Individual and Combined Treatments with Methylated Resveratrol Analogue DMU-214 and Gefitinib Inhibit Tongue Cancer Cells Growth via Apoptosis Induction and EGFR Inhibition.

Malgorzata Jozkowiak,Wieslawa Kranc,Jadwiga Jodynis-Liebert,Julia Spaczynska,Hanna Piotrowska-Kempisty,Marcin Wierzchowski,Piotr Ramlau,Mariusz Kaczmarek,Marta Dyszkiewicz-Konwinska

doi:10.3390/ijms22126180

Abstract

The methylated resveratrol analogue 3′-hydroxy-3,4,5,4′-tetramethoxystilbene (DMU-214) has been revealed to exert the anti-cancer activity by a block of the cell cycle at the G2/M phase, apoptosis induction, and metastasis inhibition. These biological events may be involved in crosstalk with the epidermal growth factor receptor (EGFR), which belongs to the ErbB family of receptor tyrosine kinases. Several cancer therapeutic approaches employ small molecules capable of inhibiting tyrosine kinases (e.g., gefitinib). According to more recent reports, combining gefitinib with chemotherapeutics, such as cisplatin, seems to be more effective than monotherapy. The present study aimed to assess the molecular mechanism of the potential anti-proliferative activity of individual and combined treatments with DMU-214 and gefitinib in SCC-25 and CAL-27 human tongue cancer cell lines. We showed for the first time the anti-cancer effects of DMU-214, gefitinib, and their combination in tongue cancer cells triggered via cell cycle arrest, apoptosis induction, and inhibition of the EGFR signaling pathway. The anti-proliferative effects of DMU-214 and gefitinib are also suggested to be related to the EGFR and EGFRP (phosphorylated epidermal growth factor receptor) expression status since we found significantly weaker cytotoxic activity of the compounds tested in SCC-25 cells, which overexpressed EGFR and EGFRP proteins.

Highlights

Head and neck cancers are important public health issues expressed by the worldwide estimates of the growing number of incidence and mortality rate
The cytotoxic effects of DMU-214, Gef, and the combination of both are suggested to be associated with the epidermal growth factor receptor (EGFR) and EGFR and its phosphorylated form (EGFRP) expression status
We found that DMU-214 and its combination with Gef caused a significant decrease in the mRNA level of EGF and EGFR accompanied by the reduced expression of EGFR protein as well as its phosphorylated form (EGFRP) in more sensitive CAL-27 cells

Summary

Introduction

Head and neck cancers are important public health issues expressed by the worldwide estimates of the growing number of incidence and mortality rate. According to the International Agency for Research on Cancer, there were over 130,000 new nasopharynx cancer cases and over 370,000 lip and oral cavity tumors in 2020 [1]. Oral cancer represents squamous cell carcinomas growing from premalignant lesions such as leukoplakia and erythroleukoplakia. According to the American Cancer Society, there will be 17,960 new cases of tongue tumors, and 2870 patients will die of this disease only in the United States in 2021 [2]. In view of these data, it is a priority to find more accurate diagnostic methods and develop new anti-cancer therapies with higher effectiveness and fewer side effects

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