Early multidrug resistance, defined by changes in intracellular doxorubicin distribution, independent of P-glycoprotein

Abstract

Summary Resistance to multiple antitumour drugs, mostly antibiotics or alkaloids, has been associated with a cellular plasma membrane P-glycoprotein (Pgp), causing energy-dependent transport of drugs out of cells. However, in many common chemotherapy resistant human cancers there is no overexpression of Pgp, which could explain drug resistance. In order to characterise early steps in multidrug resistance we have derived a series of P-glycoprotein-positive (Pgp/+) and P-glycoprotein-negative (Pgp/-) multidrug resistant cell lines, from a human non-small cell lung cancer cell line, SW-1573, by stepwise selection with increasing concentrations of doxorubicin. These cells were exposed to doxorubicin and its fluorescence in nucleus (N) and cytoplasm (C) was quantified with laserscan microscopy and image analysis. The fluorescence N/C ratio in parent cells was 3.8 and decreased both in Pgp/+ and Pgp/-cells with increasing selection pressure to

Intracellular distribution of anthracyclines in drug resistant cells

“…The acquisition of MDR is often associated with changes in both intracellular drug content and disposition (Fojo et al, 1985;Willingham et al, 1986;Schurrhuis et al, 1991;Coley et al, 1993). These changes appear to be mediated by different protein transporters which are generally overexpressed in MDR cells.…”

Design, synthesis and biological evaluation of thiosemicarbazones, hydrazinobenzothiazoles and arylhydrazones as anticancer agents with a potential to overcome multidrug resistance

“…Moreover, cancer cells that develop resistance against a single cytotoxic agent show cross-resistance to structurally and mechanistically unrelated drugs [3]. Multidrug resistance (MDR) can emerge as a result of reduced uptake or increased efflux of cytostatic agents -the latter is mediated by ATP-binding-cassette (ABC) proteins, primarily by P-glycoprotein (P-gp), which confers resistance to a wide variety of compounds [3][4][5][6][7]. There is a constant need for novel chemotherapeutics with marked and selective antitumor activity that can overcome resistance to established therapies.…”

Changes in subcellular doxorubicin distribution and cellular accumulation alone can largely account for doxorubicin resistance in SW-1573 lung cancer and MCF-7 breast cancer multidrug resistant tumour cells

“…Another important phenomenon associated with MDR is an altered intracellular drug distribution. Several studies now have shown that the development of MDR is associated with a relative shift of doxorubicin or daunorubicin fluorescence from the nucleus to the cytoplasm Gervasoni et al, 1991;Gigli et al, 1989;Hindenburg et al, 1987Hindenburg et al, , 1989Schuurhuis et al, 1989aSchuurhuis et al, , 1991Willingham et al, 1986). In previous work with Chinese hamster ovarian cells we have argued that this shift may contribute for an important part to the ineffectiveness of anthracyclines in MDR cells (Schuurhuis et al, 1989a).…”

“…Effective modulation of multidrug resistance is possible in Pglycoprotein containing cells with compounds which exhibit different structural features (Zamora et al, 1988) and it is attributed to increases in cellular drug accumulation resulting from inhibition of drug efflux (Bradley et al, 1988). Modulation of non-P-glycoprotein mediated MDR and accumulation defects by verapamil and other Pgp modulators, however, seems to be less efficient than for P-glycoprotein mediated MDR (Cole et al, 1989;Coley et al, 1991;Harker et al, 1989;Kuiper et al, 1990;Schuurhuis et al, 1991;Slovak et al, 1988;Taylor et al, 1991).…”