Benzoxazole-based Zn(II) and Cu(II) Complexes Overcome Multidrug-resistance in Cancer

Abstract

Background/Aim: Multidrug resistance (MDR) represents a significant impediment to successful cancer treatment. In this study, novel metal [Zn(II), Cu(II), Mg(II), Ni(II), Pd(II), and Ag(I)] complexes of 2-trifluoroacetonylbenzoxazole previously synthesized and characterized by our group were tested for their MDR-reversing activity in comparison with the free ligands in L5178Y mouse Tlymphoma (MDR) cells transfected with human ATP-binding cassette sub-family B member 1 (ABCB1; P-glycoprotein) gene. Materials and Methods: Cytotoxic and antiproliferative effects of the complexes were assessed by the thiazolyl blue tetrazolium bromide (MTT) method. Modulation of ABCB1 activity was measured by rhodamine 123 accumulation assay using flow cytometry. The apoptosis-inducing activity of some complexes was also tested on the multidrug resistant L5178Y mouse T-lymphoma cells, using the annexin-V/propidium iodide assay. Results: When compared to the free ligand, a remarkable enhancement in MDR reversal and cytotoxic activity was found for the Zn(II) and Cu(II) complexes. The activity of the complexes proved to be up to 29-and 5-fold higher than that of the ligands and the ABCB1 inhibitor verapamil as positive control, respectively. The complexes possessed a remarkable potential to induce apoptosis of MDR cells. Conclusion: Our results suggest that the Zn(II) and Cu(II) complexes display significant MDRreversing activity in a dose-dependent manner and possess strong cytotoxic activity and a remarkable potential to induce apoptosis in MDR L5178Y mouse T-lymphoma cells.

New Chalcone Derivative Inhibits ABCB1 in Multidrug Resistant T-cell Lymphoma and Colon Adenocarcinoma Cells

“…No. 87111908, FDA, Silver Spring, MD, USA) after transfection with pHaMDR1/A retrovirus and culturing of both cell lines, as previously described (7). The Colo 205, doxorubicin-sensitive (CCL-222) and Colo 320/MDR1-LRP multidrug resistant, overexpressing ABCB1-LRP (CCL-220.1) human colon adenocarcinoma cell lines were purchased from LGC Promochem (Teddington, UK).…”

“…The percentage of mean fluorescence intensity was calculated for the treated MDR and Colo 320 cells as compared with the untreated cells. Rhodamine 123 accumulation was expressed as a fluorescence activity ratio (FAR) that was calculated based on the equation mentioned previously (7). Drug interactions were evaluated using CompuSyn software (www.combosyn.com, ComboSyn, Inc., Paramus, NJ, USA).…”

“…The resulting values of mean fluorescence intensity of the cells (FL-1)±SD values and fluorescence activity ratio (FAR) are summarized in Table IV (for mouse T-lymphoma cells) and Table V (for human colon adenocarcinoma cells). The potential of compounds to modulate ABCB1 was estimated from FAR values, which were calculated using the formula presented previously (7). Our compound 1C at concentrations ≥1 μM was able to significantly increase rhodamine 123 accumulation in MDR cell line, compared to untreated MDR (Table IV and Table V).…”

“…However, due to their poor potency, high risk of side effects, and adverse interactions with concomitant chemotherapy, no ABCB1 inhibitor has been suitable for use in the clinic. Therefore, many researchers have focused their attention on searching for new molecules to overcome multidrug resistance (5)(6)(7). Within the last years, interest intensified in the group of natural phytochemicals and their derivatives as the fourth generation of multidrug resistance reversal agents (4,8).…”

Benzoxazole-Based Metal Complexes to Reverse Multidrug Resistance in Bacteria

“…The importance of benzoxazole core and 2-trifluoroacetonyl moiety of 2-trifluoroacetonylbenzoxazole 1 in order to express their antimicrobial activities has been previously highlighted [ 15 , 16 , 17 ]. In recent work on 2-trifluoroacetonylbenzoxazole ligand 1 for metal complexes, Zn(II) complex 4 of ligand 1 formed a stable six-membered ring in a bidentate mode to consist of 1 with Zn(II) ion in 2:1 ratio with good antibacterial activities against Gram-positive pathogens [ 18 ] and potent multidrug-resistance reversing activities in cancer cells [ 19 ]. In this article, we report the multidrug resistance-modulating activities of 2-trifluoroacetonylbenzoxazole ligands ( 1–3 ) and their metal complexes ( 4–12 ) in bacteria related to the inhibition of QS and biofilm formation.…”