Role of Glucocorticoid Receptor in the Regulation of Cellular Sensitivity to Irinotecan Hydrochloride

Akagı, Takanori; Fukagawa, Tatsuo; Kage, Yuki; To, Hideto; Matsumoto, Naoya; Koyanagi, Satoru; Uchida, Atsushi; Fujii, Asuka; Iba, Hideo; Ikemura, Toshimichi; Aramaki, Hironori; Higuchi, Shun; Ohdo, Shigehiro

doi:10.1254/jphs.08219fp

Cited by 2 publications

(1 citation statement)

References 24 publications

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“…The profile of Top1 binding was oscillatory with peaks at 12, 24 and 48 h (Figure 6C). To reset the circadian rhythm, the cells were stimulated with dexamethasone that modulates not only Top1 transcription (10) but also Top1 activity on the phosphatidylinositol 3-kinase-Akt-signaling pathway (39). Furthermore, the circadian profile of Top1 protein delays by 12 h compared with that of glucocorticoid (10).…”

Section: Discussionmentioning

confidence: 99%

Rhythmic binding of Topoisomerase I impacts on the transcription of Bmal1 and circadian period

Onishi

Kawano

2012

Nucleic Acids Research

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The Bmal1 gene is essential for the circadian system, and its promoter has a unique open chromatin structure. We examined the mechanism of topoisomerase I (Top1) to understand the role of the unique chromatin structure in Bmal1 gene regulation. Camptothecin, a Top1 inhibitor, and Top1 small interfering RNA (siRNA) enhanced Baml1 transcription and lengthened its circadian period. Top1 is located at an intermediate region between two ROREs that are critical cis-elements of circadian transcription and the profile of Top1 binding indicated anti-phase circadian oscillation of Bmal1 transcription. Promoter assays showed that the Top1-binding site is required for transcriptional suppression and that it functions cooperatively with the distal RORE, supporting that Bmal1 transcription is upregulated by Top1 inhibition. A DNA fragment between the ROREs, where the Top1-binding site is located, behaved like a right-handed superhelical twist, and modulation of Top1 activity by camptothecin and Top1 siRNA altered the footprint profile, indicating modulation of the chromatin structure. These data indicate that Top1 modulates the chromatin structure of the Bmal1 promoter, regulates Bmal1 transcription and influences the circadian period.

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Section: Discussionmentioning

confidence: 99%

Rhythmic binding of Topoisomerase I impacts on the transcription of Bmal1 and circadian period

Onishi

Kawano

2012

Nucleic Acids Research

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Sex and Dosing-Time Dependencies in Irinotecan-Induced Circadian Disruption

Ahowesso¹,

Li²,

Zampera³

et al. 2011

Chronobiology International

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Circadian disruption accelerates malignant growth; thus, it should be avoided in anticancer therapy. The circadian disruptive effects of irinotecan, a topoisomerase I inhibitor, was investigated according to dosing time and sex. In previous work, irinotecan achieved best tolerability following dosing at zeitgeber time (ZT) 11 in male and ZT15 in female mice, whereas worst toxicity corresponded to treatment at ZT23 and ZT3 in male and female mice, respectively. Here, irinotecan (50 mg/kg intravenous [i.v.]) was delivered at the sex-specific optimal or worst circadian timing in male and female B6D2F1 mice. Circadian disruption was assessed with rest-activity, body temperature, plasma corticosterone, and liver mRNA expressions of clock genes Rev-erbα, Per2, and Bmal1. Baseline circadian rhythms in rest-activity, body temperature, and plasma corticosterone were more prominent in females as compared to males. Severe circadian disruption was documented for all physiology and molecular clock endpoints in female mice treated at the ZT of worst tolerability. Conversely, irinotecan administration at the ZT of best tolerability induced slight alteration of circadian physiology and clock-gene expression patterns in female mice. In male mice, irinotecan produced moderate alterations of circadian physiology and clock-gene expression patterns, irrespective of treatment ZT. However, the average expression of Rev-erbα, Per2, and Bmal1 were down-regulated 2- to 10-fold with irinotecan at the worst ZT, while being minimally or unaffected at the best ZT, irrespective of sex. Corticosterone secretion increased acutely within 2 h with a sex-specific response pattern, resulting in a ZT-dependent phase-advance or -delay in both sex. The mRNA expressions of irinotecan clock-controlled metabolism genes Ce2, Ugt1a1, and Top1 were unchanged or down-regulated according to irinotecan timing and sex. This study shows that the circadian timing system represents an important toxicity target of irinotecan in female mice, where circadian disruption persists after wrongly timed treatment. As a result, the mechanisms underling cancer chronotherapeutics are expectedly more susceptible to disruption in females as compared to males. Thus, the optimal circadian timing of chemotherapy requires precise determination according to sex, and should involve the noninvasive monitoring of circadian biomarkers.

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Role of Glucocorticoid Receptor in the Regulation of Cellular Sensitivity to Irinotecan Hydrochloride

Cited by 2 publications

References 24 publications

Rhythmic binding of Topoisomerase I impacts on the transcription of Bmal1 and circadian period

Rhythmic binding of Topoisomerase I impacts on the transcription of Bmal1 and circadian period

Sex and Dosing-Time Dependencies in Irinotecan-Induced Circadian Disruption

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