Effect of reactivity on cellular accumulation and cytotoxicity of oxaliplatin analogues

Buss, Irina; Kalayda, Ganna V.; Lindauer, Andreas; Reithofer, Michael R.; Galanski, Markus; Keppler, Bernhard K.; Jaehde, Ulrich

doi:10.1007/s00775-012-0889-9

Cited by 16 publications

(32 citation statements)

References 41 publications

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“…In RPMI medium, which is used routinely for mammalian tissue culture, slow activation of 1 by the nucleophiles present in the medium was observed (Figure S19). This result is consistent with the previously reported activation of structurally similar platinum compounds by nucleophiles ,. No significant decomposition was noticed up to 8 h, and approximately 60 % of 1 remained unchanged even after 24 h, suggesting that the compound is highly stable in biological media.…”

Section: Figuresupporting

confidence: 93%

A Potent Glucose–Platinum Conjugate Exploits Glucose Transporters and Preferentially Accumulates in Cancer Cells

et al. 2016

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Section: Figuresupporting

confidence: 93%

A Potent Glucose–Platinum Conjugate Exploits Glucose Transporters and Preferentially Accumulates in Cancer Cells

et al. 2016

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“…Reduced cisplatin accumulation in A2780cis cells compared to the parent sensitive cell line is well-documented [ 36 ]. According to our earlier results, HCT-8 colorectal cancer cells accumulated significantly less cisplatin than A2780 ovarian cancer cells after 2 h incubation with 100 µM platinum drug (HCT-8: 10.47 ± 0.88 ng Pt/10 6 cells, mean ± SEM, n = 6, [ 37 ]; A2780: 17.68 ± 0.23 ng Pt/10 6 cells, mean ± SEM, n = 3, [ 38 ]; p < 0.001, unpaired t -test). Nevertheless, the fate of the drug in cytosol is also of great importance.…”

Section: Discussionmentioning

confidence: 90%

Cisplatin Protein Binding Partners and Their Relevance for Platinum Drug Sensitivity

Möltgen

Piumatti

Massafra

et al. 2020

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Cisplatin is a widely used drug in the treatment of various solid tumors, such as ovarian cancer. However, while the acquired resistance significantly limits the success of therapy, some tumors, such as colorectal cancer, are intrinsically insensitive to cisplatin. Only a small amount of intracellular platinum binds to the target—genomic DNA. The fate of the remaining drug is largely obscure. This work aimed to identify the cytosolic protein binding partners of cisplatin in ovarian and colorectal cancer cells and to evaluate their relevance for cell sensitivity to cisplatin and oxaliplatin. Using the fluorescent cisplatin analog BODIPY-cisplatin, two-dimensional gel electrophoresis, and mass spectrometry, we identified the protein binding partners in A2780 and cisplatin-resistant A2780cis ovarian carcinoma, as well as in HCT-8 and oxaliplatin-resistant HCT-8ox colorectal cell lines. Vimentin, only identified in ovarian cancer cells; growth factor receptor-bound protein 2, only identified in colorectal cancer cells; and glutathione-S-transferase π, identified in all four cell lines, were further investigated. The effect of pharmacological inhibition and siRNA-mediated knockdown on cytotoxicity was studied to assess the relevance of these binding partners. The silencing of glutathione-S-transferase π significantly sensitized intrinsically resistant HCT-8 and HCT-8ox cells to cisplatin, suggesting a possible involvement of the protein in the resistance of colorectal cancer cells to the drug. The inhibition of vimentin with FiVe1 resulted in a significant sensitization of A2780 and A2780cis cells to cisplatin, revealing new possibilities for improving the chemosensitivity of ovarian cancer cells.

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“…[14] Indeed we observed that 1 is highly stable in water as evidenced by no change in the 1 HNMR spectrum of 1 after 72 hi nD 2 O( Figure S18). [14] Indeed we observed that 1 is highly stable in water as evidenced by no change in the 1 HNMR spectrum of 1 after 72 hi nD 2 O( Figure S18).…”

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confidence: 86%

A Potent Glucose–Platinum Conjugate Exploits Glucose Transporters and Preferentially Accumulates in Cancer Cells

2016

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Three rationally designed glucose-platinum conjugates (Glc-Pts) were synthesized and their biological activities evaluated. The Glc-Pts, 1-3,exhibit high levels of cytotoxicity towardapanel of cancer cells.T he subcellular target and cellular uptake mechanism of the Glc-Pts were elucidated. For uptake into cells,G lc-Pt 1 exploits both glucose and organic cation transporters,b oth widely overexpressed in cancer. Compound 1 preferentially accumulates in and annihilates cancer,compared to normal epithelial, cells in vitro.Platinum-basedanticancerdrugs are among the most widely used of all chemotherapeutic treatments.T hree FDAapproved platinum anticancer drugs,c isplatin, carboplatin, and oxaliplatin, have been in the clinic for many years to treat av ariety of cancers including testicular,o varian, cervical, head and neck, non-small-cell lung, and colorectal. [1] Despite their success,p latinum compounds have an umber of deficiencies originating from al ack of tumor selectivity.O nly as mall fraction of the total administered platinum accumulates at the tumor site,r esulting in sub-optimal drug concentration at the target. Moreover,a ccumulation of platinum in healthy tissue leads to undesired side effects including nephrotoxicity,m yelosuppression, peripheral neuropathy, ototoxicity,a nd nausea. [1b, 2] These drawbacks need to be addressed when designing next-generation platinum drugs. Novel strategies for introducing tumor-targeting properties into platinum anticancer drug candidates are therefore of great interest. [3] In order to maintain cellular homeostasis,g rowth, and proliferation, cancer cells significantly increaseglucose uptake andt he fluxo fm etabolites throughg lycolysis.T his phenomenon, termed "the Warburg effect", arisesfrommitochondrial metabolic changesa nd is one of the hallmarkso fc ancer. [4] GLUT1,t he mostc ommon glucose transporter, is widely overexpressed in manyh uman cancersi ncludingh epatic, pancreatic,b reast,e sophageal, brain, renal, lung,c utaneous, colorectal, endometrial, ovarian,and cervical. [5] HighGLUT1 expressionl evelsi nt umor biopsy samples correlates trongly withp oorp rognosis. Moreover,s everalo ther glucose transporters including GLUT2,G LUT3,G LUT12,a nd SGLT1/2[*] Dr.

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Effect of reactivity on cellular accumulation and cytotoxicity of oxaliplatin analogues

Cited by 16 publications

References 41 publications

A Potent Glucose–Platinum Conjugate Exploits Glucose Transporters and Preferentially Accumulates in Cancer Cells

A Potent Glucose–Platinum Conjugate Exploits Glucose Transporters and Preferentially Accumulates in Cancer Cells

Cisplatin Protein Binding Partners and Their Relevance for Platinum Drug Sensitivity

A Potent Glucose–Platinum Conjugate Exploits Glucose Transporters and Preferentially Accumulates in Cancer Cells

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