biomedical and Clinical Pharmacy, Faculty of Pharmacy, Universitas Pancasila, Jl. Lenteng Agung Raya no. 56, Jakarta, Indonesia, 12630, Indonesia
Takuya Iwamoto  -  , Japan
Open Access Copyright 2025 Iqbal Julian, Takuya Iwamoto
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.

Citation Format:
Abstract

Background: Erlotinib's effect on the skin is greatly recognized to cause rashes. To treat the rashes effectively, it is necessary to understand the mechanism of rashes formation induced by the drug. However, the mechanism underlying the effect was not well-known. Objective: This study measured the CINC1 and TTP mRNAs’ expression to elaborate the mechanism. Methods: An experimental preclinical quantitative study was designed. Rats were divided into three groups: placebo, low dose, and high dose based on the involvement and dosage of erlotinib, and were treated for 7 days. The samples were collected from the blood on days 0 and 7 and the skin on day 7. The blood was used to measure the circulating concentration of CINC-1, whereas the skin was used to measure the tissue expression of CINC1 and TTP mRNAs. Results: At mild rashes, the tissue expression of CINC1 and TTP mRNAs tended to elevate compared to the placebo, while at severe rashes, the TTP mRNA was suppressed in contrast to the CINC1 mRNA. The level of circulating CINC1 among the three groups following 7 days of treatment tended to elevate. Conclusion: The results suggest the involvement of CINC1 and TTP during the formation of erlotinib-induced rashes and the mechanism underlying the rashes formation was proposed accordingly. Furthermore, targeting these proteins could be a reference for a clinical study on the treatment of erlotinib-induced rashes.

Fulltext View|Download
Keywords: Erlotinib; Mechanism; Rash; Tristetraprolin

Article Metrics:

Article Info
Section: Original Articles
Language : EN
Recent articles
COMPARISON OF IOP MEASUREMENT BY GOLDMANN APPLANATION TONOMETER AND NON CONTACT TONOMETER IN GLAUCOMA PATIENTS THE RELATIONSHIP BETWEEN CLINICAL STAGE AND THERAPEUTIC RESPONSE AFTER COMPLETE RADIOCHEMOTHERAPY IN NASOPHARYNGEAL CARCINOMA WHO TYPE III IN NGOERAH HOSPITAL DENPASAR FACTORS INFLUENCING TREATMENT OUTCOMES OF DRUG-SENSITIVE TUBERCULOSIS PATIENTS: STUDY IN R.A. KARTINI HOSPITAL, JEPARA, INDONESIA PROGRESSION OF CHRONIC LYMPHOCYTIC LEUKEMIA TO PROLYMPHOCYTIC LEUKEMIA: A RARE CASE REPORT CHEMOTHERAPY-INDUCED THROMBOCYTOPENIA LEADING TO LIFE-THREATENING HYPOVOLEMIC SHOCK IN CERVICAL CANCER: A CASE REPORT More recent articles
  1. Abdelgalil AA, Al-Kahtani HM, Al-Jenoobi FI. Chapter Four - Erlotinib. In: Brittain HG, editor. Profiles of Drug Substances, Excipients, and Related Methodology [Internet]. Academic Press; 2020. p. 93–117. (Profiles of Drug Substances, Excipients and Related Methodology; vol. 45). Available from: https://www.sciencedirect.com/science/article/pii/S1871512519300196
  2. Komiya N, Takahashi K, Kato G, Kubota M, Tashiro H, Nakashima C, et al. Acute Generalized Exanthematous Pustulosis Caused by Erlotinib in a Patient with Lung Cancer. Case Rep Oncol. 2021 Jan 1;14(1):599–603
  3. Eissa IH, G.Yousef R, Elkady H, Elkaeed EB, Alsfouk AA, Husein DZ, et al. A new anticancer derivative of the natural alkaloid, theobromine, as an EGFR inhibitor and apoptosis inducer. Theor Chem Acc [Internet]. 2023;143(1):1. Available from: https://doi.org/10.1007/s00214-023-03071-z
  4. Xiao T, Sun M, Kang J, Zhao C. Transient Receptor Potential Vanilloid1 (TRPV1) Channel Opens Sesame of T Cell Responses and T Cell-Mediated Inflammatory Diseases. Vol. 13, Frontiers in Immunology. Frontiers Media S.A.; 2022
  5. Tomonaga T, Higashi H, Izumi H, Nishida C, Kawai N, Sato K, et al. Investigation of pulmonary inflammatory responses following intratracheal instillation of and inhalation exposure to polypropylene microplastics. Part Fibre Toxicol [Internet]. 2024;21(1):29. Available from: https://doi.org/10.1186/s12989-024-00592-8
  6. Xing D, Hage FG, Feng W, Guo Y, Oparil S, Sanders PW. Endothelial cells overexpressing CXCR1/2 are renoprotective in rats with acute kidney injury. Am J Physiol Renal Physiol. 2023 Apr 1;324(4):F374–86
  7. Barreau C, Paillard L, Osborne HB. AU-rich elements and associated factors: are there unifying principles? Nucleic Acids Res [Internet]. 2005 Dec 1;33(22):7138–50. Available from: https://doi.org/10.1093/nar/gki1012
  8. Hsieh HH, Chen YA, Chang YJ, Wang HH, Yu YH, Lin SW, et al. The functional characterization of phosphorylation of tristetraprolin at C-terminal NOT1-binding domain. J Inflamm [Internet]. 2021;18(1):22. Available from: https://doi.org/10.1186/s12950-021-00288-2
  9. Abraham J, Nelon LD, Kubicek CB, Kilcoyne A, Hampton ST, Zarzabal LA, et al. Preclinical Testing of Erlotinib in a Transgenic Alveolar Rhabdomyosarcoma Mouse Model. Sarcoma [Internet]. 2011;2011(1):130484. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1155/2011/130484
  10. Krinke G. The Laboratory Lab. 1st ed. Bullock G, Bunton T, editors. Academic Press; 2000. 463–482 p
  11. S P, R R, R K. Blood sample collection in small laboratory animals. J Pharmacol Pharmacother [Internet]. 2010;1(2):87–93. Available from: https://doi.org/10.4103/0976-500X.72350
  12. Blacksell S, Hughes T, Lee M, Lee J. A guide for the practical implementation of the WHO laboratory biosafety manual [Internet]. 4th ed. World Health Organization; 2023. Available from: http://apps.who.int/bookorders
  13. Nischal U, KC N, Khopkar U. Techniques of Skin Biopsy and Practical Considerations. 1. Available from: https://doi.org/10.4103/0974-2077.44174
  14. Julian I, Iwamoto T. Investigation of Biomarkers and Handling Strategy of Erlotinib-Induced Skin Rash in Rats. Biol Pharm Bull. 2021;44(8):1050–9
  15. Schöttle J, Chatterjee S, Volz C, Siobal M, Florin A, Rokitta D, et al. Intermittent high-dose treatment with erlotinib enhances therapeutic efficacy in EGFR-mutant lung cancer [Internet]. Vol. 6, Oncotarget. 2015. Available from: www.impactjournals.com/oncotarget/
  16. Zang YS, Fang Z, Li B. Erlotinib Plus Parenteral Nutrition: An Opportunity to Get Through the Hardest Days of Advanced Non-Small Cell Lung Cancer With Cancer Anorexia–Cachexia Syndrome. American Journal of Hospice and Palliative Medicine® [Internet]. 2013;30(2):210–3. Available from: https://doi.org/10.1177/1049909113476930
  17. Zayed A, Al Hroot J, Mayyas A, Al-Husein B. Rapid high performance liquid chromatography method for erlotinib quantification in vitro: Application to study the effect of resveratrol on metabolism and cellular uptake of erlotinib. Fundam Clin Pharmacol [Internet]. 2023;37(5):983–93. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1111/fcp.12914
  18. Carter J, Tadi P. StatPearls [Internet]. 2024 [cited 2025 Jan 9]. Erlotinib. Available from: https://www.ncbi.nlm.nih.gov/books/NBK554484/
  19. Rappl P, Brüne B, Schmid T. Role of Tristetraprolin in the Resolution of Inflammation. Biology (Basel) [Internet]. 2021;10(1). Available from: https://www.mdpi.com/2079-7737/10/1/66
  20. Wei SG, Yu Y, Felder RB. TNF-α-induced sympathetic excitation requires EGFR and ERK1/2 signaling in cardiovascular regulatory regions of the forebrain. American Journal of Physiology-Heart and Circulatory Physiology [Internet]. 2021;320(2):H772–86. Available from: https://doi.org/10.1152/ajpheart.00606.2020
  21. Sipieter F, Cappe B, Leray A, De Schutter E, Bridelance J, Hulpiau P, et al. Characteristic ERK1/2 signaling dynamics distinguishes necroptosis from apoptosis. iScience [Internet]. 2021 Sep 24;24(9). Available from: https://doi.org/10.1016/j.isci.2021.103074
  22. Canovas B, Nebreda AR. Diversity and versatility of p38 kinase signalling in health and disease. Nat Rev Mol Cell Biol [Internet]. 2021;22(5):346–66. Available from: https://doi.org/10.1038/s41580-020-00322-w
  23. Beamer E, Corrêa SAL. The p38MAPK-MK2 Signaling Axis as a Critical Link Between Inflammation and Synaptic Transmission. Vol. 9, Frontiers in Cell and Developmental Biology. Frontiers Media S.A.; 2021
  24. Rezcallah MC, Al-mazi T, Ammit AJ. Cataloguing the phosphorylation sites of tristetraprolin (TTP): Functional implications for inflammatory diseases. Cell Signal [Internet]. 2021;78:109868. Available from: https://www.sciencedirect.com/science/article/pii/S0898656820303454
  25. Jiang W, Zhu D, Wang C, Zhu Y. Tumor suppressing effects of tristetraprolin and its small double-stranded RNAs in bladder cancer. Cancer Med [Internet]. 2021;10(1):269–85. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1002/cam4.3622

Last update:

No citation recorded.

Last update:

No citation recorded.