Class III β-tubulin expression and in vitro resistance to microtubule targeting agents

Stengel, Chloe; Newman, Simon P.; Leese, Mathew P.; Potter, Barry V. L.; Reed, Michael J.; Purohit, Atul

doi:10.1038/sj.bjc.6605489

Cited by 176 publications

(153 citation statements)

References 29 publications

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“…A reduction in the amount of class III b-tubulin isotype was observed in nonsmall cell lung carcinoma cells with acquired resistance to CA-4 (Wehbe et al, 2005). These findings contradict other studies demonstrating that the therapeutic efficacy of colchicine sitebinding agents is not influenced by changes in class III b-tubulin expression (Stengel et al, 2010). However, both studies support the findings that the combretastatins are active in cells overexpressing class III b-tubulin displaying resistance to paclitaxel.…”

Section: Cell Survival/resistancecontrasting

confidence: 57%

Combretastatins: More Than Just Vascular Targeting Agents?

Greene

Meegan

Zisterer

2015

J Pharmacol Exp Ther

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Several prodrugs of the naturally occurring combretastatins have undergone extensive clinical evaluation as vascular targeting agents (VTAs). Their increased selectivity toward endothelial cells together with their innate ability to rapidly induce vascular shutdown and inhibit tumor growth at doses up to 10-fold less than the maximum tolerated dose led to the clinical evaluation of combretastatins as VTAs. Tubulin is well established as the molecular target of the combretastatins and the vast majority of its synthetic derivatives. Furthermore, tubulin is a highly validated molecular target of many direct anticancer agents routinely used as front-line chemotherapeutics. The unique vascular targeting properties of the combretastatins have somewhat overshadowed their development as direct anticancer agents and the delineation of the various cell death pathways and anticancer properties associated with such chemotherapeutics. Moreover, the ongoing clinical trial of OXi4503 (combretastatin-A1 diphosphate) together with preliminary preclinical evaluation for the treatment of refractory acute myelogenous leukemia has successfully highlighted both the indirect and direct anticancer properties of combretastatins. In this review, we discuss the development of the combretastatins from nature to the clinic. The various mechanisms underlying combretastatin-induced cell cycle arrest, mitotic catastrophe, cell death, and survival are also reviewed in an attempt to further enhance the clinical prospects of this unique class of VTAs.

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Section: Cell Survival/resistancecontrasting

confidence: 57%

Combretastatins: More Than Just Vascular Targeting Agents?

Greene

Meegan

Zisterer

2015

J Pharmacol Exp Ther

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“…Although many studies have focused on paclitaxel, such characteristics might also be pertinent for docetaxel. Interestingly, recent reports further showed that βIII-tubulin confers resistance to microtubule-destabilizing agents such as vinorelbine in breast cancer cells (44). In the setting of non-small cell lung cancer, βIII-tubulin was shown to affect significantly the response to both tubulin-targeting agents and DNA-damaging agents (45).…”

Section: Discussionmentioning

confidence: 99%

Class III β-Tubulin Expression Predicts Prostate Tumor Aggressiveness and Patient Response to Docetaxel-Based Chemotherapy

et al. 2010

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Expression of class III β-tubulin (βIII-tubulin) correlates with tumor progression and resistance to taxanebased therapies for several human malignancies, but its use as a biomarker of tumor behavior in prostate cancer (PCa) remains largely unexplored. Here, we describe βIII-tubulin immunohistochemical staining patterns of prostate tumors obtained from a broad spectrum of PCa patients, some of whom subsequently received docetaxel therapy for castration-resistant PCa (CRPC). Elevated βIII-tubulin expression was significantly associated with tumor aggressiveness in PCa patients with presumed localized disease, as it was found to be an independent marker of biochemical recurrence after treatment. Additionally, βIII-tubulin expression in tumor cells was an independent predictor of lower overall survival for patients receiving docetaxel-based chemotherapy for CRPC. Manipulation of βIII-tubulin expression in human PCa cell lines using a human βIII-tubulin expression vector or βIII-tubulin small interfering RNA altered cell survival in response to docetaxel treatment in a manner that supports a role for βIII-tubulin expression as a mediator of PCa cell resistance to docetaxel therapy. Our findings suggest a role for βIII-tubulin as candidate theranostic biomarker to predict the response to docetaxel-based chemotherapy as well as to target for treatment of docetaxel-resistant CRPC.

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“…The growth inhibitory IC 50 for STX1383 and STX2171 in LNCaPwt and PC-3 prostate cancer cells plated at a density of 3500 cells/well was determined as described previously (Stengel et al 2010). A known anti-proliferative compound, STX140 (Leese et al 2006, Day et al 2009a, was included in the assay as a positive control.…”

Section: Proliferation Assaymentioning

confidence: 99%

STX2171, a 17β-hydroxysteroid dehydrogenase type 3 inhibitor, is efficacious in vivo in a novel hormone-dependent prostate cancer model

Day

Foster²,

Tutill³

et al. 2012

Endocrine-Related Cancer

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Abstract17b-Hydroxysteroid dehydrogenases (17b-HSDs) catalyse the 17-position reduction/oxidation of steroids. 17b-HSD type 3 (17b-HSD3) catalyses the reduction of the weakly androgenic androstenedione (adione) to testosterone, suggesting that specific inhibitors of 17b-HSD3 may have a role in the treatment of hormone-dependent prostate cancer and benign prostate hyperplasia. STX2171 is a novel selective non-steroidal 17b-HSD3 inhibitor with an IC 50 of w200 nM in a whole-cell assay. It inhibits adione-stimulated proliferation of 17b-HSD3-expressing androgen receptor-positive LNCaP(HSD3) prostate cancer cells in vitro. An androgen-stimulated LNCaP(HSD3) xenograft proof-of-concept model was developed to study the efficacies of STX2171 and a more established 17b-HSD3 inhibitor, STX1383 (SCH-451659, Schering-Plough), in vivo. Castrated male MF-1 mice were inoculated s.c. with 1!10 7 cells 24 h after an initial daily dose of testosterone propionate (TP) or vehicle. After 4 weeks, tumours had not developed in vehicle-dosed mice, but were present in 50% of those mice given TP. One week after switching the stimulus to adione, mice were dosed additionally with the vehicle or inhibitor for a further 4 weeks. Both TP and adione efficiently stimulated tumour growth and increased plasma testosterone levels; however, in the presence of either 17b-HSD3 inhibitor, adione-dependent tumour growth was significantly inhibited and plasma testosterone levels reduced. Mouse body weights were unaffected. Both inhibitors also significantly lowered plasma testosterone levels in intact mice. In conclusion, STX2171 and STX1383 significantly lower plasma testosterone levels and inhibit androgen-dependent tumour growth in vivo, indicating that 17b-HSD3 inhibitors may have application in the treatment of hormone-dependent prostate cancer.

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Class III β-tubulin expression and in vitro resistance to microtubule targeting agents

Cited by 176 publications

References 29 publications

Combretastatins: More Than Just Vascular Targeting Agents?

Combretastatins: More Than Just Vascular Targeting Agents?

Class III β-Tubulin Expression Predicts Prostate Tumor Aggressiveness and Patient Response to Docetaxel-Based Chemotherapy

STX2171, a 17β-hydroxysteroid dehydrogenase type 3 inhibitor, is efficacious in vivo in a novel hormone-dependent prostate cancer model

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