Effect of dequalinium on K1735-M2 melanoma cell growth, directional migration and invasion in vitro

doi:10.1016/0959-8049(93)90589-8

European Journal of Cancer

Volume 29, Issue 1, 1993, Pages 124-128

https://doi.org/10.1016/0959-8049(93)90589-8 Get rights and content

Abstract

Cationic lipophilic compounds have an antiproliferative effect on certain tumour systems in vitro and in vivo. We have investigated whether the cationic lipophilic compound dequalinium affects not only proliferation but also motility and invasion of the highly metastatic and highly invasive melanoma cell line K1735-M2. Proliferation was assessed in monolayer cultures and in multicellular spheroids, motility was estimated in the assay of directional migration, and invasiveness was tested through confrontation cultures of tumour multicellular spheroids with embryonic chick heart tissue evaluated by computerized image analysis. 2 μmol/l dequalinium impaired melanoma cell proliferation, reduced directional migration and significantly blocked invasion in vitro. On the ultrastructural level, dequalinium caused obvious changes in mitochondria of both melanoma and embryonic chick heart cells. The mechanisms of the antiproliferative, antimigrating and antiinvasive effects remain to be determined. Inhibition of protein kinase C, calmodulin antagonism, DNA intercalation and/or direct effects on mitochondrial functions may be considered.

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Mitochondrial and glycolytic inhibitors have been shown to significantly block the migration and invasion capacity of a variety of cancer cells, including breast cancer (Pacheco-Velázquez et al., 2018; Wu et al., 2018), lung cancer (Jeon et al., 2016), ovarian cancer (Wu et al., 2012), prostate cancer (Senthilkumar et al., 2011; Shiraishi et al., 2015), gastric cancer (Xu et al., 2018), melanoma (Cao et al., 2015; Cerezo et al., 2013; Helige et al., 1992), and osteosarcoma (Sottnik et al., 2011). Many of these inhibitors have demonstrated anti-tumor and anti-metastatic effects in vivo (Dai et al., 2012; Davis et al., 2020; Helige et al., 1992; Wilson et al., 2019; Wu et al., 2012, 2018; Yoshinaka et al., 2006). Inhibiting pyruvate dehydrogenase kinase, which shifts metabolism from aerobic glycolysis toward OXPHOS also inhibits metastasis in vivo (Sun et al., 2010).
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Medicinal applications and molecular targets of dequalinium chloride
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The drug efficacy was also evidenced using two other models of colon carcinoma in mice and rats, and again DQ was found to reduce tumor growth efficiently [33]. The anticancer effects have been characterized in different models, including ovarian cancer [34], prostate cancer [35] and melanoma [36,37]. A marked antiproliferative activity has also been evidenced using NB4 and K562 leukemia cell lines, with the induction of mitochondrial damages, apoptosis and/or necrosis [38,39].
For more than 60 years dequalinium chloride (DQ) has been used as anti-infective drug, mainly to treat local infections. It is a standard drug to treat bacterial vaginosis and an active ingredient of sore-throat lozenges. As a lipophilic bis-quaternary ammonium molecule, the drug displays membrane effects and selectively targets mitochondria to deplete DNA and to block energy production in cells. But beyond its mitochondriotropic property, DQ can interfere with the correct functioning of diverse proteins. A dozen of DQ protein targets have been identified and their implication in the antibacterial, antiviral, antifungal, antiparasitic and anticancer properties of the drug is discussed here. The anticancer effects of DQ combine a mitochondrial action, a selective inhibition of kinases (PKC-α/β, Cdc7/Dbf4), and a modulation of Ca²⁺-activated K⁺ channels. At the bacterial level, DQ interacts with different multidrug transporters (QacR, AcrB, EmrE) and with the transcriptional regulator RamR. Other proteins implicated in the antiviral (MPER domain of gp41 HIV-1) and antiparasitic (chitinase A from Vibrio harveyi) activities have been identified. DQ also targets α -synuclein oligomers to restrict protofibrils formation implicated in some neurodegenerative disorders. In addition, DQ is a typical bolaamphiphile molecule, well suited to form liposomes and nanoparticules useful for drug entrapment and delivery (DQAsomes and others). Altogether, the review highlights the many pharmacological properties and therapeutic benefits of this old 'multi-talented' drug, which may be exploited further. Its multiple sites of actions in cells should be kept in mind when using DQ in experimental research.
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
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Citation Excerpt :
Thus DQAsomes have been used as mitochondriotropic carriers delivering antitumoral drugs or DNA into mitochondria [6,9–11]. Although cytotoxicity mechanism is not fully understood, DQA has shown to display a potent anticancer activity in cells from different malignancies [9–16]. 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.
Delocalized lipophilic cation dequalinium (DQA) selectively accumulates in mitochondria and displays anticancer activity in different malignancies. Our previous studies indicate a DQA-induced cytotoxicity in human acute promyelocytic leukemia NB4 cells by early disturbance in mitochondrial function and oxidative stress. This study shows the ability of DQA to downregulate Raf/MEK/ERK1/2 and PI3K/Akt signaling pathways in NB4 cells which leads to cell death by apoptosis and/or necrosis. Moreover, DQA potentiates the action of specific inhibitors of these pathways. These DQA effects could be mediated by redox regulation of Akt. Our results contribute to a better understanding of the cytotoxic DQA mechanism on leukemia cells and encourage the performance of further studies in combination with other agents such as kinase inhibitors for improving the efficacy of therapies against acute promyelocytic leukemia.
Dequalinium induces human leukemia cell death by affecting the redox balance
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This amphiphilic quinolinium derivative forms liposome-like vesicles positively charged (DQAsomes) which are attracted by the highly negative mitochondrial transmembrane potential of tumor cells [2,3]. Although antitumor mechanism is not fully understood, DQA shows a potent anticancer activity in cells from different malignancies [4–8]. DQA antileukemic properties in the human leukemia cell lines K562 (chronic myeloid leukemia in blastic crisis) and NB4 (acute promyelocytic leukemia) are being studied in our group.
Dequalinium, an amphiphilic quinolinium derivative, selectively accumulates in mitochondria and displays anticancer activity in cells from different malignancies. Previous studies indicate a differential DQA-induced cytotoxicity in NB4 and K562 human leukemia cells as a consequence of an early disturbance in mitochondrial function. Results in this paper show that DQA induces a concentration-dependent oxidative stress by decreasing GSH level and increasing ROS in a cell type specific way. Inhibitors of the JNK and p38 stress regulated kinases potentiate DQA-induced NB4 cell death suggesting a protective function for these enzymes. K562 cells with relatively high GSH levels remained resistant to DQA action.
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Citation Excerpt :
Dequalinium and antimycin A displayed the greatest inhibition of all cytokines by >50%, followed by emetine, benzethonium derivative, alexidine and coralyne (Table 2A). Consistent with our results, dequalinium, alexidine and coralyne have been previously reported to either inhibit cytokine production or induce potent anti-cancer activities [13–16]. Twelve compounds exhibited selective inhibition at high level of >90% (Table 2B), whereas 58 compounds showed selective inhibitory effects at levels of >75% (data not shown).
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Alterations in mitochondrial structure and functions have long been observed in cancer cells. Targeting mitochondria as a cancer therapeutic strategy has gained momentum in the recent years. The signaling pathways that govern mitochondrial function, apoptosis and molecules that affect mitochondrial integrity and cell viability have been important topics of the recent review in the literature. In this article, we first briefly summarize the rationale and biological basis for developing mitochondrial-targeted compounds as potential anti-cancer agents, and then provide key examples of small molecules that either directly impact mitochondria or functionally affect the metabolic alterations in cancer cells with mitochondrial dysfunction. The main focus is on the small molecular weight compounds with potential applications in cancer treatment. We also summarize information on the drug developmental stages of the key mitochondria-targeted compounds and their clinical trial status. The advantages and potential shortcomings of targeting the mitochondria for cancer treatment are also discussed.

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PaperEffect of dequalinium on K1735-M2 melanoma cell growth, directional migration and invasion in vitro

Abstract

Int Rev Cytol

Crit Rev Oncol Hematol

Biochem Biophys Res Commun

J Biol Chem

J Biol Chem

J Biol Chem

The role of cancer cell motility in invasion

Cancer Metast Rev

Tumor invasion and metastases-role of the extracellular matrix: rhoads memorial award lecture

Cancer Res

Dequalinium, a topical antimicrobial agent, displays anticarcinoma activity based on selective mitochondrial accumulation

Effects of ring substituents and linker chains on the bifunctional intercalation of diacridines into deoxyribonucleic-acid

Biochemistry

Targeting calmodulin for the development of noyel cancer chemotherapeutic agents

Anti-Cancer Drug Design

Inhibition of rodent protein kinase C by the anticarcinoma agent dequalinium

Cancer Res

Paper
Effect of dequalinium on K1735-M2 melanoma cell growth, directional migration and invasion in vitro