P-glycoprotein, glutathione and glutathione S-transferase increase in a colon carcinoma

Abstract

The acquisition of resistance to anticancer agents used in chemotherapy is the main cause of treatment failure in malignant disorders, provoking tumours to become resistant during treatment, although they initially respond to it. The main multidrug resistance (MDR) mechanism in tumour cells is the expression of P-gly-coprotein (P-gly), that acts as an ATP-dependent active efflux pump of chemotherapeutic agents. Furthermore, an increased detoxification of compounds mediated by high levels of glutathione (GSH) and glutathione S-transferase (GST), has been found in resistant cells. We developed a study aiming to evaluate the evolution of the main drug resistance markers in tumour cells: P-gly, GSH and GST, during the acquisition of resistance to colchicine, for the purpose of studying the adaptation process and its contribution to the MDR phenomenon. A human colon adenocarcinoma cell line was exposed to colchicine during 82 days, being P-gly, GSH levels and GST activity evaluated by flow cytometry, spectrofluorimetry and spectrophotometry, during exposure time. P-gly and GSH levels increased gradually during the exposure to colchicine, reaching 2.35 and 3.21 fold each. On day 82, GST activity increased 1.84 fold at the end of the exposure period. Moreover, an increment in drug cross-resistance was obtained that ranges from 2.62 to 5.22 fold for colchicine, vinblastine, vincristine and mitomycin C. The increments obtained in P-gly, GSH and GST could probably contribute to the MDR phenomenon in this human colon adenocarcinoma cell line.

Colchicine Suppresses Osteopontin Expression and Inflammatory Cell Infiltration in Chronic Cyclosporine Nephrotoxicity

“…An antioxidant therapy such as vitamin E has been previously shown to prevent CsA-induced toxicity [38, 39, 40, 41]. Moreover, a recent publication reveals that colchicine treatment upregulates P-glycoprotein expression [42], a transmembrane efflux pump, that functions as the extrusion of toxic hydrophobic xenobiotics and drugs such as the immunosuppressants (CsA and FK506) out of cells, and that this may act to protect against chronic CsA nephrotoxicity [43, 44]. Additionally, our recent study (ASN/ISN, Abstract No.…”

Glutathione-S-Transferase Variants are not Associated With Increased Carotid Intima-Media Thickness in Turkish Familial Mediterranean Fever Patients

“…In in vitro studies, especially those performed with the multidrug resistant cell lines, it has been demonstrated that colchicine increases the glutathione level and GST activity. [51][52][53] Therefore, colchicine therapy may be responsible for less aggressive course of atherogenesis in most studies on FMF. 37 In this study; LDL, ESR, and fibrinogen levels were statistically significantly higher in the patient group.…”

The Anti-cancer Drug Chlorambucil as a Substrate for the Human Polymorphic Enzyme Glutathione Transferase P1-1: Kinetic Properties and Crystallographic Characterisation of Allelic Variants

“…The acquired resistance that eventually arises in patients, after an initial period of successful treatment, has been related in some cases to the presence of these enzymes. The Pi class GST enzyme, GST P1-1, is believed to be an important factor in such resistance and its over-expression has been reported in a number of different human malignancies including lung, 4 colon, 5,6 ovary, 7 testis, 8 bladder, 9 mouth, 10 kidney, 11 esophagus, 12 and stomach. 13 GST P1-1 has been proposed as a possible tumour marker for certain types of cancer (e.g.…”