Dequalinium induces apoptosis in peripheral blood mononuclear cells isolated from human chronic lymphocytic leukemia

Abstract

B-cell chronic lymphocytic leukemia (B-CLL) is an abnormal neoplasic proliferation of B cells, which accumulate mainly in the bone marrow and blood preventing both B cells development in the lymph nodes and the ability to fight against infection. The antitumor agents used in chemotherapy are aimed at inducing malignant cell death, thus limiting the growth and spreading of these cells. However, the lack of specificity for tumor cells exhibited by these agents causes undesirable side effects that have led to the investigation of new therapeutic strategies designed to specifically target malignant cells and thus trigger selective cell destruction. Dequalinium (DQA) is an antitumoral agent that selectively accumulates in the mitochondria and has been shown to display anticancer activity in cells from different malignancies. In the present study, the DQA-induced cytotoxicity in B-CLL cells was analyzed by measuring cell viability and cell death, either by necrosis or apoptosis. Our results support the importance of DQA as a selective and potential antileukemic drug with a higher cytotoxic effect on peripheral blood mononuclear cells from B-CLL patients than in those from healthy donors and encourage the performance of further studies in combination with other agents.

Dequalinium induces cytotoxicity in human leukemia NB4 cells by downregulation of Raf/MEK/ERK and PI3K/Akt signaling pathways and potentiation of specific inhibitors of these pathways

“…also show that treatments with high 20 M DQA concentrations during a short time (16 h) produce some cell accumulation in the S and G2/M phases of cell cycle as it has been previously observed [16]. Necrotic PI permeable cells were always lower than 10% even in the presence of the UO126 inhibitor (results not shown).…”

“…We have reported the ability of DQA as a selective and potential antileukemic agent by interfering mitochondrial function, decreasing ATP and inducing oxidative stress which results in apoptosis by the intrinsic mitochondrial pathway [17][18][19][20]. Our previous results also support a cytotoxic effect of DQA on peripheral blood mononuclear cells from B-CLL patients that was higher than those from healthy donors [16]. These studies encourage the importance of DQA as a selective and potential antileukemic drug.…”

“…Thus DQAsomes have been used as mitochondriotropic carriers delivering antitumoral drugs or DNA into mitochondria [6,[9][10][11]. Although cytotoxicity mechanism is not fully understood, DQA has shown to display a potent anticancer activity in cells from different malignancies [9][10][11][12][13][14][15][16]. Antileukemic properties of DQA against the human leukemia cell lines, NB4 derived from acute promyelocytic leukemia, and K562, derived from chronic myeloid leukemia, are being studied in our group.…”

Characterization of dequalinium as a XIAP antagonist that targets the BIR2 domain

“…Dq is a classic bacteriostatic indicated for the use in mouth, skin and vaginal infections having also cytostatic activity in tumour cells [20,22,24]. It was also shown that Dq was able to induce size reduction in rat colon tumour isografts [25].…”

“…Dq is a cation delocalized lipidic drug that has been described to accumulate in mitochondria due to the high mitochondrial membrane potential [20] inducing cell death in different cell lines. However, the molecular mechanism behind cell death induction is still unclear and different pathways have been postulated to be affected by Dq [20][21][22]. In this study we have discovered that Dq, in vitro and in cell extracts, targets the complex XIAP/caspase-3 which seems to indicate that apoptosis induction could be at the basis of the molecular mechanism of action of Dq.…”