Novel bexarotene derivatives: Synthesis and cytotoxicity evaluation for glioma cells in 2D and 3D in vitro models

Gretskaya, N. M.; Gamisonia, Alina M.; Dudina, Polina V.; Zakharov, Stanislav S.; Sherstyanykh, Galina; Akasov, Roman; Буров, С. В.; Серков, И. В.; Akimov, M. G.; Безуглов, В. В.; Марквичева, Елена

doi:10.1016/j.ejphar.2020.173346

Cited by 9 publications

(6 citation statements)

References 28 publications

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“…Recently, we have developed a simple universal approach based on RGD‐induced cell self‐assembly technique 21 . This approach has been already successfully used by us to generate multicellular spheroids from different tumor cells 31–33 as well as coculture spheroids from tumor and healthy (normal) cells 34 …”

Section: Resultsmentioning

confidence: 99%

“…Recently, we have developed a simple universal approach based on RGD-induced cell self-assembly technique. 21 This approach has been already successfully used by us to generate multicellular spheroids from different tumor cells [31][32][33] as well as coculture spheroids from tumor and healthy (normal) cells. 34 After 1 h incubation, the PEGylated liposomes were found to be attached to the outer spheroid surface, while after 3 h incubation they were already observed everywhere within the spheroid, including its center.…”

Section: Cellular Uptake Of the Liposomesmentioning

confidence: 99%

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Transfection efficacy and drug release depends upon the PEG derivative in cationic lipoplexes: Evaluation in 3D in vitro model and in vivo

et al. 2023

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The goal of the study was to estimate transfection efficacy and drug release in function of the PEG derivative in cationic liposomes and lipoplexes in both 2D and 3D in vitro models as well as in a mouse model (in vivo). For this purpose, cationic PEGylated nanocarriers based on OrnOrnGlu(C 16 H 33 ) 2 lipopeptides were fabricated and characterized. The nanocarriers were loaded with DNA plasmid pGL3 or with siRNA targeting 5 0 -UTR region of Hepatitis C virus, and their transfection efficacies were studied by luciferase test or by PCR technique, respectively. The pGL3-lipoplexes containing PEG derivative b (6 mol % PEG) were selected as the most promising nanocarriers for further in vivo study. In vitro cytotoxicity assay of the pGL3-lipoplexes with the PEG derivative b showed 2-and 1.5-fold enhancements of IC 50 levels for HEK293T and HepG2 cells, respectively. Accumulation of the liposomes in the cells was studied by confocal microscopy using both 2D (monolayer culture) and 3D (multicellular spheroids) in vitro models. The PEGylated liposomes were found to penetrate cells more slowly than unmodified ones (without PEG). Thus, maximum liposomes in the HEK293T cells was observed after 1 and 3 h in the case of 2D and 3D in vitro models, respectively. Biodistribution study in mice showed that the PEGylated lipoplexes containing the PEG derivative b were eliminated from the bloodstream more slowly, namely with the doubled half-life time, than unmodified ones. Thus, the enhanced transfection efficacy and prolonged drug release of the PEGylated lipoplexes containing the optimal PEG derivative was demonstrated. This approach could be promising for development of novel siRNA-based drugs.

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Section: Resultsmentioning

confidence: 99%

Section: Cellular Uptake Of the Liposomesmentioning

confidence: 99%

Transfection efficacy and drug release depends upon the PEG derivative in cationic lipoplexes: Evaluation in 3D in vitro model and in vivo

et al. 2023

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“…In order to evaluate whether RXR signaling might improve the cytotoxic effects of TMZ, we treated the RXR mock clones with the rexinoid bexarotene. We chose bexarotene for these assays since it has been approved by the FDA for clinical applications, it possesses more favorable K D s than CD3254, and the effects of bexarotene derivatives have been examined in the context of GBM cell lines [51]. Bexareotene did not deplete Sox2+ cells from the cultures of edited RXR clones or the mock controls, and 1 µM bexarotene mediated a dose-dependent pro-proliferative effect in a subset of clones.…”

Section: Discussionmentioning

confidence: 99%

RAR-Dependent and RAR-Independent RXR Signaling in Stem-like Glioma Cells

Dabrock,

Ernesti,

Will

et al. 2023

IJMS

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Retinoic acid (RA) exerts pleiotropic effects during neural development and regulates homeostasis in the adult human brain. The RA signal may be transduced through RXR (retinoid-X receptor)-non-permissive RA receptor/RXR heterodimers or through RXR-permissive RXR heterodimers. The significance of RA signaling in malignant brain tumors such as glioblastoma multiforme (GBM) and gliosarcoma (GS) is poorly understood. In particular, the impact RA has on the proliferation, survival, differentiation, or metabolism of GBM- or GS-derived cells with features of stem cells (SLGCs) remains elusive. In the present manuscript, six GBM- and two GS-derived SLGC lines were analyzed for their responsiveness to RAR- and RXR-selective agonists. Inhibition of proliferation and initiation of differentiation were achieved with a RAR-selective pan-agonist in a subgroup of SLGC lines, whereas RXR-selective pan-agonists (rexinoids) supported proliferation in most SLGC lines. To decipher the RAR-dependent and RAR-independent effects of RXR, the genes encoding the RAR or RXR isotypes were functionally inactivated by CRISPR/Cas9-mediated editing in an IDH1-/p53-positive SLGC line with good responsiveness to RA. Stemness, differentiation capacity, and growth behavior were preserved after editing. Taken together, this manuscript provides evidence about the positive impact of RAR-independent RXR signaling on proliferation, survival, and tumor metabolism in SLGCs.

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“…Additionally, Bexarotene is approved by the FDA for the treatment of cutaneous lymphoma. Furthermore, Bexarotene IC 50 for suppressing HBV infection (IC 50 1.89 ± 0.98 μM) is much lower than that reported to induce suppression of cancer cells (IC 50 50–152 μM) [ 43 , 44 ]. Because HBV entry inhibition reduces the intrahepatic cccDNA pool [ 45 ], entry inhibitors are expected to be useful in preventing de novo infection in clinical settings such as vertical transmission and HBV recurrence post-LT.…”

Section: Discussionmentioning

confidence: 99%

The kinesin KIF4 mediates HBV/HDV entry through the regulation of surface NTCP localization and can be targeted by RXR agonists in vitro

et al. 2022

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Intracellular transport via microtubule-based dynein and kinesin family motors plays a key role in viral reproduction and transmission. We show here that Kinesin Family Member 4 (KIF4) plays an important role in HBV/HDV infection. We intended to explore host factors impacting the HBV life cycle that can be therapeutically addressed using siRNA library transfection and HBV/NLuc (HBV/NL) reporter virus infection in HepG2-hNTCP cells. KIF4 silencing resulted in a 3-fold reduction in luciferase activity following HBV/NL infection. KIF4 knockdown suppressed both HBV and HDV infection. Transient KIF4 depletion reduced surface and raised intracellular NTCP (HBV/HDV entry receptor) levels, according to both cellular fractionation and immunofluorescence analysis (IF). Overexpression of wild-type KIF4 but not ATPase-null KIF4 mutant regained the surface localization of NTCP and significantly restored HBV permissiveness in these cells. IF revealed KIF4 and NTCP colocalization across microtubule filaments, and a co-immunoprecipitation study revealed that KIF4 interacts with NTCP. KIF4 expression is regulated by FOXM1. Interestingly, we discovered that RXR agonists (Bexarotene, and Alitretinoin) down-regulated KIF4 expression via FOXM1-mediated suppression, resulting in a substantial decrease in HBV-Pre-S1 protein attachment to HepG2-hNTCP cell surface and subsequent HBV infection in both HepG2-hNTCP and primary human hepatocyte (PXB) (Bexarotene, IC50 1.89 ± 0.98 μM) cultures. Overall, our findings show that human KIF4 is a critical regulator of NTCP surface transport and localization, which is required for NTCP to function as a receptor for HBV/HDV entry. Furthermore, small molecules that suppress or alleviate KIF4 expression would be potential antiviral candidates targeting HBV and HDV entry.

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Novel bexarotene derivatives: Synthesis and cytotoxicity evaluation for glioma cells in 2D and 3D in vitro models

Cited by 9 publications

References 28 publications

Transfection efficacy and drug release depends upon the PEG derivative in cationic lipoplexes: Evaluation in 3D in vitro model and in vivo

Transfection efficacy and drug release depends upon the PEG derivative in cationic lipoplexes: Evaluation in 3D in vitro model and in vivo

RAR-Dependent and RAR-Independent RXR Signaling in Stem-like Glioma Cells

The kinesin KIF4 mediates HBV/HDV entry through the regulation of surface NTCP localization and can be targeted by RXR agonists in vitro

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