An in vitro and in vivo study of a novel zinc complex, zinc N-(2-hydroxyacetophenone)glycinate to overcome multidrug resistance in cancer

Abstract

Multiple drug resistance (MDR) remains a major clinical challenge for cancer treatment. P-glycoprotein is the major contributor and they exceed their role in the chemotherapy resistance of most of the malignancies. Attempts in several preclinical and clinical studies to reverse the MDR phenomenon by using MDR modulators have not yet generated promising results. In the present study, a co-ordination complex of zinc viz., Zn N-(2-hydroxyacetophenone)glycinate (ZnNG) has been synthesized, characterized and its antitumour activity was tested in vitro against drug sensitive and resistant human T-lymphoblastic leukemic cell lines (CCRF/CEM and CEM/ADR5000 respectively) and in vivo against Ehrlich ascites carcinoma (EAC) implanted in female Swiss albino mice. To evaluate the cytotoxic potential of ZnNG, we used sensitive CCRF/CEM and drug resistant CEM/ADR 5000 cell lines in vitro. Moreover, ZnNG also has the potential ability to reverse the multidrug resistance phenotype in drug resistant CEM/ADR 5000 cell line and induces apoptosis in combination with vinblastine. ZnNG remarkably increases the life span of Swiss albino mice bearing sensitive and doxorubicin resistant subline of EAC in presence and in absence of doxorubicin. In addition, intraperitoneal application of ZnNG in mice does not show any systemic toxicity in preliminary trials in normal mice. To conclude, a novel metal chelate of zinc viz., ZnNG, may be a promising therapeutic agent against sensitive as well as drug resistant cancers.

Unprecedented collateral sensitivity for cisplatin-resistant lung cancer cells presented by new ruthenium organometallic compounds

“…For example, Choudhuri and coworkers developed a series of [M(N-(2-hydroxy acetophenone)glycinate)(H 2 O) n ] complexes, where the M is Fe III (n = 3), 16 Ni II (n = 1), 17 Cu II (n = 3) 18 or Zn II (n = 1). 19 In particular, the Cu II complex was shown to directly interact with P-gp showing potential to reverse P-gp mediated drug resistance. 18 Interestingly, it did not compete for the substrate binding or to verapamil-, vinblastine-and progesterone-binding sites.…”

Reprogramming of TAM toward proimmunogenic type through regulation of MAP kinases using a redox-active copper chelate

“…7). Our ongoing studies in this direction with other structurally similar, nontoxic compounds, e.g., zinc N-(2-hydroxyacetophenone)glycinate [53] and iron N-(2-hydroxy acetophenone) glycinate [35], generating ROS in TAMs, showed that they can modulate the cytokine profile in macrophages temporarily (unpublished results). Therefore, further research is necessary to establish a structure-activity relationship among these structurally similar redox-active compounds.…”

Complexes of Zn(ii) with a mixed tryptanthrin derivative and curcumin chelating ligands as new promising anticancer agents

“…74,75,81,91,92 It plays a role in the elimination of damaged, aged, and/or mutated cells. 74,75,81,91,92 To further study whether the cell death caused by Zn(TA) (3.04 μM) and Zn(TAC) (0.14 μM) was via apoptosis, we stained A549/DDP cells with 7-AAD, which stains necrotic cells, and annexin V-APC, which detects phosphatidylserine residues translocated from the inner cell membrane to the outer cell membrane in the early apoptotic stages. 72,74,75,81,91,92 As shown in Fig.…”

“…74,75,81,91,92 To further study whether the cell death caused by Zn(TA) (3.04 μM) and Zn(TAC) (0.14 μM) was via apoptosis, we stained A549/DDP cells with 7-AAD, which stains necrotic cells, and annexin V-APC, which detects phosphatidylserine residues translocated from the inner cell membrane to the outer cell membrane in the early apoptotic stages. 72,74,75,81,91,92 As shown in Fig. 6, 3.04 μM Zn(TA) and 0.14 μM Zn(TAC) induced apoptosis in 31.63% and 66.86% of A549/DDP cells (early + late), respectively; these rates were higher than the apoptosis rate observed (8.28%) in untreated cells.…”