Inhibitory Effects of Glucosylceramide on Tumorigenesis Induced by a Carcinogen in Mice

Abstract

Objective: Glucosylceramide (Glu-Cer), a glycosylated form of ceramide, has been reported to have cytotoxic effects in the cells of various cancers. We previously reported that dietary Glu-Cer from rice bran had inhibitory effects on human head and neck squamous cell carcinoma (HNSCC) in nonobese diabetes (NOD)/severe combined immunodeficiency (SCID) mice. In HNSCC, preventing recurrence and second primary cancer is required to improve prognosis. The purpose of the present study was to determine whether dietary Glu-Cer had anticarcinogenic and antitumorigenic effects in a mouse model of HNSCC.

Methods: A total of 40 CB6F1-Tg rasH2@Jcl mice were divided into two groups: control and Glu-Cer. All mice were given 4-nitroquinoline 1-oxide for 24 weeks. Control group mice were fed the normal diet without Glu-Cer. The Glu-Cer group mice were given a mixture of the normal diet plus 0.25% Glu-Cer for 24 weeks. Microscopic examination was performed to identify grossly visible preneoplasms and neoplasms in the mouth, pharynx, and esophagus. Epithelial regions were classified as normal tissue, carcinoma in situ (CIS), or SCC; and the number of each type of region was counted.

Results: Compared with the Glu-Cer group mice, control group mice more frequently developed individual and multiple tumors of each type, including CIS and SCC, in the mouth, pharynx, or esophagus.

Conclusion: Tumor development was effectively inhibited by dietary Glu-Cer derived from rice bran, indicating that this and related compounds show promise as prophylactic agents for human HNSCC.

Level of evidence: NA Laryngoscope, 130:E593-E597, 2020.

Keywords: Glucosylceramide; carcinogenesis; ceramide; head and neck squamous cell carcinoma; tumorigenesis.

Figure 1

Feed dosage and water supply. Glu‐cer group mice consumed more food than control group mice (A). However, there was no significant difference between the two groups in the total volume of drinking water consumed (B). Glu‐cer = glucosylceramide; NS = nonsignificant.

Figure 2

Morphological observation of mouse tongue, pharynx, and esophagus. Multiple tumors formed on the tongue, pharynx, and esophagus of a control group mouse (A). Few tumors were observed in these regions in a Glu‐cer group mouse (B). 4‐NQO = 4‐nitroquinoline 1‐oxide; Glu‐cer = glucosylceramide.

Figure 3

Development of tongue, pharyngeal, and esophageal tumors (SCC and carcinoma in situ). Tumors of any type developed in 16 control group mice (80%) and eight Glu‐Cer group mice (40%), indicating a significantly higher incidence in the control group (A). Control group mice developed multiple tumors significantly more frequently than Glu‐Cer group mice (6.15 ± 1.51 vs. 0.9 ± 0.28 per mouse, respectively) (B). Tumors classified as SCC developed in 16 control group mice (80%) and in seven Glu‐Cer group mice (35%), indicating a significantly higher incidence in the control group (C). Control group mice developed multiple tumors significantly more frequently than Glu‐Cer group mice (4.75 ± 1.38 vs. 0.65 ± 0.23 per mouse, respectively) (D). 4‐NQO = 4‐nitroquinoline 1‐oxide; CIS = carcinoma in situ; Glu‐cer = glucosylceramide; SCC = squamous cell carcinoma.

Figure 4

Overall survival. The median survival period was 181 days in control group mice and 159 days in Glu‐cer group mice, indicating no significant difference between the two groups. 4‐NQO = 4‐nitroquinoline 1‐oxide; Glu‐cer = glucosylceramide.