Enoxacin and bis-enoxacin stimulate 4T1 murine breast cancer cells to release extracellular vesicles that inhibit osteoclastogenesis

Vracar, Taylor C.; Zuo, Jian; Park, Jeong-Su; Azer, Samy A.; Mikhael, Christy; Holliday, Sophia A.; Holsey, Dontreyl; Han, Guanghong; VonMoss, Lindsay; Neubert, John K.; Rody, Wellington J.; Chan, Edward K. L.; Holliday, L. Shannon

doi:10.1038/s41598-018-34698-9

Cited by 18 publications

(17 citation statements)

References 61 publications

(86 reference statements)

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“…Another possibility is that V‐ATPases are known to be integrated into various metabolic and physiological pathways 46 . BE may disrupt the targeting of V‐ATPases thus leading to the release of extracellular vesicles causing alterations in microRNA levels 47 . Subsequently, stimulation of microRNAs, rescue of p53 48 or stimulation of the JNK pathway may produce a variety of cellular effects that are distinct from BP action on bone.…”

Section: Discussionmentioning

confidence: 99%

Bisphosphonate‐enoxacin inhibit osteoclast formation and function by abrogating RANKL‐induced JNK signalling pathways during osteoporosis treatment

Zhan

et al. 2021

J Cellular Molecular Medi

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Osteoporosis is an age‐related disease characterized by low mineral density, compromised bone strength and increased risk of fragility fracture. Most agents for treating osteoporosis focus primarily on anti‐resorption by inhibiting osteoclast activity. Bisphosphonate (BP) is a potent anti‐resorptive agent that has been used clinically for decades and is proven to be effective. However, BP has a variety of side effects and is far from being an ideal anti‐osteoporosis agent. BP selectively binds to calcium crystals, which are subsequently taken up or released by osteoclasts. Based on the action of BP, we previously demonstrated the inhibitory effect of a novel bone‐targeting BP derivative, bisphosphonate‐enoxacin (BE). In the current study, we used bone marrow‐derived osteoclast cultures to further assess the inhibitory effect of BE on osteoclastogenesis and employed reverse transcription PCR and real‐time PCR to examine expression of osteoclast‐specific genes. Additionally, we used bone resorption and F‐actin immunofluorescence assays to evaluate the effect of BE on osteoclast function and investigated the potential mechanisms affecting osteoclast differentiation and function in vitro. Furthermore, an ovariectomized (OVX) rat model was established to evaluate the therapeutic effects of BE on preventing bone loss. Results showed that BE exerted potent inhibitory effects on osteoclast formation and bone resorption by specifically abrogating RANKL‐induced JNK signalling, and that it preserved OVX rat bone mass in vivo without any notable side effects. Collectively, these results indicated that the BP derivative BE may have significant potential as a treatment for osteoporosis and other osteolytic diseases.

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Section: Discussionmentioning

confidence: 99%

Bisphosphonate‐enoxacin inhibit osteoclast formation and function by abrogating RANKL‐induced JNK signalling pathways during osteoporosis treatment

Zhan

et al. 2021

J Cellular Molecular Medi

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“…All mentioned miRNAs are involved in the regulation of bone remodeling and osteoclastogenesis. Additionally, EVs from enoxacin-treated 4T1 cells enhanced the proliferation of murine macrophage cells [49]. The effective concentration range affecting miRNA biogenesis (see Table 1) was from 50 to 124 µM; however, an achievable serum concentration for a standard clinical dose 400 mg two times a day was ca.…”

Section: Other Consequences Of Enoxacin-mediated Mirna Dysregulationmentioning

confidence: 99%

The New Face of a Well-Known Antibiotic: A Review of the Anticancer Activity of Enoxacin and Its Derivatives

Jałbrzykowska

Chrzanowska

Roszkowski

et al. 2022

Cancers

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Enoxacin as a second-generation synthetic quinolone is known for its antibacterial action; however, in recent years there have been studies focusing on its anticancer potential. Interestingly, it turns out that compared to other fluoroquinolones, enoxacin exhibits uncommon cytotoxic properties. Besides its influence on apoptosis, the cell cycle and cell growth, it exhibits a regulatory action on microRNA biogenesis. It was revealed that the molecular targets of the enoxacin-mediated inhibition of osteoclastogenesis are vacuolar H+-ATPase subunits and the c-Jun N-terminal kinase signaling pathway, causing a decrease in cell invasiveness. Interestingly, the prooxidative nature of the subjected fluoroquinolone enhanced the cytotoxic effect. Crucial for the anticancer activity were the carboxyl group at the third carbon atom, fluorine at the seventh carbon atom and nitrogen at the eighth position of naphyridine. Modifications of the parent drug improved the induction of oxidative stress, cell cycle arrest and the dysregulation of microRNA. The inhibition of V-ATPase–microfilament binding was also observed. Enoxacin strongly affected various cancer but not normal cells, excluding keratinocytes, which suffered from phototoxicity. It seems to be an underestimated anticancer drug with pleiotropic action. Furthermore, its usage as a safe antibiotic with well-known pharmacokinetics and selectivity will enhance the development of anticancer treatment strategies. This review covers articles published within the years 2000–2021, with a strong focus on the recent years (2016–2021). However, some canonical papers published in twentieth century are also mentioned.

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“…Depleting CD99 in cells affects the amount of CD99 in EVs, and the effect of EVs can be altered by depleting CD99 in Ewing sarcoma cells [ 110 ]. It has been reported that 4T1 cells treated with antibacterial drugs secrete EVs that can inhibit osteoclastogenesis [ 233 ]. A natural killer cell line treated with IL-15-secreted EVs can inhibit cancer growth [ 234 ].…”

Section: Potential Of Evs For Cancer Treatmentmentioning

confidence: 99%

Anti-Cancer Role and Therapeutic Potential of Extracellular Vesicles

Tominaga

2021

Cancers

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Cell–cell communication is an important mechanism in biological processes. Extracellular vesicles (EVs), also referred to as exosomes, microvesicles, and prostasomes, are microvesicles secreted by a variety of cells. EVs are nanometer-scale vesicles composed of a lipid bilayer and contain biological functional molecules, such as microRNAs (miRNAs), mRNAs, and proteins. In this review, “EVs” is used as a comprehensive term for vesicles that are secreted from cells. EV research has been developing over the last four decades. Many studies have suggested that EVs play a crucial role in cell–cell communication. Importantly, EVs contribute to cancer malignancy mechanisms such as carcinogenesis, proliferation, angiogenesis, metastasis, and escape from the immune system. EVs derived from cancer cells and their microenvironments are diverse, change in nature depending on the condition. As EVs are thought to be secreted into body fluids, they have the potential to serve as diagnostic markers for liquid biopsy. In addition, cells can encapsulate functional molecules in EVs. Hence, the characteristics of EVs make them suitable for use in drug delivery systems and novel cancer treatments. In this review, the potential of EVs as anti-cancer therapeutics is discussed.

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Enoxacin and bis-enoxacin stimulate 4T1 murine breast cancer cells to release extracellular vesicles that inhibit osteoclastogenesis

Cited by 18 publications

References 61 publications

Bisphosphonate‐enoxacin inhibit osteoclast formation and function by abrogating RANKL‐induced JNK signalling pathways during osteoporosis treatment

Bisphosphonate‐enoxacin inhibit osteoclast formation and function by abrogating RANKL‐induced JNK signalling pathways during osteoporosis treatment

The New Face of a Well-Known Antibiotic: A Review of the Anticancer Activity of Enoxacin and Its Derivatives

Anti-Cancer Role and Therapeutic Potential of Extracellular Vesicles

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