Article

Reduced drug accumulation is more important in acquired resistance against oxaliplatin than against cisplatin in isogenic colon cancer cells.

Department of Oncology, Lund University, Lund, Sweden.
Anti-cancer drugs (Impact Factor: 2.23). 02/2010; 21(5):523-31. DOI: 10.1097/CAD.0b013e328337b867
Source: PubMed

ABSTRACT Preclinical studies have indicated that there is only partial cross-resistance between cisplatin and oxaliplatin. The molecular background for this is incompletely known. To investigate the differences in resistance, we rendered a colon cancer cell line (S1) resistant against cisplatin and oxaliplatin and characterized the subclones with regard to cross-resistance, platinum uptake, and gene expression profiles. Four oxaliplatin and four cisplatin-resistant cell lines were produced from S1 by step-wise increasing the concentrations of the drugs in the growth medium. Cytotoxicity was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and platinum accumulation in cell lysates and DNA preparations by inductively coupled plasma mass spectroscopy. Gene expression was investigated by cDNA microarrays. The protein expression of the ATP-binding cassette B1 (ABCB1) was measured by immunohistochemistry. The cisplatin-resistant cell lines were 1.5-6.2-fold resistant against cisplatin and the oxaliplatin-resistant sublines 2.6-17-fold resistant against oxaliplatin. There was a limited degree of cross-resistance. Oxaliplatin resistance could be explained to a larger degree by reduced drug accumulation whereas mechanisms for increased tolerance against platinum incorporation in DNA seemed to be of higher importance for resistance against cisplatin. A greater number of ABC transporters were upregulated in the oxaliplatin-resistant cell lines compared with those selected for cisplatin resistance. ABCB1 was highly overexpressed in the three most oxaliplatin-resistant sublines, but significantly underexpressed in the two most cisplatin-resistant cell lines. This was also confirmed by immunohistochemistry. However, functional tests did not show any increase in ABCB1 transport activity in the oxaliplatin-resistant sub-lines compared with S1.

0 Bookmarks
 · 
68 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: The gold standard for the treatment of metastatic colorectal cancer consists of combination chemotherapy. Over time, however, the development of chemoresistant tumor clones leads to relapse. It may be possible to overcome oxaliplatin chemoresistance in colorectal cancer cells by exploiting a complex obtained from the insertion of the cyclohexane-1R,2R-diamine carrier ligand (the same diamine present in oxaliplatin) into an octahedral PtIV scaffold with high lipophilicity conferred by two benzoate axial ligands. Herein we report the synthesis, characterization (including X-ray structure), biological activity, and cellular accumulation of trans,cis,cis-bis(benzoato)dichlorido(cyclohexane-1R,2R-diamine)platinum(IV) complex in a panel of several human cancer cell lines, including a colon carcinoma cell line resistant to oxaliplatin. The compound under investigation shows the best performance in terms of in vitro anti-proliferative activity and ability to overcome chemoresistance, with respect to oxaliplatin and some other PtII reference complexes. This result is likely related to the high lipophilicity shown by the title compound that favors its cellular accumulation by passive diffusion.
    ChemMedChem 04/2014; · 2.84 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) can induce drug transporter genes such as the ATP-binding cassette G member 2 (ABCG2), which contributes to multidrug resistance. We investigated the effect of TCDD pretreatment on drug transporters induction from cancer cells of various origins. Cell viabilities after treatment of cisplatin were measured to evaluate acquiring cisplatin resistance by TCDD. Acquring cisplatin resistance was found only in cisplatin senstivie cancer cells including gastric SNU601, colon LS180, brain CRT-MG and lymphoma Jurkat cells which showed a significant increase in cell viability after combined treatment with TCDD and cisplatin. High increase of ABCG2 gene expression was found in SNU601 and LS180 cells with a mild increase in the expression of the ABCC3, ABCC5,and SLC29A2 genes in SNU601 cells, and of major vault protein (MVP) in LS180 cells. The AhR inhibitor kaempferol suppressed the upregulation of ABCG2 expression and reversed the TCDD-induced increase in cell viability in LS180 cells. However, in CRT-MG cells, other transporter genes including ABCC1, ABCC5, ABCA3, ABCA2, ABCB4, ABCG1, and SLC29A1 were up-regulated. These findings suggested the acquiring cisplatin resistance by TCDD associated with cancer cell-type-specific induction of drug transporters.
    Journal of Korean Medical Science 09/2014; 29(9):1188-98. · 1.25 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Src is a member of a superfamily of membrane-associated non-receptor protein tyrosine kinases. It is stimulated by receptors of growth hormone, cytokines, and adipokines, and it regulates multiple signaling pathways including PI3K/Akt, MAPK, STAT3, IL-8, VEGF, cytoskeletal pathways to cause a cascade of cellular responses. Eighty percent of colon cancer patients over-express Src in the tumor tissue. Evidence has shown that the over-expression of Src in colon cancer accelerates metastasis and causes chemotherapeutic drug resistance via multiple down-stream signaling pathways. Therefore, the inhibition of Src may be useful for the treatment of colon cancer. However, the inhibition of Src may also weaken immune responses that are essential for the eradication of cancer cells. Overcoming the problem to inhibit Src in cancer cells and at meantime to retain immune system efficacy is the key to the successful application of Src inhibition therapy. Different Src members are used by the immune system and colon cancer. This differential use may provide a good opportunity to develop Src member-specific inhibitors to avoid immune inhibition.
    Clinical Colorectal Cancer 01/2013; · 1.80 Impact Factor