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Partial Substitution of Glucose with Xylitol Prolongs Survival and Suppresses Cell Proliferation and Glycolysis of Mice Bearing Orthotopic Xenograft of Oral Cancer - PubMed

  • ️Sat Jan 01 2022

Partial Substitution of Glucose with Xylitol Prolongs Survival and Suppresses Cell Proliferation and Glycolysis of Mice Bearing Orthotopic Xenograft of Oral Cancer

Yuraporn Sahasakul et al. Nutrients. 2022.

Abstract

Many types of cancer have metabolic alterations with increased glycolysis. Identification of alternative sweeteners that do not fuel cancer is a novel approach to cancer control. The present study aimed to investigate the effects of xylitol on tumor growth and survival of mice bearing orthotopic xenograft of tongue cancers. The results showed that partial substitution of glucose with xylitol (glucose 0.35 g plus xylitol 2.06 g/kg body weight) non-significantly reduced tumor volume, and significantly prolonged the median survival time from 19 days in the control to 30.5 days in the xylitol group. Immunohistochemical data of the tongue tissue shows significantly lower intense-to-mild staining ratios of the proliferation marker Ki-67 in the xylitol than those of the control group (p = 0.04). Furthermore, the xylitol substitution significantly reduced the expression of the rate-limiting glycolytic enzyme, phosphofructokinase-1 (PFK-1) (p = 0.03), and showed a non-significant inhibition of PFK activity. In summary, partial substitution of glucose with xylitol at the equivalent dose to human household use of 10 g/day slows down tumor proliferation and prolongs survival of mice bearing an orthotopic oral cancer xenograft, possibly through glycolytic inhibition, with minimal adverse events. The insight warrants clinical studies to confirm xylitol as a candidate sweetener in food products for cancer survivors.

Keywords: PFK; glucose; glycolysis; oral cancer; orthotopic xenograft model; sweetener; xylitol.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1

Orthotopic tongue cancer developed by submucosal injection with CAL-27 cells. A round-shaped marker with a 0.5 cm diameter was placed on the forceps when taking tumor photographs.

Figure 2
Figure 2

Tongue section of CAL-27 xenograft-bearing mice stained with H&E at 400× magnification. (A) Well-differentiated squamous cell carcinomas. (B) Perineural invasion surrounding the nerve fiber (N). (C) Histiocytosis in the lymph node.

Figure 3
Figure 3

Changes in body weights (percent of baseline body weight) of CAL-27 xenograft-bearing mice receiving glucose solution (control), low-xylitol solution (experimental group 1), and high-xylitol solution (experimental group 2). Results are shown as mean ± SEM. p-value was obtained from a two-way ANOVA.

Figure 4
Figure 4

Food and water consumption. (A) Average daily diet intake, (B) average daily water intake, and (C) average daily hydrogel intake of CAL-27 xenograft mice given the glucose solution (control), low-xylitol solution (experimental group 1), and high-xylitol solution (experimental group 2). Results are shown as mean ± SEM. p-values were obtained from two-way ANOVA.

Figure 5
Figure 5

Tumor volumes: (A) Baseline tumor volume of CAL-27 xenograft mice given the glucose solution (■ control), low-xylitol solution (■), and high-xylitol solution (■). Results are shown as mean ± SD. p-value was obtained from one-way ANOVA. (B) Baseline fold change of tumor volume, results are shown as mean ± SEM. p-values were obtained from a two-way ANOVA.

Figure 6
Figure 6

Percent survival of CAL-27 xenograft mice given the glucose solution (control), low-xylitol solution (experimental group 1), and high-xylitol solution (experimental group 2). Changes over time for each group were depicted as Kaplan–Meier curves. * represents p < 0.05, obtained from the log-rank test. p = 0.0105 comparing between high-xylitol and control groups, p = 0.2337 comparing between low-xylitol and control groups.

Figure 7
Figure 7

Expression of Ki-67 proliferation marker in tumor sections of CAL-27 xenograft mice. (A) Photos were depicted from mice in the control group, (B) low-xylitol group, (C) and high-xylitol group. (D) Ki-67 labeling index of CAL-27 xenograft mice. (E) Ki-67 intense-to-mild staining ratios of CAL-27 xenograft mice given the glucose solution (■ control), low-xylitol solution (■), and high-xylitol solution (■). Results are shown as mean ± SEM. * represents p < 0.05, obtained by using one-way ANOVA followed by Tukey’s multiple comparison test.

Figure 7
Figure 7

Expression of Ki-67 proliferation marker in tumor sections of CAL-27 xenograft mice. (A) Photos were depicted from mice in the control group, (B) low-xylitol group, (C) and high-xylitol group. (D) Ki-67 labeling index of CAL-27 xenograft mice. (E) Ki-67 intense-to-mild staining ratios of CAL-27 xenograft mice given the glucose solution (■ control), low-xylitol solution (■), and high-xylitol solution (■). Results are shown as mean ± SEM. * represents p < 0.05, obtained by using one-way ANOVA followed by Tukey’s multiple comparison test.

Figure 8
Figure 8

Expression and activity of PFK in tumor specimens of CAL-27 xenograft mice. PFK-1 expression of control (A), low-xylitol (B), and high-xylitol (C) groups. Bar graphs show the mean ± SEM of PFK-1 expression combined score (D) or PFK activities (E) of CAL-27 xenograft mice given the glucose solution (■ control), low-xylitol solution (■), and high-xylitol solution (■). * represents p < 0.05 obtained from one-way ANOVA followed by Tukey’s multiple comparison test.

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