Moxifloxacin enhances etoposide-induced cytotoxic, apoptotic and anti-topoisomerase II effects in a human colon carcinoma cell line

Fabian,

doi:10.3892/ijo_00000695

Int J Oncol

2010

DOI: 10.3892/ijo_00000695

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Moxifloxacin enhances etoposide-induced cytotoxic, apoptotic and anti-topoisomerase II effects in a human colon carcinoma cell line

Fabian Fabian¹

Abstract: Abstract. Etoposide (VP-16) is a topoisomerase-II (topo II) inhibitor chemotherapeutic agent. Studies have shown that a combination of VP-16 with other drugs demonstrates better clinical responses. The aim of this study was to investigate the effects of moxifloxacin (MXF) and VP-16 on cellular topo II activity in drug-treated cells and evaluate the influence of MXF on the mode of action of VP-16, on proliferation and apoptosis of HT-29 cells. Decatenation assay, band depletion and Western blot analysis, cytoto… Show more

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Cited by 9 publications

References 30 publications

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Moxifloxacin rescues SMA phenotypes in patient-derived cells and animal model

Januel

Menduti

Mamchaoui

et al. 2022

Cell. Mol. Life Sci.

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Spinal muscular atrophy (SMA) is a genetic disease resulting in the loss of α-motoneurons followed by muscle atrophy. It is caused by knock-out mutations in the survival of motor neuron 1 (SMN1) gene, which has an unaffected, but due to preferential exon 7 skipping, only partially functional human-specific SMN2 copy. We previously described a Drosophila-based screening of FDA-approved drugs that led us to discover moxifloxacin. We showed its positive effect on the SMN2 exon 7 splicing in SMA patient-derived skin cells and its ability to increase the SMN protein level. Here, we focus on moxifloxacin's therapeutic potential in additional SMA cellular and animal models. We demonstrate that moxifloxacin rescues the SMA-related molecular and phenotypical defects in muscle cells and motoneurons by improving the SMN2 splicing. The consequent increase of SMN levels was higher than in case of risdiplam, a potent exon 7 splicing modifier, and exceeded the threshold necessary for a survival improvement. We also demonstrate that daily subcutaneous injections of moxifloxacin in a severe SMA murine model reduces its characteristic neuroinflammation and increases the SMN levels in various tissues, leading to improved motor skills and extended lifespan. We show that moxifloxacin, originally used as an antibiotic, can be potentially repositioned for the SMA treatment.

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Moxifloxacin rescues SMA phenotypes in patient-derived cells and animal model

Januel

Menduti

Mamchaoui

et al. 2022

Cell. Mol. Life Sci.

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Interaction between moxifloxacin and Mcl-1 and MITF proteins: the effect on growth inhibition and apoptosis in MDA-MB-231 human triple-negative breast cancer cells

et al. 2022

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Background Microphthalmia-associated transcription factor (MITF) activates the expression of genes involved in cellular proliferation, DNA replication, and repair, whereas Mcl-1 is a member of the Bcl-2 family of proteins that promotes cell survival by preventing apoptosis. The objective of the present study was to verify whether the interaction between moxifloxacin (MFLX), one of the fluoroquinolones, and MITF/Mcl-1 protein, could affect the viability, proliferation, and apoptosis in human breast cancer using both in silico and in vitro models. Methods Molecular docking analysis (in silico), fluorescence image cytometry, and Western blot (in vitro) techniques were applied to assess the contribution of MITF and Mcl-1 proteins in the MFLX-induced anti-proliferative and pro-apoptotic effects on the MDA-MB-231 breast cancer cells. Results We indicated the ability of MFLX to form complexes with MITF and Mcl-1 as well as the drug’s capacity to affect the expression of the tested proteins. We also showed that MFLX decreased the viability and proliferation of MDA-MB-231 cells and induced apoptosis via the intrinsic death pathway. Moreover, the analysis of the cell cycle progression revealed that MFLX caused a block in the S and G2/M phases. Conclusions We demonstrated for the first time that the observed effects of MFLX on MDA-MB-231 breast cancer cells (growth inhibition and apoptosis induction) could be related to the drug’s ability to interact with MITF and Mcl-1 proteins. Furthermore, the presented results suggest that MITF and Mcl-1 proteins could be considered as the target in the therapy of breast cancer. Graphical abstract

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Discovery of 4,6-O-Thenylidene-β-d-glucopyranoside-(2″-acetamido, 3″-acetyl-di-S-5-fluorobenzothizole/5-fluorobenzoxazole)-4′-demethylepipodophyllotoxin as Potential Less Toxic Antitumor Candidate Drugs by Reducing DNA Damage and Less Inhibition of PI3K

et al. 2020

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As an FDA-approved drug, teniposide, was utilized in cancer treatment but was accompanied by a strong side effect in long-term clinical trials. This work discovered potential candidate drugs with low toxicity by modifying the molecule structure of teniposide through a structure-guided drug design approach. The IC 50 value of novel 4,6-O-thenylidene-β-D-glucopyranoside-(2″acetamido, 3″-acetyl-di-S-5-fluorobenzothizole/5-fluorobenzoxazole)-4′-demethylepipodophyllotoxin (compounds 15 and 16) was 120.4−125.1 μM, which was significantly improved by around 10 times more than teniposide (11.5−22.3 μM) against healthy human cells (i.e., HL-7702, H8, MRC-5, and HMEC). In vivo studies demonstrated compounds 15 and 16 significantly suppressed the tumor growth in the HepG2 cell xenograft model without exhibiting obvious toxicity (LD 50 values of 208.45 and 167.52 mg/kg), which was lower than that of teniposide (LD 50 = 46.12 mg/kg). Compounds 15 and 16 caused mild γH2AX phosphorylation for low DNA toxicity and less inhibition of PI3K/Akt. Compounds 15 and 16 might be potential antitumor drugs with low toxicity.

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Moxifloxacin enhances etoposide-induced cytotoxic, apoptotic and anti-topoisomerase II effects in a human colon carcinoma cell line

Cited by 9 publications

References 30 publications

Moxifloxacin rescues SMA phenotypes in patient-derived cells and animal model

Moxifloxacin rescues SMA phenotypes in patient-derived cells and animal model

Interaction between moxifloxacin and Mcl-1 and MITF proteins: the effect on growth inhibition and apoptosis in MDA-MB-231 human triple-negative breast cancer cells

Discovery of 4,6-O-Thenylidene-β-d-glucopyranoside-(2″-acetamido, 3″-acetyl-di-S-5-fluorobenzothizole/5-fluorobenzoxazole)-4′-demethylepipodophyllotoxin as Potential Less Toxic Antitumor Candidate Drugs by Reducing DNA Damage and Less Inhibition of PI3K

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