Oxaliplatin activity in selected and unselected human ovarian and colorectal cancer cell lines

Noordhuis, Paul; Laan, A.C.; Born, Kasper van de; Losekoot, Nienke; Kathmann, Ietje; Peters, Godefridus J.

doi:10.1016/j.bcp.2008.04.007

Cited by 45 publications

(52 citation statements)

References 35 publications

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“…The absence of CTR1 expression renders yeast and mammalian cells resistant to copper, DDP, carboplatin, and oxaliplatin (Lin et al, 2002;Holzer et al, 2004bHolzer et al, , 2006aLarson et al, 2009), whereas overexpression of CTR1 was found to sensitize cells to the toxic effects of these agents Noordhuis et al, 2008). These changes in sensitivity are accompanied by proportionate changes in the uptake of all four agents; time course studies showed that CTR1 mainly regulates the initial phase of DDP uptake .…”

Section: Ctr1 Controls Uptake Of the Platinum-containing Drugsmentioning

confidence: 99%

“…However, a survey of tumors and cell lines with acquired DDP resistance, using immunohistochemical and quantitative reverse transcriptase-polymerase chain reaction, has only identified a few cases in which this occurs (Matsumoto et al, 2007;Zisowsky et al, 2007;Noordhuis, 2008). New insight regarding the role of trafficking factors and glycosylation of CTR1 provides a possible explanation for this discrepancy.…”

Section: Ctr1 and Acquired Resistance To The Platinum-containing Drugsmentioning

confidence: 99%

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Copper Transporters and the Cellular Pharmacology of the Platinum-Containing Cancer Drugs

Howell¹,

Safaei²,

Larson³

et al. 2010

Mol Pharmacol

298

243

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Multiple lines of evidence indicate that the platinum-containing cancer drugs enter cells, are distributed to various subcellular compartments, and are exported from cells via transporters that evolved to manage copper homeostasis. The cytotoxicity of the platinum drugs is directly related to how much drug enters the cell, and almost all cells that have acquired resistance to the platinum drugs exhibit reduced drug accumulation. The major copper influx transporter, copper transporter 1 (CTR1), has now been shown to control the tumor cell accumulation and cytotoxic effect of cisplatin, carboplatin, and oxaliplatin. There is a good correlation between change in CTR1 expression and acquired cisplatin resistance among ovarian cancer cell lines, and genetic knockout of CTR1 renders cells resistant to cisplatin in vivo. The expression of CTR1 is regulated at the transcriptional level by copper via Sp1 and at the post-translational level by the proteosome. Copper and cisplatin both trigger the down-regulation of CTR1 via a process that involves ubiquitination and proteosomal degradation and requires the copper chaperone antioxidant protein 1 (ATOX1). The cisplatin-induced degradation of CTR1 can be blocked with the proteosome inhibitor bortezomib, and this increases the cellular uptake and the cytotoxicity of cisplatin in a synergistic manner. Copper and platinum(II) have similar sulfur binding characteristics, and the presence of stacked rings of methionines and cysteines in the CTR1 trimer suggest a mechanism by which CTR1 selectively transports copper and the platinum-containing drugs via sequential transchelation reactions similar to the manner in which copper is passed from ATOX1 to the copper efflux transporters.

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Section: Ctr1 Controls Uptake Of the Platinum-containing Drugsmentioning

confidence: 99%

Section: Ctr1 and Acquired Resistance To The Platinum-containing Drugsmentioning

confidence: 99%

Copper Transporters and the Cellular Pharmacology of the Platinum-Containing Cancer Drugs

Howell¹,

Safaei²,

Larson³

et al. 2010

Mol Pharmacol

298

243

View full text Add to dashboard Cite

show abstract

“…Its' proposed mode of action is the formation of DNA adducts, typically on adjacent guanine residues. Adduct formation leads to intrastrand/interstrand cross-link formation and it is speculated that the repair of some of these lesions involves the formation of DNA double-strand breaks (DSBs) [11].…”

Section: Introductionmentioning

confidence: 99%

Irinotecan and DNA-PKcs inhibitors synergize in killing of colon cancer cells

et al. 2011

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This study sought to measure the degree of synergy induced by specific small molecule inhibitors of DNA-PK [NU7026 and IC486241 (ICC)], a major component of the non-homologous end-joining (NHEJ) pathway, with SN38 or oxaliplatin. Synergy between the DNA damaging drugs and the DNA-PK inhibitors was assessed using the sulforhodamine-B assay (SRB). Effects of drug combinations on cell cycle and DNA-PK activity were determined using flow cytometry and western blot analysis. DNA damage was assessed via comet assay and quantification of γH2AX. The role of homologous recombination repair (HRR) was determined by nuclear Rad51 protein levels and a GFP reporter recombination assay. Significant reductions in the IC(50) values of SN38 were observed at 5 and 10 μM of DNA-PK inhibitors. Moreover, at 1-2 μM (attainable concentrations with ICC in mice) these DNA-PKcs inhibitors demonstrated synergistic reductions in the IC(50) of SN38. Flow cytometric data indicated that SN38 and SN38 in combination with DNA-PKcs inhibitors showed dramatic G2/M arrest at 24 h. Furthermore, reduced phosphorylation of DNA-PKcs and increased DNA damage were observed at this time point with SN38 in combination with DNA-PKcs inhibitors as compared to cells treated with SN38 alone. SN38 alone and in the presence of ICC increased nuclear Rad51 protein levels. Furthermore, inhibition of DNA-PKcs increased HRR suggesting that NHEJ is a negative regulator of HRR. These data indicate that small molecule inhibitors of DNA-PKcs dramatically enhance the efficacy of SN38 in colon cancer cell lines.

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“…Evaluations of cellular platinum and DNA adduct levels were conducted in complete medium at 37°C, as described previously [28, 29]. In these biochemical pharmacologic studies, subconfluent cultures of A2780 cells (3-4 × 10 6 ) in 10-cm dishes were exposed for 4 h to freshly prepared cisplatin alone or simultaneously with either emodin or DRB.…”

Section: Methodsmentioning

confidence: 99%

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

Kurokawa

Siddik

2009

Cancer Chemother Pharmacol

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Purpose Protein kinase inhibitors (PKI) have become prominent agents in cancer therapeutics. However, the specificity for target kinase inhibition can be poor and unwanted effects can emerge in combination regimens. The PKI emodin, for instance, can produce mixed results when combined with cisplatin, and we have sought a biochemical pharmacologic explanation for the negative cytotoxic effects. Methods Human ovraian A2780 tumor cells were exposed to the PKI emodin or dichloro-ribofuranosylbenzimidazole (DRB) with cisplatin using several schedules, and cytotoxicity determined by a growth inhibition assay. Intracellular platinum levels and DNA adducts were estimated by flameless atomic absorption spectrophotomotery. Results When A2780 cells were exposed first to emodin or DRB and then to cisplatin alone, the cytotoxic effects of cisplatin were significantly enhanced, whereas simultaneous exposure did not enhance the cytotoxicity, but instead inhibited it in the case of DRB. The increase in activity of cisplatin in the sequenced schedule was not due to increases in intracellular levels of cisplatin or DNA adducts, whereas the cytotoxic inhibition was related to a significant fall in both intracellular platinum levels and DNA adducts, which were ascribed to inhibition in cisplatin uptake. Knockdowm of hCtr1 (the human copper transporter 1) by siRNA abrogated this inhibition in cisplatin uptake. Conclusion The results demonstrate that co-exposure of tumor cells to emodin or DRB with cisplatin inhibits platinum drug uptake by impacting the hCtr1 transporter and, thereby, reduce the cytotoxicity of cisplatin. Based on our findings, scheduling of the PKI and the cytotoxic agent should be a major consideration in the clinical design of combination regimens.

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Oxaliplatin activity in selected and unselected human ovarian and colorectal cancer cell lines

Cited by 45 publications

References 35 publications

Copper Transporters and the Cellular Pharmacology of the Platinum-Containing Cancer Drugs

Copper Transporters and the Cellular Pharmacology of the Platinum-Containing Cancer Drugs

Irinotecan and DNA-PKcs inhibitors synergize in killing of colon cancer cells

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

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