Retention of activity by selected anthracyclines in a multidrug resistant human large cell lung carcinoma line without P-glycoprotein hyperexpression

Abstract

Summary A subline (COR-L23/R) of the human large cell lung cancer line COR-L23, derived by in vivo exposure to doxorubicin, exhibits an unusual multidrug resistant (MDR) phenotype. This subline shows cross-resistance to daunorubicin, vincristine, colchicine and etoposide but does not express P-glycoprotein. Interestingly, COR-L12/R shows little or no resistance to a range of structurally-modified analogues of doxorubicin comprising 9-alkyl and/or sugar modified anthracyclines. We have previously identified these same compounds as effective agents against P-glycoprotein-positive MDR cell lines. In contrast to typical MDR cell lines, COR-L12/R shows only minimal chemosensitisation by verapamil and no collateral sensitivity to verapamil. Compared to the parental cell line, COR-L12/R displays reduced accumulation of doxorubicin and daunorubicin. Accumulation defects were apparent only after 0.5-1 h of incubation of cells with these agents. The rate of daunorubicin efflux was shown to be enhanced by COR-L12/R and this efflux was demonstrated to be energy-dependent. The use of anthracyclines which retain activity in MDR cells thus appears to be a valid approach for the circumvention of MDR, not only in cells which express P-glycoprotein, but also where defective drug accumulation is due to other mechanisms possibly involving an alternative multidrug transporter.

Genistein modulates the decreased drug accumulation in non-P-glycoprotein mediated multidrug resistant tumour cells

“…We have previously shown by using a digitonin based assay that the decrease in DNR accumulation occurred against a concentration gradient in a number of Pgp and non-Pgp MDR cell lines (Versantvoort et al, 1992a). Furthermore in some non-Pgp MDR cell lines the accumulation of drugs was shown to be decreased due to an energy-dependent mechanism (Coley et al, 1991;Marquardt et al, 1990;Versantvoort et al, 1992b). Therefore other drug transporters than Pgp have to be present in those non-Pgp MDR cells.…”

“…Thus far at least two mechanisms have been shown to be operative in drug resistance in non-Pgp MDR cells. The first mechanism is a decreased drug concentration at target due to a decreased cellular accumulation of drugs (McGrath et al, 1989;Kuiper et al, 1990;Coley et al, 1991;Slovak et al, 1988;Taylor et al, 1991) and/or an altered distribution of drugs (Schuurhuis et al, 1991;Takeda et al, 1991). We have previously shown by using a digitonin based assay that the decrease in DNR accumulation occurred against a concentration gradient in a number of Pgp and non-Pgp MDR cell lines (Versantvoort et al, 1992a).…”

“…A number of drug-selected cell lines has now been reported to show the MDR phenotype (resistance to a wide range of cytostatic agents with no common structure or target) but without the overexpression of Pgp (so called non-Pgp MDR) (McGrath et al, 1989Coley et al, 1991;Slovak et al, 1988;Ta.ylor et al, 1991). In some of these non-Pgp MDR cell lines the expression of mdrl is even decreased (Baas et al, 1990).…”

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

“…Reduced drug accumulation may also be a parameter of drug resistance for some (Coley et al, 1991;Haber et al, 1989;Hindenburg et al, 1989;Kuiper et al, 1990;McGrath & Center, 1988;Slapak et al, 1990;Slovak et al, 1988;Taylor et al, 1991) but not for all (Cole et al, 1991;Danks et al, 1987;Harker et al, 1989;McGrath et al, 1989) MDR cells which do not overexpress P-glycoprotein. 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).…”

“…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).…”