Approaches for Developing Novel Microtubule Targeting Agents (MTAs) for Therapeutic Exploitation

Krishnan, Aswini; Wilson, James M.; Leung, Hing Y.

doi:10.2174/138161212800626111

Cited by 6 publications

(6 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The observed enrichment for cell cycle-related genes, including down-regulation of expression of positive regulators of cell cycle progression, is in keeping with the known actions of docetaxel in vitro on the induction of G2/M arrest [ 5 ]. In the light of evidence suggesting that androgen withdrawal may diminish docetaxel-induced apoptosis in vitro [ 32 ], we wished to ensure that our in vivo observations were consistent with the mechanism of action of docetaxel in vitro in the absence of androgens.…”

Section: Resultssupporting

confidence: 58%

“…The anti-mitotic agent docetaxel was the first chemotherapeutic agent to demonstrate a significant survival advantage for patients with CRPCa [ 3 , 4 ]. Docetaxel stabilizes microtubules, thereby interrupting microtubule dynamics (including the mitotic spindle) causing mitotic arrest and accumulation of cells in G2/M (due to failure chromosome segregation and cytokinesis) and apoptosis [ 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Identification of a candidate prognostic gene signature by transcriptome analysis of matched pre- and post-treatment prostatic biopsies from patients with advanced prostate cancer

et al. 2014

View full text Add to dashboard Cite

BackgroundAlthough chemotherapy for prostate cancer (PCa) can improve patient survival, some tumours are chemo-resistant. Tumour molecular profiles may help identify the mechanisms of drug action and identify potential prognostic biomarkers. We performed in vivo transcriptome profiling of pre- and post-treatment prostatic biopsies from patients with advanced hormone-naive prostate cancer treated with docetaxel chemotherapy and androgen deprivation therapy (ADT) with an aim to identify the mechanisms of drug action and identify prognostic biomarkers.MethodsRNA sequencing (RNA-Seq) was performed on biopsies from four patients before and ~22 weeks after docetaxel and ADT initiation. Gene fusion products and differentially-regulated genes between treatment pairs were identified using TopHat and pathway enrichment analyses undertaken. Publically available datasets were interrogated to perform survival analyses on the gene signatures identified using cBioportal.ResultsA number of genomic rearrangements were identified including the TMPRSS2/ERG fusion and 3 novel gene fusions involving the ETS family of transcription factors in patients, both pre and post chemotherapy. In total, gene expression analyses showed differential expression of at least 2 fold in 575 genes in post-chemotherapy biopsies. Of these, pathway analyses identified a panel of 7 genes (ADAM7, FAM72B, BUB1B, CCNB1, CCNB2, TTK, CDK1), including a cell cycle-related geneset, that were differentially-regulated following treatment with docetaxel and ADT. Using cBioportal to interrogate the MSKCC-Prostate Oncogenome Project dataset we observed a statistically-significant reduction in disease-free survival of patients with tumours exhibiting alterations in gene expression of the above panel of 7 genes (p = 0.015).ConclusionsHere we report on the first “real-time” in vivo RNA-Seq-based transcriptome analysis of clinical PCa from pre- and post-treatment TRUSS-guided biopsies of patients treated with docetaxel chemotherapy plus ADT. We identify a chemotherapy-driven PCa transcriptome profile which includes the down-regulation of important positive regulators of cell cycle progression. A 7 gene signature biomarker panel has also been identified in high-risk prostate cancer patients to be of prognostic value. Future prospective study is warranted to evaluate the clinical value of this panel.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2407-14-977) contains supplementary material, which is available to authorized users.

show abstract

Section: Resultssupporting

confidence: 58%

Section: Introductionmentioning

confidence: 99%

Identification of a candidate prognostic gene signature by transcriptome analysis of matched pre- and post-treatment prostatic biopsies from patients with advanced prostate cancer

et al. 2014

View full text Add to dashboard Cite

show abstract

“…In contrast, the cells incubated with micellar formulations showed a smaller green fluorescent staining distribution and more condensed microtubules around nuclei. 42 The cells treated with DTX/XNMs exhibited the most condensed green fluorescence as they achieved the best effect on tubulin polymerization. The morphology of nuclei in cells treated with DTX-loaded nanomicelles became larger and more irregular in comparison with that of untreated cells.…”

mentioning

confidence: 92%

Effects of X-shaped reduction-sensitive amphiphilic block copolymer on drug delivery

Xiao¹,

Wang²

2015

IJN

View full text Add to dashboard Cite

To study the effects of X-shaped amphiphilic block copolymers on delivery of docetaxel (DTX) and the reduction-sensitive property on drug release, a novel reduction-sensitive amphiphilic copolymer, (PLGA) 2 -SS-4-arm-PEG 2000 with a Gemini-like X-shape, was successfully synthesized. The formation of nanomicelles was proved with respect to the blue shift of the emission fluorescence as well as the fluorescent intensity increase of coumarin 6-loaded particles. The X-shaped polymers exhibited a smaller critical micelle concentration value and possessed higher micellar stability in comparison with those of linear ones. The size of X-shaped (PLGA) 2 -SS-4-arm-PEG 2000 polymer nanomicelles (XNMs) was much smaller than that of nanomicelles prepared with linear polymers. The reduction sensitivity of polymers was confirmed by the increase of micellar sizes as well as the in vitro drug release profile of DTX-loaded XNMs (DTX/XNMs). Cytotoxicity assays in vitro revealed that the blank XNMs were nontoxic against A2780 cells up to a concentration of 50 µg/mL, displaying good biocompatibility. DTX/XNMs were more toxic against A2780 cells than other formulations in both dose- and time-dependent manners. Cellular uptake assay displayed a higher intracellular drug delivery efficiency of XNMs than that of nanomicelles prepared with linear polymers. Besides, the promotion of tubulin polymerization induced by DTX was visualized by immunofluorescence analysis, and the acceleration of apoptotic process against A2780 cells was also imaged using a fluorescent staining method. Therefore, this X-shaped reduction-sensitive (PLGA) 2 -SS-4-arm-PEG 2000 copolymer could effectively improve the micellar stability and significantly enhance the therapeutic efficacy of DTX by increasing the cellular uptake and selectively accelerating the drug release inside cancer cells.

show abstract

“…To date, none of the earlier efforts to identify a synergiser for docetaxel in prostate cancer using a candidate approach have been confirmed in patients. 27,28 We hypothesised that a drug-repurposing screen using murine prostate cancer cells harbouring genetic lesions implicated in treatment resistance may identify authentic hits that would not otherwise have been revealed using long-term cultured human cancer cell lines. The genotypes driving carcinogenesis in CP2 and SP1 cells represent a significant proportion (> 60%) of invasive prostate cancer ( Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

Repurposing screen identifies mebendazole as a clinical candidate to synergise with docetaxel for prostate cancer treatment

et al. 2019

View full text Add to dashboard Cite

BACKGROUND: Docetaxel chemotherapy in prostate cancer has a modest impact on survival. To date, efforts to develop combination therapies have not translated into new treatments. We sought to develop a novel therapeutic strategy to tackle chemoresistant prostate cancer by enhancing the efficacy of docetaxel. METHODS: We performed a drug-repurposing screen by using murine-derived prostate cancer cell lines driven by clinically relevant genotypes. Cells were treated with docetaxel alone, or in combination with drugs (n = 857) from repurposing libraries, with cytotoxicity quantified using High Content Imaging Analysis. RESULTS: Mebendazole (an anthelmintic drug that inhibits microtubule assembly) was selected as the lead drug and shown to potently synergise docetaxel-mediated cell killing in vitro and in vivo. Dual targeting of the microtubule structure was associated with increased G2/M mitotic block and enhanced cell death. Strikingly, following combined docetaxel and mebendazole treatment, no cells divided correctly, forming multipolar spindles that resulted in aneuploid daughter cells. Liposomes entrapping docetaxel and mebendazole suppressed in vivo prostate tumour growth and extended progression-free survival. CONCLUSIONS: Docetaxel and mebendazole target distinct aspects of the microtubule dynamics, leading to increased apoptosis and reduced tumour growth. Our data support a new concept of combined mebendazole/docetaxel treatment that warrants further clinical evaluation.

show abstract

Approaches for Developing Novel Microtubule Targeting Agents (MTAs) for Therapeutic Exploitation

Cited by 6 publications

References 0 publications

Identification of a candidate prognostic gene signature by transcriptome analysis of matched pre- and post-treatment prostatic biopsies from patients with advanced prostate cancer

Identification of a candidate prognostic gene signature by transcriptome analysis of matched pre- and post-treatment prostatic biopsies from patients with advanced prostate cancer

Effects of X-shaped reduction-sensitive amphiphilic block copolymer on drug delivery

Repurposing screen identifies mebendazole as a clinical candidate to synergise with docetaxel for prostate cancer treatment

Contact Info

Product

Resources

About