Induction of chemoresistance in HL-60 cells concomitantly causes a resistance to apoptosis and the synthesis of P-glycoprotein

Abstract

The appearance of multidrug-resistant (MDR) proteins or the acquisition of a defective apoptotic programme are major drawbacks in the treatment of cancers since both induce a resistance to classical chemotherapy. However, a link between the two mechanisms has not, as yet, been clearly established. In this study, HL-60 cells cultured in the continual presence of a sub-lethal dose of doxorubicin (dox; HL-60/Dox) were used as a model to study acquired chemoresistance. During the induction of chemoresistance, the appearance of a functional P-glycoprotein (P-gp), in addition to the expression of anti-apoptotic Bcl-2, Bcl-XL and pro-apoptotic Bax proteins was assessed. Parental cells which are sensitive to dox, have no P-gp activity and express Bcl-2 and Bax. After 4 weeks of treatment, a functional P-gp was detected in HL-60/Dox cells. In addition, the synthesis of Bcl-2 appeared to be replaced by Bcl-XL while that of Bax remained unchanged. These cells were also resistant to apoptosis induced by both P-gp and non-P-gp substrates. This inability to induce apoptosis could have resulted from the induction of the expression of the inhibitor of apoptosis protein (XIAP). Our data show that acquired chemoresistance could involve a parallel induction of P-gp and an impairment of the apoptotic pathway. Leukemia (2001) 15, 1377-1387.

Regulation of the multidrug resistance transporter P‐glycoprotein in multicellular prostate tumor spheroids by hyperthermia and reactive oxygen species

“…16 The induction of P-glycoprotein may require higher levels of ROS generation that confer oxidative stress activate p38 MAPK and initiate the cellular antiapoptotic machinery that has been previously shown to involve P-glycoprotein. 21,42 The data of the present study show that hyperthermia increases P-glycoprotein expression in multicellular tumor spheroids by a signaling pathway that involves ROS, p38 MAPK and HIF-1␣. Hence, the beneficial role of hyperthermia in treatment of cancer patients may be counteracted by the induction of a MDR phenotype.…”

“…16,19,20 The observed upregulation of P-glycopotein may be related to its anti-apoptotic properties, which have been previously reported and are presumably linked to P-glycoproteinmediated overexpression of the anti-apoptotic Bcl-xL protein. [21][22][23] Hyperthermia-induced upregulation of P-glycoprotein may be associated to an elevation of intracellular ROS levels. Indeed it has been recently shown that hyperthermia increases generation of ROS in HL-60 cells 24 as well as in mice, 25 and it has been suggested that hyperthermia-induced ROS may play a role as signaling molecules that transduce the stress signal to the cell nucleus.…”

Effects of permeability transition inhibition and decrease in cytochrome c content on doxorubicin toxicity in K562 cells

“…Among the multiple mechanisms leading to resistance to DOX (Nielsen et al, 1996), the overexpression of P-glycoprotein (P-gp), a protein that pumps out of the cell unrelated agents including DOX, is believed to account for resistance to DOX in several cell lines. It must be noted, however, that P-gp inhibition did not systematically restore DOX cytotoxicity in P-gp overexpressing cells (success (Smyth et al, 1998;Fukushima et al, 2000); failure (Campone et al, 2001)). Moreover, cells overexpressing P-gp have also been reported to resist to non-P-gp substrates such as cytosine arabinoside, staurosporine, UV irradiation, Fas receptor ligation and serum starvation (Smyth et al, 1998;Trindade et al, 1999;Campone et al, 2001).…”

“…It must be noted, however, that P-gp inhibition did not systematically restore DOX cytotoxicity in P-gp overexpressing cells (success (Smyth et al, 1998;Fukushima et al, 2000); failure (Campone et al, 2001)). Moreover, cells overexpressing P-gp have also been reported to resist to non-P-gp substrates such as cytosine arabinoside, staurosporine, UV irradiation, Fas receptor ligation and serum starvation (Smyth et al, 1998;Trindade et al, 1999;Campone et al, 2001). Taken together, these findings suggest that other mechanisms of resistance may exist in addition to P-gp overexpression.…”

Monitoring a Nuclear Factor-κB Signature of Drug Resistance in Multiple Myeloma

“…Alterations in the apoptotic machinery have also been identified as causative determinants in melphalan resistance (2,13,14). Interactions between pro-and anti-apoptotic proteins determine cell fate in response to a host of internal and external stimuli.…”