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New-Generation Heterocyclic Bis-Pentamethinium Salts as Potential Cytostatic Drugs with Dual IL-6R and Mitochondria-Targeting Activity.

ABSTRACT: IL-6 signaling is involved in the pathogenesis of a number of serious diseases, including chronic inflammation and cancer. Targeting of IL-6 receptor (IL-6R) by small molecules is therefore an intensively studied strategy in cancer treatment. We describe the design, synthesis, and characteristics of two new bis-pentamethinium salts 5 and 6 (meta and para) bearing indole moieties. Molecular docking studies showed that both compounds have the potential to bind IL-6R (free energy of binding -9.5 and -8.1 kcal/mol). The interaction with IL-6R was confirmed using microscale thermophoresis analyses, which revealed that both compounds had strong affinity for the IL-6R (experimentally determined dissociation constants 26.5 ± 2.5 nM and 304 ± 27.6 nM, respectively). In addition, both compounds were cytotoxic for a broad spectrum of cancer cell lines in micromolar concentrations, most likely due to their accumulation in mitochondria and inhibition of mitochondrial respiration. In summary, the structure motif of bis-pentamethinium salts represents a promising starting point for the design of novel multitargeting compounds with the potential to inhibit IL-6 signaling and simultaneously target mitochondrial metabolism in cancer cells.

SUBMITTER: Talianova V

PROVIDER: S-EPMC9416741 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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New-Generation Heterocyclic Bis-Pentamethinium Salts as Potential Cytostatic Drugs with Dual IL-6R and Mitochondria-Targeting Activity.

Talianová Veronika V Kejík Zdeněk Z Kaplánek Robert R Veselá Kateřina K Abramenko Nikita N Lacina Lukáš L Strnadová Karolína K Dvořánková Barbora B Martásek Pavel P Masařík Michal M Megová Magdalena Houdová MH Bušek Petr P Křížová Jana J Zdražilová Lucie L Hansíková Hana H Vlčák Erik E Filimonenko Vlada V Šedo Aleksi A Smetana Karel K Jakubek Milan M

Pharmaceutics 20220817 8

IL-6 signaling is involved in the pathogenesis of a number of serious diseases, including chronic inflammation and cancer. Targeting of IL-6 receptor (IL-6R) by small molecules is therefore an intensively studied strategy in cancer treatment. We describe the design, synthesis, and characteristics of two new bis-pentamethinium salts <b>5</b> and <b>6</b> (meta and para) bearing indole moieties. Molecular docking studies showed that both compounds have the potential to bind IL-6R (free energy of b ...[more]

PMID: 36015338

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Project description:Prostate cancer (PCa) is a key public health problem worldwide; at diagnosis, a high percentage of patients exhibit tumor cell invasion of adjacent tissue. STAT‑3, IL‑6 receptor (R) and IL‑6 serum levels are associated with enhanced PCa migratory, invasive, clonogenic and metastatic ability. Inhibiting the STAT‑3 pathway at different levels (cytokines, receptors, and kinases) exhibits relative success in cancer. The present study investigated the effect of Stattic (Stt) + Tocilizumab (Tcz) on proliferative, clonogenic, migratory and invasive ability of human metastatic PCa (assessed by colony formation, wound healing and migration assay). RWPE‑1 (epithelial prostate immortalized cells), 22Rv1 (Tumor cells), LNCaP (Metastatic cells) and DU‑145 (metastatic, castration‑resistant prostate cells) cells were used in vitro to evaluate levels of cytokines, chemokines, growth factors (Cytometric Bead Array), STAT‑3, phosphorylated STAT‑3 (In‑Cell Western), IL‑6R, vimentin and epithelial (E‑) cadherin (Western Blot). The effect of inhibition of STAT‑3 (expressed constitutively in DU‑145 cells) with Stt and/or Tcz on expression levels of vimentin, VEGF, and E‑cadherin, as well as proliferative, clonogenic, migratory and invasive capacity of metastatic PCa cells was assessed. The expression levels of IL‑6, C‑X‑C chemokine ligand 8, VEGF and vimentin, as well as proliferation and migration, were increased in metastatic PCa cells. Treatment with Stt or Tcz decreased vimentin and VEGF and increased E‑cadherin expression levels and inhibited proliferative, clonogenic, migratory and invasive capacity of DU‑145 cells; addition of IL‑6 decreased this inhibitory effect. However, Stt + Tcz maintained inhibition even in the present of high concentrations of IL‑6. Stt + Tcz decreased expression of vimentin and VEGF and inhibited the proliferative, clonogenic, migratory and invasive capacity of metastatic PCa cells. To the best of our knowledge, the present study is the first to combine Stt, a STAT‑3 inhibitor, with Tcz, an antibody against IL‑6R, to target tumor cells.

Dataset Information

New-Generation Heterocyclic Bis-Pentamethinium Salts as Potential Cytostatic Drugs with Dual IL-6R and Mitochondria-Targeting Activity.

Publications

New-Generation Heterocyclic Bis-Pentamethinium Salts as Potential Cytostatic Drugs with Dual IL-6R and Mitochondria-Targeting Activity.

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