Protein kinase inhibitors emodin and dichloro-ribofuranosylbenzimidazole modulate the cellular accumulation and cytotoxicity of cisplatin in a schedule-dependent manner

Kurokawa, Tetsuji; He, Guangan; Siddik, Zahid H.

doi:10.1007/s00280-009-1045-2

Cited by 9 publications

(5 citation statements)

References 36 publications

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“…In an earlier study, the protein kinase inhibitors emodin and dichlororibofuranosylbenzimidazole, which are structurally similar to sorafenib, were found to decrease cisplatin uptake and DNA platination. The effect was, however, abrogated by CTR1 knockdown (40). Sorafenib modulation of CTR1 expression may be mediated through inhibition of MAPK signaling as the MEK inhibitor U0126 had a similar effect.…”

Section: Discussionmentioning

confidence: 92%

Transporter-Mediated Interaction Between Platinum Drugs and Sorafenib at the Cellular Level

Schneider

Chaib

Spanier

et al. 2017

AAPS J

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Combining the multikinase inhibitor sorafenib with the platinum-based chemotherapy of solid tumors was expected to improve treatment outcome. However, in many clinical trials, no benefit from sorafenib addition to the platinum-containing regimen could be demonstrated. Moreover, in some studies, decreased survival of ovarian cancer patients as well as non-small cell lung cancer patients with squamous cell histology was observed. The aim of this study was to investigate the cellular mechanisms of the pharmacological interaction between platinum drugs and sorafenib in different cancer cell lines. The interaction was characterized by combination index analysis, platinum accumulation and DNA platination were determined using flameless atomic absorption spectrometry, and protein expression was assessed with Western blot. In the sensitive A2780 ovarian carcinoma and H520 squamous cell lung carcinoma cell lines, sorafenib induced downregulation of Na,K-ATPase. In A2780 cells, the kinase inhibitor also decreased the expression of copper transporter 1 (CTR1). As a result, sorafenib treatment led to a diminished cellular accumulation of cisplatin and carboplatin and to a decrease in DNA platination in these cell lines. This was not the case in the cisplatin-resistant A2780cis ovarian carcinoma and H522 lung adenocarcinoma cell lines featuring lower basal expression of the above-mentioned transporters. In all cell lines studied, an antagonistic interaction between platinum drugs and sorafenib was found. Our results suggest that sorafenib impairs cisplatin and carboplatin uptake through downregulation of CTR1 and/or Na,K-ATPase resulting in reduction of DNA platination. This effect is not observed in cancer cells with defects in platinum accumulation.

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Section: Discussionmentioning

confidence: 92%

Transporter-Mediated Interaction Between Platinum Drugs and Sorafenib at the Cellular Level

Schneider

Chaib

Spanier

et al. 2017

AAPS J

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“…However, emodin exerts a downregulatory effect on Mdr-1 protein in prostate cells, with over-activated HiF-1 and potent Mdr (9). in previous studies, emodin has been shown to synergize with cisplatin (29,30), paclitaxel (6) and celecoxib (31), leading to an enhanced antiproliferation effect in several cancer cell lines. Therefore, we hypothesized that emodin combined with gemcitabine may also have a synergistic effect on pancreatic cancer cell proliferation and apoptosis.…”

Section: Discussionmentioning

confidence: 98%

Emodin potentiates the antitumor effects of gemcitabine in pancreatic cancer cells via inhibition of nuclear factor-κB

Liu

Chen²,

Tong³

et al. 2011

Mol Med Rep

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Abstract. Many studies have demonstrated that emodin inhibits the growth and induces the apoptosis and chemosensitization of various cancer cells in animal models. The aim of this study was to investigate the molecular mechanism of the chemo-sensitization potential of emodin on gemcitabine in pancreatic cancer cell lines via inhibition of nuclear factor-κB (nF-κB). SW1990 and SW1990/GZ cells were treated with: i) emodin (20 µmol/l), ii) nF-κB inhibitor Bay 11-7082 (5 µmol/l), iii) gemcitabine (20 µmol/l), iv) pretreated with emodin for 24 h followed by coincubation with gemcitabine for 24 h, or v) pre-treated with Bay 11-7082 for 1 h followed by treatment with gemcitabine for 24 h. SW1990 and SW1990/GZ cells were also treated with emodin (20, 40 and 80 µmol/l). cellular proliferation and apoptosis were detected by the Cell Counting Kit-8 (CCK-8) assay and flow cytometry. nF-κB protein was detected by Western blotting. SW1990/GZ cell morphological changes were observed under optical and fluorescence microscopes. Emodin strongly inhibited the proliferation and induced the apoptosis of both pancreatic cancer cell lines. Furthermore, emodin combined with gemcitabine induced a higher percentage of growth inhibition and apoptosis in both pancreatic cancer cell lines compared to gemcitabine alone. Pre-treatment of SW1990/ GZ cells with Bay 11-7082 for 1 h followed by gemcitabine resulted in greater inhibitory and apoptosis rates compared to gemcitabine alone. The resistant pancreatic cell line SW1990/ GZ presented higher constitutive nF-κB protein expression compared to the SW1990 cells. emodin not only downregulated nF-κB in a dose-dependent manner in SW1990 and SW1990/GZ cells under unstimulated conditions, but also inhibited gemcitabine-induced nF-κB protein expression. emodin potentiated the antitumor effects of gemcitabine in pancreatic cancer, which was related to the down-regulation of nF-κB.

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“…Cisplatin has been previously shown to be potentiated by other polyphenols such as emodin, in non-small cell lung cancer (NSCLC) with HER-2/neu-overexpressing [28], merkel cell carcinoma (MCC) [29], human ovarian tumour cell lines (A2780) [30], and gallbladder carcinoma cells (SGC996) [31, 32]. Likewise, here cisplatin and cyclophosphamide in combination with quercetin synergistically reduced ATP levels, induced apoptosis, and accumulated the cells at S phase and/or G 2 /M phase in both lymphoid and myeloid cell lines.…”

Section: Discussionmentioning

confidence: 99%

Polyphenols enhance the activity of alkylating agents in leukaemia cell lines

et al. 2019

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Polyphenols have been shown to sensitize solid tumours to alkylating agents such as cisplatin, and induce apoptosis and/or cell-cycle arrest. Here, we assess the effects of five polyphenols alone and in combination with three alkylating agents: cisplatin, cyclophosphamide and chlorambucil in lymphoid and myeloid leukaemia cells lines, and non-tumour control cells. In lymphoid leukaemia cell lines there was a synergistic reduction in ATP and glutathione levels, an induction of cell cycle arrest, DNA damage and apoptosis when quercetin, apigenin, emodin and rhein were combined with cisplatin and cyclophosphamide; and when apigenin and rhein were combined with chlorambucil. In myeloid leukaemia cells quercetin, apigenin and emodin showed a similar synergistic effect with all alkylating agents; however antagonistic effects were observed with some or all alkylating agents when combined with emodin, rhein and cis-stilbene. All synergistic effects were associated with reduced glutathione levels, DNA damage and apoptosis; whilst during antagonism the reverse effects were observed. The combination of alkylating agents, particularly cisplatin with polyphenols could be promising for the treatment of lymphoid leukaemias, with apigenin showing the greatest effects. Likewise in myeloid cells apigenin also synergised the action of all alkylating agents, suggesting that apigenin may also be beneficial in myeloid leukaemias.

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Protein kinase inhibitors emodin and dichloro-ribofuranosylbenzimidazole modulate the cellular accumulation and cytotoxicity of cisplatin in a schedule-dependent manner

Cited by 9 publications

References 36 publications

Transporter-Mediated Interaction Between Platinum Drugs and Sorafenib at the Cellular Level

Transporter-Mediated Interaction Between Platinum Drugs and Sorafenib at the Cellular Level

Emodin potentiates the antitumor effects of gemcitabine in pancreatic cancer cells via inhibition of nuclear factor-κB

Polyphenols enhance the activity of alkylating agents in leukaemia cell lines

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