Assessment of platinum sensitivity human tumor cells

Zisowsky, Jochen; Becker, Annette; Weykam, S; Kassack, Matthias U.; Jaehde, Ulrich

doi:10.5414/cpp41612

Cited by 3 publications

(3 citation statements)

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“…Platin was measured in supernatants and pellets by a validated graphite furnaceflameless atomic absorption spectrometry assay reported previously. 23,24 Cell lysates were measured directly without dilution. Cell pellets were dissolved by concentrated nitrogen acid and diluted with water before measurement.…”

Section: Uptake Of Cis-platin By Hoct2-hek293 and Hek293 Cellsmentioning

confidence: 99%

Cisplatin Nephrotoxicity Is Critically Mediated via the Human Organic Cation Transporter 2

Ciarimboli

Ludwig

Lang

et al. 2005

The American Journal of Pathology

383

282

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Cis-platin is an effective anti-neoplastic agent, but it is also highly nephrotoxic. Here, we clearly identify the human organic cation transporter 2 (hOCT2) as the critical transporter for cis-platin nephrotoxicity in isolated human proximal tubules and offer a potential mechanism for reducing nephrotoxicity in clinical practice. Interaction of cis-platin with hOCT2 in kidney or hOCT1 in liver was investigated with the fluorescent cation 4-[4-(dimethyl-amino)styril]-methylpyridinium in stably transfected HEK293 cells and for the first time in tissues physiologically expressing these transporters, human proximal tubules, and human hepatocyte couplets. Cis-platin (100 micromol/L) inhibited transport via hOCT2-HEK293 but not hOCT1-HEK293. In human proximal tubules cis-platin competed with basolateral organic cation transport, whereas it had no effect in tubules from a diabetic kidney or in hepatocytes. In hOCT2-HEK293 cells treated for 15 hours, incubation with cis-platin induced apoptosis, which was completely suppressed by contemporaneous incubation with the hOCT2 substrate cimetidine (100 micromol/L). These findings demonstrate that uptake of cis-platin is mediated by hOCT2 in renal proximal tubules, explaining its organ-specific toxicity. A combination of cis-platin with other substrates that compete for hOCT2 offers an effective option to decrease nephrotoxicity in the clinical setting.

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Section: Uptake Of Cis-platin By Hoct2-hek293 and Hek293 Cellsmentioning

confidence: 99%

Cisplatin Nephrotoxicity Is Critically Mediated via the Human Organic Cation Transporter 2

Ciarimboli

Ludwig

Lang

et al. 2005

The American Journal of Pathology

383

282

View full text Add to dashboard Cite

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“…A2780cis cells were reported to have higher intracellular GSH concentrations and intracellular GSH was reported to be involved in causing resistance to cisplatin by facilitating its efflux from the cell [7,11] . ATP treatment reportedly resulted in decreased intracellular GSH concentrations [19][20][21] .…”

Section: Discussionmentioning

confidence: 99%

“…The decreased accumulation of cisplatin and increased intracellular GSH levels in the cisplatin-resistant ovarian carcinoma cell line (A2780cis) as compared to its cisplatin-sensitive variant (A2780) are well established [10,11] . Though uptake has been shown to be mediated by the copper transporter CTR1, passive diffusion of the drug across the membrane is also equally documented and assumed to play a major role [12][13][14][15][16] .…”

Section: Introductionmentioning

confidence: 99%

Effect of Extracellular ATP on Cisplatin-Induced Cytotoxicity in Human Ovarian Carcinoma Cells

Rotte

Garmann²,

Buβ³

et al. 2010

Chemotherapy

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Background: Cisplatin resistance has been mainly associated with decreased cellular accumulation and increased intracellular glutathione (GSH) levels. ATP is known to increase the membrane permeability of cells and to decrease intracellular GSH levels. Our study aimed at using extracellular ATP to sensitize ovarian carcinoma cells towards cisplatin. Methods: The MTT assay was used to determine the EC₅₀ of cisplatin in the human ovarian carcinoma cell line A2780 and its cisplatin-resistant variant A2780cis. Intracellular platinum concentrations were determined using flameless atomic absorption spectrometry. Results: Preincubation and concomitant incubation with ATP did not alter the EC₅₀ of cisplatin. The presence of 100 µM ATP along with cisplatin decreased cell survival in A2780 but not in A2780cis cells. Extracellular ATP did not increase the cellular accumulation of cisplatin in both A2780 and A2780cis cells. Conclusion: The presence of extracellular ATP during treatment with cisplatin leads to additive cytotoxicity in the sensitive A2780 but not in cisplatin-resistant A2780cis cells.

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L-Carnitine halts apoptosis and myelosuppression induced by carboplatin in rat bone marrow cell cultures (BMC)

et al. 2005

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Carboplatin (CP), a second generation platinum compound, is effective against various types of cancers, producing less nephrotoxicity and ototoxicity but more myelotoxicity than cisplatinum. CP-myelosuppression is the rate-limiting step of its clinical use. Prevention of CP-myelosuppression is a major target in the field of chemotherapy. Therefore, the present study investigates the use of L-carnitine (LCR)-an antioxidant, cardioprotective, neuroprotective, and immunostimulant nontoxic natural compound-to protect against CP-induced myelosuppression. The viability of BMC was studied using a trypan blue exclusion technique following incubation with CP and/or LCR as a function of time and concentration. Apoptosis was tested for by detecting the amount of DNA fragmentation and the visualization of DNA ladders upon gel electrophoresis. Bone marrow progenitor cell function was examined by colony forming unit assay. Cellular contents of glutathione (GSH) and malondialdehyde (MDA) were also estimated. Results revealed that LC50 of CP is 4.7 mM and the highest safe concentration of LCR is 5 mM. Co-exposure of LCR+CP rescued BMC viability by 37% compared to the CP-treated cultures. The LCR halts CP-induced apoptosis and it significantly improves the function of the bone marrow progenitors by increasing the number of colony-forming units as a response to granulocyte/macrophage colony stimulating factors. Finally, LCR restores CP-induced GSH depletion and prevents MDA elevation in BMC. In summary, the results suggest that LCR is able to protect against CP-induced myelosuppression, which suggests its use as an adjuvant therapy. This finding merits further investigation into the mechanism(s) of such protection as well as its interaction with CP antitumor activity.

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Assessment of platinum sensitivity human tumor cells

Cited by 3 publications

References 0 publications

Cisplatin Nephrotoxicity Is Critically Mediated via the Human Organic Cation Transporter 2

Cisplatin Nephrotoxicity Is Critically Mediated via the Human Organic Cation Transporter 2

Effect of Extracellular ATP on Cisplatin-Induced Cytotoxicity in Human Ovarian Carcinoma Cells

L-Carnitine halts apoptosis and myelosuppression induced by carboplatin in rat bone marrow cell cultures (BMC)

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