Interactions of cisplatin and the copper transporter CTR1 in human colon cancer cells

Åkerfeldt, Mia C.; Tran, Carmen M.-N.; Shen, Clara; Hambley, Trevor W.; New, Elizabeth J.

doi:10.1007/s00775-017-1467-y

Cited by 37 publications

(28 citation statements)

References 42 publications

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“…Cisplatin's ability to induce CTR1 degradation has been disputed for a long time . Western blot analysis by Ivy et al and Akerfeldt et al reported that the relationship between cDDP stimulation and CTR1 expression was irrelevant, whereas Holzer et al and Akerfeldt et al observed a rapid downregulation of CTR1 in reaction to cDDP treatment. In agreement with the results reported by Wang et al, we observed an overall CTR1 decrease at a much slower rate after cDDP treatment.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies reported that expression of the copper transporter CTR1 is closely related to cellular and tissue platinum accumulation and clinical outcomes. 18,[20][21][22] In this case, we investigated cellular CTR1 expression and localization when treated with BODIPY-Pt. Cellular CTR1 expression ( Figure 3A, red) underwent a minor decrease shortly after exposure to BODIPY-Pt and then remained steady ( Figures 3A,S2).…”

Section: Ipy-pt In Both the Cells Transfected With Siezh2 And The Conmentioning

confidence: 99%

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Enhancer of zeste homolog 2 promotes cisplatin resistance by reducing cellular platinum accumulation

et al. 2018

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Enhancer of zeste homolog 2 (EZH2), which is overexpressed in a wide range of tumors, contributes to ovarian cancer malignancy in several different ways. We aimed to illustrate the role of EZH2 in ovarian cancer cisplatin resistance and to identify possible underlying mechanisms of this role that may provide a rationale for targeting EZH2 in cancer treatment. Here, we present data indicating that EZH2 overexpression is associated with cisplatin resistance and intracellular platinum drug accumulation. Measurements of EZH2 in 84 ovarian cancer patients suggested that patients with high EZH2 levels tend to have poor responses to cisplatin. The EZH2 level progressively increased in cells receiving repeated cisplatin exposure. Downregulation of EZH2 not only sensitized cellular reactions to cisplatin and increased cellular platinum accumulation when cells were exposed to both cisplatin and BODIPY‐Pt (a fluorescent cisplatin complex) but also protected copper transporter 1, a high‐affinity copper transporter closely related to cisplatin resistance, from cisplatin‐induced proteasomal degradation. Overall, these findings identify a new mechanism that expands the unrecognized role of EZH2 in ovarian cancer cisplatin resistance.

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Section: Discussionmentioning

confidence: 99%

Section: Ipy-pt In Both the Cells Transfected With Siezh2 And The Conmentioning

confidence: 99%

Enhancer of zeste homolog 2 promotes cisplatin resistance by reducing cellular platinum accumulation

et al. 2018

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“…Nonetheless, it is well-known that the transport of either substance is suppressed competitively or noncompetitively when substances transported by the same transporter coexist. CDDP uptake by the copper transporter, SLC31A1, was reported to not be affected when the coexistent copper concentration is low but is increased when the concentration is greater than or equal to 500 µM [21,22]. In this study, the additional application of the constitutive element, Mg, might not have affected the transport of CDDP and the intracellular Mg levels.…”

Section: Discussionmentioning

confidence: 78%

Effect of Magnesium Supplementation to Prevent Nephrotoxicity on the Antitumor Activity of Cisplatin

Yasuda¹,

Kishimoto²,

Ebara³

et al. 2019

JCTR

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Background: Cisplatin (CDDP) is one of the most widely used anticancer drugs, but CDDP often leads to nephrotoxicity, which limits its clinical effectiveness. Magnesium (Mg) supplementation is recommended for the avoidance of CDDP-induced nephrotoxicity. However, there is a concern that exposing cancer cells to Mg may suppress the antitumor effect of CDDP. Methods: Transporter expression, intracellular platinum and Mg levels, and cytotoxicity of CDDP after Mg exposure were assessed in human hepatocellular carcinoma (HepG2) and human ovarian carcinoma (2008) cells. Results: In HepG2 cells, Mg exposure significantly increased mRNA levels of multidrug and toxin extrusion 1 (MATE1), which mediates the renal excretion of CDDP, but did not alter its protein levels, including those of organic cation transporter 1 (OCT1), which mediates CDDP uptake in renal tubular and cancer cells, and multidrug resistance-associated protein 2 (MRP2), which mediates CDDP efflux in cancer cells. In 2008 cells, MATE1 protein expression could not be detected, but a slight increase in MRP2 and OCT1 protein expression was observed after Mg exposure. Intracellular Mg levels were significantly increased due to Mg exposure in both cells. However, intracellular platinum levels and cytotoxicity of CDDP were not affected in both cells, even with 2 mM Mg co-exposure. Conclusion: This study found that Mg exposure only slightly changed transporter expression and did not affect intracellular platinum levels and CDDP cytotoxicity in HepG2 and 2008 cells. Thus, Mg supplementation can be used to avoid CDDP-induced renal toxicity without affecting the accumulation of CDDP in cancer cells and its cytotoxicity.

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“…However, more recent works mostly exclude this hypothesis (53,(61)(62)(63)(64). Although some studies show a positive correlation between the presence of CTr1 in the membrane and the high transport rate of cisplatin, they do not necessarily show an increase of the cell death rate.…”

Section: Introductionmentioning

confidence: 98%

“…Although some studies show a positive correlation between the presence of CTr1 in the membrane and the high transport rate of cisplatin, they do not necessarily show an increase of the cell death rate. This may suggest that cisplatin appears in the cytoplasm in inactivated chemical form after being transported by CTr1 (61,(65)(66)(67). Currently passive diffusion through the lipid bilayer is considered as the only known way of transport of cisplatin in its active form (53,58,65,68).…”

Section: Introductionmentioning

confidence: 99%

Permeation of cisplatin through the membranes of normal and cancer cells: a molecular dynamics study

Rivel¹,

Ramseyer²,

Yesylevskyy³

2018

Preprint

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In this work, realistic models of membranes of normal and cancer cells are developed. A special focus is given to their cholesterol content. It is shown that the loss of lipid asymmetry in the membranes of cancer cells leads to a decrease of their permeability to cisplatin by one order of magnitude in comparison to the membranes of normal cells. The change of cholesterol molar ratio from 0% to 33% also decreases the permeability of the membrane by approximately one order of magnitude. The permeability of pure DOPC membrane is 5-6 orders of magnitude higher than one of the membrane with realistic lipid composition, which makes it as an inadequate model for the studies of drug permeability.

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Interactions of cisplatin and the copper transporter CTR1 in human colon cancer cells

Cited by 37 publications

References 42 publications

Enhancer of zeste homolog 2 promotes cisplatin resistance by reducing cellular platinum accumulation

Enhancer of zeste homolog 2 promotes cisplatin resistance by reducing cellular platinum accumulation

Effect of Magnesium Supplementation to Prevent Nephrotoxicity on the Antitumor Activity of Cisplatin

Permeation of cisplatin through the membranes of normal and cancer cells: a molecular dynamics study

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