Cisplatin-Induced Inhibition of p34<sup>cdc2</sup>is Abolished by 5-Fluorouracil

Nylén, Urban; He, Qing; Welander, Ingrid; Lewin, Freddi; Skog, Sven

doi:10.1080/028418698430575

Cited by 4 publications

(1 citation statement)

References 26 publications

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“…Therefore, G2/M-arrest by cisplatin (Fig. 1C) is due to a mechanism that inhibits Cdc2 dephosphorylation, as previously suggested [27], and accumulation of cells in G2/M is likely responsible for the increase in phosphotyrosine-Cdc2 levels.…”

Section: Resultssupporting

confidence: 74%

The impact of S- and G2-checkpoint response on the fidelity of G1-arrest by cisplatin and its comparison to a non-cross-resistant platinum(IV) analog

He¹,

Kuang²,

Khokhar³

et al. 2011

Gynecologic Oncology

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Objective Cisplatin is a DNA-damaging antitumor agent that is highly effective in treating ovarian cancer. It activates the p53/p21 pathway for its cytotoxic mode of action, but it does not induce p21-dependent cell cycle arrest in G1. Therefore, we investigated this paradox, and used the model analog DAP as a positive control for p21-dependent G1-arrest. Methods Studies were conducted in p53-proficient ovarian A2780 tumor cells to examine Cdk activity, cell cycle distribution and DNA damage signaling after cisplatin or DAP in combination with the mitotic inhibitor nocodazole. Results Cisplatin consistently induced transient S-phase arrest by inhibiting Cdk2/cyclin A complex in S-phase at 12 h and then a durable G2/M-arrest by inhibiting Cdc2/cyclin B complex at 12–18 h. These inhibitions were associated with Chk1 and Chk2 activation and resultant increase in inhibitory tyrosine phosphorylation of Cdk2 and Cdc2. Cisplatin also potently inhibited G1-phase Cdk4/cyclin D1 and Cdk2/cyclin E activities at ~18 h. In agreement, exposure of cisplatin-treated A2780, HCT-116p53−/− and HCT-116p21−/− tumor cells to nocodazole revealed limited G1-arrest that was dependent on p53 and p21. In contrast, the durable G1-arrest by DAP, which failed to activate Chk1 and Chk2, was unaffected by nocodazole. Conclusions Cisplatin induced G1-arrest, but at an attenuated level. This was primarily due to orchestration of Cdk inhibition in S-phase first, then in G2, and finally in G1 that effectively blocked cells in G2 and prevented cells from progressing and arresting in G1. These studies demonstrate that cisplatin unequivocally activates G1-checkpoint response, but the fidelity of G1-arrest is compromised by Chk1/2 activation and checkpoint response in S- and G2/M-phase.

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Section: Resultssupporting

confidence: 74%

The impact of S- and G2-checkpoint response on the fidelity of G1-arrest by cisplatin and its comparison to a non-cross-resistant platinum(IV) analog

He¹,

Kuang²,

Khokhar³

et al. 2011

Gynecologic Oncology

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Laser-assisted delivery of synergistic combination chemotherapy in in vivo skin

Wenande

Tam

Bhayana

et al. 2018

Journal of Controlled Release

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High Labeling Indices of cdc25B is Linked to Progression of Gastric Cancers and Associated With a Poor Prognosis

Takahashi

Murai

Tsuneyama

et al. 2007

Applied Immunohistochemistry &Amp; Molecular Morphology

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To clarify the significance of cdc25B, which plays an important physiologic role in regulation of the G2/M check point, in progression of gastric cancer, 125 samples of paraffin-embedded gastric cancers were investigated by immunohistochemistry. In addition, 3 human gastric cancer cell lines were studied to determine the cellular localization of cdc25B by immunohistochemistry and cell fractionation followed by Western blotting. In the cell lines cdc25B was found to be present in both nuclei and cytoplasm, but predominantly in nuclei. High labeling indices of cdc25B in invasion front of gastric cancer was observed in 31 out of 125 cases (24.8%), linked to an advanced depth of cancer invasion (P=0.02), high rates of lymphatic invasion (P=0.03), and lymph node metastasis (P<0.01). Furthermore, the Kaplan-Meier method demonstrated a poor prognosis for cdc25B high labeling indices cases (P=0.02), although multivariate analysis revealed it not to be an independent factor. In conclusion, it seems likely that cdc25B is located predominantly in nuclei when overexpressed and this has some linkage with progression of gastric cancer.

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Cisplatin-Induced Inhibition of p34^cdc2is Abolished by 5-Fluorouracil

Cited by 4 publications

References 26 publications

The impact of S- and G2-checkpoint response on the fidelity of G1-arrest by cisplatin and its comparison to a non-cross-resistant platinum(IV) analog

The impact of S- and G2-checkpoint response on the fidelity of G1-arrest by cisplatin and its comparison to a non-cross-resistant platinum(IV) analog

Laser-assisted delivery of synergistic combination chemotherapy in in vivo skin

High Labeling Indices of cdc25B is Linked to Progression of Gastric Cancers and Associated With a Poor Prognosis

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Cisplatin-Induced Inhibition of p34cdc2is Abolished by 5-Fluorouracil

Cited by 4 publications

References 26 publications

The impact of S- and G2-checkpoint response on the fidelity of G1-arrest by cisplatin and its comparison to a non-cross-resistant platinum(IV) analog

The impact of S- and G2-checkpoint response on the fidelity of G1-arrest by cisplatin and its comparison to a non-cross-resistant platinum(IV) analog

Laser-assisted delivery of synergistic combination chemotherapy in in vivo skin

High Labeling Indices of cdc25B is Linked to Progression of Gastric Cancers and Associated With a Poor Prognosis

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Cisplatin-Induced Inhibition of p34^cdc2is Abolished by 5-Fluorouracil