Combined SN-38 and gefitinib treatment promotes CD44 degradation in head and neck squamous cell carcinoma cells

Nanbu,Toshiyuki; Umemura,Naoki; Ohkoshi,Emika; Nanbu,Kumi; Sakagami,Hiroshi; Shimada,Jun

doi:10.3892/or.2017.6105

Combined SN-38 and gefitinib treatment promotes CD44 degradation in head and neck squamous cell carcinoma cells

Authors:
- Toshiyuki Nanbu
- Naoki Umemura
- Emika Ohkoshi
- Kumi Nanbu
- Hiroshi Sakagami
- Jun Shimada
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Affiliations: Division of Oral and Maxillofacial Surgery, Department of Diagnostic and Therapeutic Sciences, Meikai University, Sakado, Saitama 350-0283, Japan, Department of Oral Biochemistry, Asahi University School of Dentistry, Gifu 501‑0296, Japan, Department of Natural and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Aomori University, Aomori 030-0943, Japan, Meikai University Research Institute of Odontology, Sakado, Saitama 350-0283, Japan
Published online on: November 21, 2017 https://doi.org/10.3892/or.2017.6105
Pages: 367-375

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Abstract

The aim of the present study was to search for an effective regimen among existing chemotherapies for head and neck squamous cell carcinoma (HNSCC). Among the tested drugs, we focused on combined SN-38, which is the active metabolite produced from irinotecan hydrochloride - a type I DNA topoisomerase inhibitor - after it is metabolized by carboxylesterase in the liver and gefitinib, an EGFR tyrosine kinase inhibitor treatment, based on the ability of this combination to inhibit HNSCC cell growth. Contrary to our expectation, in vivo, there was no significant difference in tumor growth suppression between gefitinib-only treatment and gefitinib plus SN-38. However, when tumor measurements were continued after treatment ceased, we found that several tumors showed renewed growth in the gefitinib-only group. The tumors that resumed growing after treatment showed increased CD44 expression compared with tumors from the combined treatment group. Next, we investigated the mechanism whereby SN-38 and gefitinib inhibited CD44 expression in vitro. These studies revealed that the combined treatment promoted lysosomal degradation of CD44. The present study revealed that combined gefitinib and SN-38 treatment inhibits CD44 expression by promoting its lysosomal degradation in HNSCC cells. However, it is still unclear whether inhibition of CD44 expression in HNSCC cells can directly suppress tumor regrowth after therapy. Thus, it may be necessary to elucidate the relationship between the effects of these chemotherapeutic agents on CD44 expression and tumor recurrence/metastasis in future studies.

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