The direct effect of nuclear pores on nuclear chemotherapeutic concentration in multi-drug resistant bladder cancer: the nuclear sparing phenomenon

Abstract

Purpose: multidrug resistance commonly limits effectiveness in treating malignancy with chemotherapy. Multidrug resistance has classically been described as a cell membrane phenomenon. Multidrug resistant cells are known to specifically exclude chemotherapy from the nucleus, resulting in lower nuclear concentrations than in the cytoplasm. This phenomenon is known as nuclear sparing and little is known of its etiology. We hypothesized that a component of the nuclear membrane, the nuclear pore, is responsible for the phenomenon.
Materials and methods: in this in vitro study we used the drug sensitive urothelial cancer cell line Massachusetts General Hospital urothelial 1 sensitive and its multidrug resistant subline Massachusetts General Hospital urothelial 1 resistant. After quantitative assessment of nuclear pores resistant and sensitive cells were fused using polyethylene glycol and laser scanning confocal microscopy was used to identify if drug resistant and sensitive nuclei can coexist within the same cell. The effect of inhibiting nuclear pore function using the specific pore inhibitor, wheat germ agglutinin, was assessed in whole cells using confocal microscopy and cytotoxicity assay as well as in isolated nuclei.
Results: nuclear pores appeared more numerous in multidrug resistance cells. Cell fusion experiments showed that multidrug resistance and sensitive nuclei could coexist with the same cell milieu. Wheat germ agglutinin reversed multidrug resistance in whole cells and isolated nuclei.
Conclusions: multidrug resistance is a complex phenomenon occurring at many cellular levels, of which all may be potential therapeutic targets. The nuclear pore is involved in this process, which is to our knowledge a previously undescribed phenomenon. These experiments suggest that it may act to export drug from the nucleus, which is a process inhibited by wheat germ agglutinin.

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ORCID for Bashir A. Lwaleed: orcid.org/0000-0001-5748-4892

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