Binding modes of cabazitaxel with the different human β-tubulin isotypes: DFT and MD studies

Zhu, Lijuan; Zhang, Chao; Lu, Xudong; Song, Ce; Wang, Cuihong; Zhang, Meiling; Xie, Yaoming; Schaefer, Henry F.

doi:10.1007/s00894-020-04400-w

Cited by 7 publications

(6 citation statements)

References 79 publications

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“…A saturation effect was observed when the drug concentration was above 25 μM. Among these three taxanes, cabazitaxel was most potent in inhibiting ciliary disassembly, which is consistent with the data that these taxanes have different binding abilities to β-tubulins with cabazitaxel having a higher III–tubulin binding ability …”

Section: Resultssupporting

confidence: 88%

“…Among these three taxanes, cabazitaxel was most potent in inhibiting ciliary disassembly, which is consistent with the data that these taxanes have different binding abilities to β-tubulins with cabazitaxel having a higher III−tubulin binding ability. 25 Cilia are dynamic structures, the axonemal microtubules undergo continuous turnover. 26 Thus, the taxanes may also affect microtubule assembly/stability in steady state cilia.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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Identification of Regulators for Ciliary Disassembly by a Chemical Screen

Dong

Pan

2021

ACS Chem. Biol.

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Cilia are organelles for cellular signaling and motility. They are assembled in G0/G1 and disassembled prior to mitosis. Compared to what is known about ciliary assembly, less is understood about ciliary disassembly. To uncover new mechanisms of ciliary disassembly, we performed an unbiased chemical screen. Chlamydomonas reinhardtii cells were experimentally induced for ciliary disassembly by treatment with sodium pyrophosphate. An FDA approved drug library (HY-L022P-1, MedChemExpress) was used for the screening. Primary screening with further experiments has identified microtubule stabilizer taxanes, CDK4/6 inhibitor abemaciclib and Raf inhibitor dabrafenib being effective in inhibiting ciliary disassembly induced experimentally but also under physiological conditions. In addition, their effects on ciliary disassembly in mammalian cells has also been confirmed. Thus, our studies have not only revealed new mechanisms in ciliary disassembly but also provided new tools for studying ciliary disassembly. These discovered drugs may be used for therapeutic interventions of disorders involving ciliary degeneration such as retinopathies.

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Section: Resultssupporting

confidence: 88%

Section: ■ Results and Discussionmentioning

confidence: 99%

Identification of Regulators for Ciliary Disassembly by a Chemical Screen

Dong

Pan

2021

ACS Chem. Biol.

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“…Even further, TUBB3 knockdown restored sensitivity to CBZ in CBZ-resistant cell lines and increased the sensitivity of CBZ-resistant cells to DTX [342], indicating that MT composition and their binding to taxanes could be a shared mechanism in DTX and CBZ resistance. However, other research claims that CBZ demonstrates better MT dynamics suppression when βIII-tubulin levels are high (or are at normal levels compared to depleted levels) [343], suggesting that CBZ may bind better to this isotype than other taxanes [344]. It should be noted that just because CBZ binds better to βIII-tubulin, it does not only bind to βIII-tubulin, meaning that CBZ efficacy is not completely inhibited when TUBB3 is knocked down.…”

Section: β-Tubulin Isotypes and Mutationsmentioning

confidence: 99%

Mechanisms of Taxane Resistance

Maloney

Hoover

Morejon-Lasso

et al. 2020

Cancers

129

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The taxane family of chemotherapy drugs has been used to treat a variety of mostly epithelial-derived tumors and remain the first-line treatment for some cancers. Despite the improved survival time and reduction of tumor size observed in some patients, many have no response to the drugs or develop resistance over time. Taxane resistance is multi-faceted and involves multiple pathways in proliferation, apoptosis, metabolism, and the transport of foreign substances. In this review, we dive deeper into hypothesized resistance mechanisms from research during the last decade, with a focus on the cancer types that use taxanes as first-line treatment but frequently develop resistance to them. Furthermore, we will discuss current clinical inhibitors and those yet to be approved that target key pathways or proteins and aim to reverse resistance in combination with taxanes or individually. Lastly, we will highlight taxane response biomarkers, specific genes with monitored expression and correlated with response to taxanes, mentioning those currently being used and those that should be adopted. The future directions of taxanes involve more personalized approaches to treatment by tailoring drug–inhibitor combinations or alternatives depending on levels of resistance biomarkers. We hope that this review will identify gaps in knowledge surrounding taxane resistance that future research or clinical trials can overcome.

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“…Drug combination is an important factor in effective treatment of gliomas [ 24 , 25 ]. Studies report that cabazitaxel (CTX) inhibits proliferation of cancer cells by binding to tubulin [ 26 ]. In addition, CTX is a substrate of P-gp , and for P-gp has a low affinity for CTX thus it does not easily cause drug resistance [ 27 , 28 ].…”

Section: Introductionmentioning

confidence: 99%

Active targeting of orthotopic glioma using biomimetic liposomes co-loaded elemene and cabazitaxel modified by transferritin

Zeng²,

You

et al. 2021

J Nanobiotechnol

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Background Effective treatment of glioma requires a nanocarrier that can cross the blood–brain barrier (BBB) to target the tumor lesion. In the current study, elemene (ELE) and cabazitaxel (CTX) liposomes were prepared by conjugating liposomes with transferrin (Tf) and embedding the cell membrane proteins of RG2 glioma cells into liposomes (active-targeting biomimetic liposomes, Tf-ELE/CTX@BLIP), which exhibited effective BBB infiltration to target glioma. Results The findings showed that Tf-ELE/CTX@BLIP was highly stable. The liposomes exhibited highly significant homologous targeting and immune evasion in vitro and a 5.83-fold intake rate compared with classical liposome (ELE/CTX@LIP). Bioluminescence imaging showed increased drug accumulation in the brain and increased tumor penetration of Tf-ELE/CTX@BLIP in orthotopic glioma model nude mice. Findings from in vivo studies indicated that the antitumor effect of the Tf-ELE/CTX@BLIP led to increased survival time and decreased tumor volume in mice. The average tumor fluorescence intensity after intravenous administration of Tf-ELE/CTX@BLIP was 65.2, 12.5, 22.1, 6.6, 2.6, 1.5 times less compared with that of the control, CTX solution, ELE solution, ELE/CTX@LIP, ELE/CTX@BLIP, Tf-ELE/CTX@LIP groups, respectively. Histopathological analysis showed that Tf-ELE/CTX@BLIP were less toxic compared with administration of the CTX solution. Conclusion These findings indicate that the active-targeting biomimetic liposome, Tf-ELE/CTX@BLIP, is a promising nanoplatform for delivery of drugs to gliomas. Graphic Abstract

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Binding modes of cabazitaxel with the different human β-tubulin isotypes: DFT and MD studies

Cited by 7 publications

References 79 publications

Identification of Regulators for Ciliary Disassembly by a Chemical Screen

Identification of Regulators for Ciliary Disassembly by a Chemical Screen

Mechanisms of Taxane Resistance

Active targeting of orthotopic glioma using biomimetic liposomes co-loaded elemene and cabazitaxel modified by transferritin

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