Modulatory effects of 5-fluorouracil on the rhythmic expression of circadian clock genes: A possible mechanism of chemotherapy-induced circadian rhythm disturbances

Hideyuki Terazono, Ahmed Hamdan, Naoya Matsunaga, Naoto Hayasaka, Hiroaki Kaji, Takashi Egawa, Kazutaka Makino, Yasufumi Shigeyoshi, Satoru Koyanagi, Shigehiro Ohdo

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

The circadian clock system is necessary to adapt endogenous physiological functions to daily variations in environmental conditions. Abnormality in circadian rhythms, such as the sleep-wake cycle and the timing of hormonal secretions, is implicated in various physiological and psychiatrical disorders. Recent molecular studies have revealed that oscillation in the transcription of specific clock genes plays a central role in the generation of 24 h cycles of physiology and behavior. It has been noticed that patients receiving chemotherapeutic agents experience disturbances in their behavioral and physical performances, including circadian rhythms. To explore the underlying mechanism of chemotherapeutic agent-induced disturbance of these rhythms, we investigated the influence of 5-fluorouracil (5-FU), one of the most widely used chemotherapeutic agents for the treatment of cancers, on the expression of clock genes. Treatment of cultured NIH3T3 cells with 5-FU for 48 h resulted in a significant reduction of mRNA levels of Period1 (Per1) and Period2 (Per2) without affecting cell viability; however, treatment with the same amount of uracil, a structural analog of 5-FU, had little effect on the expression of clock genes. Consistent with its inhibitory actions, continuous administration of 5-FU (2 mg/kg/h) to mice attenuated the oscillation in the expressions of Per1 and Per2 in the liver and suprachiasmatic nuclei, the center of the mammalian circadian clock. These results reveal a possible pharmacological action by the chemotherapeutic agent 5-FU on the circadian clock mechanism, which is the underlying cause of its adverse effects on 24-h rhythms of physiology and behavior.

Original languageEnglish
Pages (from-to)1616-1622
Number of pages7
JournalBiochemical Pharmacology
Volume75
Issue number8
DOIs
Publication statusPublished - 2008 Apr 15
Externally publishedYes

Fingerprint

Circadian Clocks
Chemotherapy
Circadian Rhythm
Fluorouracil
Clocks
Genes
Drug Therapy
Physiology
Gene Expression
Suprachiasmatic Nucleus
Uracil
Transcription
Cultured Cells
Cell Survival
Sleep
Liver
Therapeutics
Pharmacology
Messenger RNA
Cells

Keywords

  • 5-Fluorouracil
  • Chemotherapy
  • Circadian rhythm
  • Clock genes
  • Suprachiasmatic nuclei

ASJC Scopus subject areas

  • Pharmacology

Cite this

Modulatory effects of 5-fluorouracil on the rhythmic expression of circadian clock genes : A possible mechanism of chemotherapy-induced circadian rhythm disturbances. / Terazono, Hideyuki; Hamdan, Ahmed; Matsunaga, Naoya; Hayasaka, Naoto; Kaji, Hiroaki; Egawa, Takashi; Makino, Kazutaka; Shigeyoshi, Yasufumi; Koyanagi, Satoru; Ohdo, Shigehiro.

In: Biochemical Pharmacology, Vol. 75, No. 8, 15.04.2008, p. 1616-1622.

Research output: Contribution to journalArticle

Terazono, H, Hamdan, A, Matsunaga, N, Hayasaka, N, Kaji, H, Egawa, T, Makino, K, Shigeyoshi, Y, Koyanagi, S & Ohdo, S 2008, 'Modulatory effects of 5-fluorouracil on the rhythmic expression of circadian clock genes: A possible mechanism of chemotherapy-induced circadian rhythm disturbances', Biochemical Pharmacology, vol. 75, no. 8, pp. 1616-1622. https://doi.org/10.1016/j.bcp.2008.01.011
Terazono, Hideyuki ; Hamdan, Ahmed ; Matsunaga, Naoya ; Hayasaka, Naoto ; Kaji, Hiroaki ; Egawa, Takashi ; Makino, Kazutaka ; Shigeyoshi, Yasufumi ; Koyanagi, Satoru ; Ohdo, Shigehiro. / Modulatory effects of 5-fluorouracil on the rhythmic expression of circadian clock genes : A possible mechanism of chemotherapy-induced circadian rhythm disturbances. In: Biochemical Pharmacology. 2008 ; Vol. 75, No. 8. pp. 1616-1622.
@article{44a68b5474f54aecb60636eb30204393,
title = "Modulatory effects of 5-fluorouracil on the rhythmic expression of circadian clock genes: A possible mechanism of chemotherapy-induced circadian rhythm disturbances",
abstract = "The circadian clock system is necessary to adapt endogenous physiological functions to daily variations in environmental conditions. Abnormality in circadian rhythms, such as the sleep-wake cycle and the timing of hormonal secretions, is implicated in various physiological and psychiatrical disorders. Recent molecular studies have revealed that oscillation in the transcription of specific clock genes plays a central role in the generation of 24 h cycles of physiology and behavior. It has been noticed that patients receiving chemotherapeutic agents experience disturbances in their behavioral and physical performances, including circadian rhythms. To explore the underlying mechanism of chemotherapeutic agent-induced disturbance of these rhythms, we investigated the influence of 5-fluorouracil (5-FU), one of the most widely used chemotherapeutic agents for the treatment of cancers, on the expression of clock genes. Treatment of cultured NIH3T3 cells with 5-FU for 48 h resulted in a significant reduction of mRNA levels of Period1 (Per1) and Period2 (Per2) without affecting cell viability; however, treatment with the same amount of uracil, a structural analog of 5-FU, had little effect on the expression of clock genes. Consistent with its inhibitory actions, continuous administration of 5-FU (2 mg/kg/h) to mice attenuated the oscillation in the expressions of Per1 and Per2 in the liver and suprachiasmatic nuclei, the center of the mammalian circadian clock. These results reveal a possible pharmacological action by the chemotherapeutic agent 5-FU on the circadian clock mechanism, which is the underlying cause of its adverse effects on 24-h rhythms of physiology and behavior.",
keywords = "5-Fluorouracil, Chemotherapy, Circadian rhythm, Clock genes, Suprachiasmatic nuclei",
author = "Hideyuki Terazono and Ahmed Hamdan and Naoya Matsunaga and Naoto Hayasaka and Hiroaki Kaji and Takashi Egawa and Kazutaka Makino and Yasufumi Shigeyoshi and Satoru Koyanagi and Shigehiro Ohdo",
year = "2008",
month = "4",
day = "15",
doi = "10.1016/j.bcp.2008.01.011",
language = "English",
volume = "75",
pages = "1616--1622",
journal = "Biochemical Pharmacology",
issn = "0006-2952",
publisher = "Elsevier Inc.",
number = "8",

}

TY - JOUR

T1 - Modulatory effects of 5-fluorouracil on the rhythmic expression of circadian clock genes

T2 - A possible mechanism of chemotherapy-induced circadian rhythm disturbances

AU - Terazono, Hideyuki

AU - Hamdan, Ahmed

AU - Matsunaga, Naoya

AU - Hayasaka, Naoto

AU - Kaji, Hiroaki

AU - Egawa, Takashi

AU - Makino, Kazutaka

AU - Shigeyoshi, Yasufumi

AU - Koyanagi, Satoru

AU - Ohdo, Shigehiro

PY - 2008/4/15

Y1 - 2008/4/15

N2 - The circadian clock system is necessary to adapt endogenous physiological functions to daily variations in environmental conditions. Abnormality in circadian rhythms, such as the sleep-wake cycle and the timing of hormonal secretions, is implicated in various physiological and psychiatrical disorders. Recent molecular studies have revealed that oscillation in the transcription of specific clock genes plays a central role in the generation of 24 h cycles of physiology and behavior. It has been noticed that patients receiving chemotherapeutic agents experience disturbances in their behavioral and physical performances, including circadian rhythms. To explore the underlying mechanism of chemotherapeutic agent-induced disturbance of these rhythms, we investigated the influence of 5-fluorouracil (5-FU), one of the most widely used chemotherapeutic agents for the treatment of cancers, on the expression of clock genes. Treatment of cultured NIH3T3 cells with 5-FU for 48 h resulted in a significant reduction of mRNA levels of Period1 (Per1) and Period2 (Per2) without affecting cell viability; however, treatment with the same amount of uracil, a structural analog of 5-FU, had little effect on the expression of clock genes. Consistent with its inhibitory actions, continuous administration of 5-FU (2 mg/kg/h) to mice attenuated the oscillation in the expressions of Per1 and Per2 in the liver and suprachiasmatic nuclei, the center of the mammalian circadian clock. These results reveal a possible pharmacological action by the chemotherapeutic agent 5-FU on the circadian clock mechanism, which is the underlying cause of its adverse effects on 24-h rhythms of physiology and behavior.

AB - The circadian clock system is necessary to adapt endogenous physiological functions to daily variations in environmental conditions. Abnormality in circadian rhythms, such as the sleep-wake cycle and the timing of hormonal secretions, is implicated in various physiological and psychiatrical disorders. Recent molecular studies have revealed that oscillation in the transcription of specific clock genes plays a central role in the generation of 24 h cycles of physiology and behavior. It has been noticed that patients receiving chemotherapeutic agents experience disturbances in their behavioral and physical performances, including circadian rhythms. To explore the underlying mechanism of chemotherapeutic agent-induced disturbance of these rhythms, we investigated the influence of 5-fluorouracil (5-FU), one of the most widely used chemotherapeutic agents for the treatment of cancers, on the expression of clock genes. Treatment of cultured NIH3T3 cells with 5-FU for 48 h resulted in a significant reduction of mRNA levels of Period1 (Per1) and Period2 (Per2) without affecting cell viability; however, treatment with the same amount of uracil, a structural analog of 5-FU, had little effect on the expression of clock genes. Consistent with its inhibitory actions, continuous administration of 5-FU (2 mg/kg/h) to mice attenuated the oscillation in the expressions of Per1 and Per2 in the liver and suprachiasmatic nuclei, the center of the mammalian circadian clock. These results reveal a possible pharmacological action by the chemotherapeutic agent 5-FU on the circadian clock mechanism, which is the underlying cause of its adverse effects on 24-h rhythms of physiology and behavior.

KW - 5-Fluorouracil

KW - Chemotherapy

KW - Circadian rhythm

KW - Clock genes

KW - Suprachiasmatic nuclei

UR - http://www.scopus.com/inward/record.url?scp=41249090029&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=41249090029&partnerID=8YFLogxK

U2 - 10.1016/j.bcp.2008.01.011

DO - 10.1016/j.bcp.2008.01.011

M3 - Article

C2 - 18329632

AN - SCOPUS:41249090029

VL - 75

SP - 1616

EP - 1622

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

SN - 0006-2952

IS - 8

ER -