Growth suppression of human oral cancer cells by candidate agents for cetuximab-side effects

Katsuhiro Uzawa; Atsushi Kasamatsu; Tomoaki Saito; Akihiro Kita; Yuki Sawai; Yuriko Toeda; Kazuyuki Koike; Dai Nakashima; Yosuke Endo; Masashi Shiiba; Yuichi Takiguchi; Hideki Tanzawa

doi:10.1016/j.yexcr.2019.01.016

Growth suppression of human oral cancer cells by candidate agents for cetuximab-side effects

Exp Cell Res. 2019 Mar 15;376(2):210-220. doi: 10.1016/j.yexcr.2019.01.016. Epub 2019 Jan 25.

Authors

Affiliations

¹ Department of Oral Science, Graduate School of Medicine, Chiba University, 1-8- 1 Inohana, Chuo-ku, Chiba 260-8670, Japan; Department of Dentistry and Oral-Maxillofacial Surgery, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba 260-8677, Japan. Electronic address: uzawak@faculty.chiba-u.jp.
² Department of Dentistry and Oral-Maxillofacial Surgery, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba 260-8677, Japan.
³ Department of Oral Science, Graduate School of Medicine, Chiba University, 1-8- 1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
⁴ Department of Medical Oncology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
⁵ Department of Oral Science, Graduate School of Medicine, Chiba University, 1-8- 1 Inohana, Chuo-ku, Chiba 260-8670, Japan; Department of Dentistry and Oral-Maxillofacial Surgery, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba 260-8677, Japan.

PMID: 30690028
DOI: 10.1016/j.yexcr.2019.01.016

Abstract

Cetuximab, an inhibitor of the epidermal growth factor receptor that is used widely to treat human cancers including oral squamous cell carcinoma (OSCC), has characteristic side effects of skin rash and hypomagnesemia. However, the mechanisms of and therapeutic agents for skin rashes and hypomagnesemia are still poorly understood. Our gene expression profiling analyses showed that cetuximab activates the p38 MAPK pathways in human skin cells (human keratinocyte cell line [HaCaT]) and inhibits c-Fos-related signals in human embryonic kidney cells (HEK293). We found that while the p38 inhibitor SB203580 inhibited the expression of p38 MAPK targets in HaCaT cells, flavagline reactivated c-Fos-related factors in HEK293 cells. It is noteworthy that, in addition to not interfering with the effect of cetuximab by both compounds, flavagline has additive effect for OSCC growth inhibition in vivo. Collectively, our results indicate that combination of cetuximab and these potential therapeutic agents for cetuximab-related toxicities could be a promising therapeutic strategy for patients with OSCC.

Keywords: Cetuximab side effects; Flavagline; SB203580; TRPM6; Tumor growth suppression; p38.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents, Immunological / adverse effects*
Carcinoma, Squamous Cell / complications
Carcinoma, Squamous Cell / drug therapy*
Cell Line, Tumor
Cetuximab / adverse effects*
Drug Therapy, Combination
ErbB Receptors / antagonists & inhibitors
Exanthema / chemically induced
Exanthema / genetics
Exanthema / prevention & control
Female
Gene Expression Regulation, Neoplastic / drug effects
Gene Regulatory Networks
Growth Inhibitors / adverse effects
Growth Inhibitors / antagonists & inhibitors
Growth Inhibitors / therapeutic use*
HEK293 Cells
Humans
Hypercalciuria / chemically induced
Hypercalciuria / genetics
Hypercalciuria / prevention & control
Imidazoles / therapeutic use*
MAP Kinase Signaling System / drug effects
Mice
Mice, Inbred BALB C
Mice, Nude
Mouth Neoplasms / complications
Mouth Neoplasms / drug therapy*
Mouth Neoplasms / genetics
Nephrocalcinosis / chemically induced
Nephrocalcinosis / genetics
Nephrocalcinosis / prevention & control
Pyridines / therapeutic use*
Renal Tubular Transport, Inborn Errors / chemically induced
Renal Tubular Transport, Inborn Errors / genetics
Renal Tubular Transport, Inborn Errors / prevention & control
Transcriptome
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents, Immunological
Growth Inhibitors
Imidazoles
Pyridines
EGFR protein, human
ErbB Receptors
SB 203580
Cetuximab

Supplementary concepts

Hypomagnesemia primary