Overexpression of P-glycoprotein in Mammalian Tumor Cell Lines After Fractionated X Irradiation In Vitro

Abstract

We observed that in vitro exposure of mammalian tumor cells to fractionated x irradiation results in the expression of drug resistance. The cause of this resistance was investigated in a series of Chinese hamster ovary cell lines that had survived exposure to multiple lethal doses of radiation. These cell lines had increased levels of P-glycoprotein (Pgp), the multidrug-resistance-associated membrane glycoprotein. Consistent with the classic multidrug resistance phenotype, they exhibited cross-resistance to multiple drugs, as well as sensitivity to reversal of vincristine resistance by verapamil. However, the cell lines showed no change in their sensitivity to x rays. Pgp overexpression occurred in these cells, despite a lack of Pgp gene amplification or of significant alteration in Pgp messenger RNA levels. Although the cause of increased Pgp levels is not yet known, these data suggest a biological basis for the clinical problem of drug resistance that can occur in previously irradiated tumors.

The ATP-Binding Cassette Transporters and Their Implication in Drug Disposition: A Special Look at the Heart

“…On the other hand, no increase in the transcripts of mdr1a was detected (Granzotto et al, 2004). The increase in protein expression without an increase in mRNA was observed by other investigators who attributed this observation to an increased half-life of the ABC transporter protein or a post-translational effect of drugs (Hill et al, 1990;Westphal et al, 2000). However, another recent study demonstrated that in a tubular renal cell line, a 15-day treatment with rifampicin significantly increased the mRNA levels of P-gp, MRP1, MRP2, LRP, and CYP3A4 but an increase in protein was observed only for P-gp and MRP2 transporters (Magnarin et al, 2004).…”

Activity of a Novel Hec1-Targeted Anticancer Compound against Breast Cancer Cell Lines In Vitro and In Vivo

“…Overexpression of the multidrug transporter Pgp and MDR protein (MRP1) has been extensively studied for its role in MDR (29). Pgp may be induced in cancer cells through exposure to irradiation (30) or cytotoxic agents such as paclitaxel, doxorubicin, or cisplatin (31). On average 40% and 50% of untreated breast cancers show expression of Pgp and MRP-1, respectively, and exposure to chemotherapy increases the expression of both proteins (29).…”

“…To examine in vitro antitumor efficacy of TAI-95, 11 breast cancer cell lines were screened and 9 of 11 tested cell lines were found to be highly sensitive to TAI-95, including MDA-MB-231, MDA-MB-468, T47D, Hs578T, ZR-75-1, MCF7, HCC1954, BT474, and ZR-75- 30 between 14.29 and 73.65 nmol/L. Notably, some of these cell lines which were resistant (GI 50 > 10 mmol/L) to other tested cytotoxic agents, including approved breast cancer drugs paclitaxel, doxorubicin, gemcitabine, and sorafenib, were very sensitive to TAI-95 (Table 1).…”

Effects of the combination of camptothecin and doxorubicin or etoposide on rat glioma cells and camptothecin-resistant variants

“…On the one hand, P-glycoprotein has been consistently found to be overexpressed in response to various kinds of stress, such as irradiation (Hill et al, 1990) or cytotoxic compounds not even expelled by this pump (Chaudhary and Roninson, 1993). In our camptothecin-resistant cell lines, there is a slight increase in P-glycoprotein expression at the first level of selection (probably responsible for the 3-fold resistance of this cell line to vincristine) and an important increase in this expression in the most resistant lines, C6 CPT50 and C6 CPT100 .…”