Combinations of pacliataxel and vinblastine and their effects on tublin polymerization and cellular cytotoxicity: Characterization of a synergistic schedule

Giannakakou, Paraskevi; Villalba, Lourdes; Li, Hang; Poruchynsky, Marianne S.; Fojo, Tito

doi:10.1002/(sici)1097-0215(19980105)75:1<57::aid-ijc10>3.0.co;2-a

Cited by 54 publications

(20 citation statements)

References 17 publications

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“…Paclitaxel binds to stabilized microtubules (Giannakakou et al, 1998) and pulls the equilibrium of microtubule formation towards the stable state, as measured by acetylated α-tubulin. Vinblastine binds to tubulin dimers (Giannakakou et al, 1998) and will bias the equilibrium towards that state. Our results indicate that low doses of paclitaxel or vinblastine (less than 0.1-0.5 nM) restored the levels of acetylated α-tubulin in patient cells to the levels found in control cells at baseline (0 nM).…”

Section: Discussionmentioning

confidence: 99%

A patient-derived stem cell model of hereditary spastic paraplegia with SPAST mutations

Abrahamsen

Fan

Matigian

et al. 2013

Disease Models &Amp; Mechanisms

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SUMMARYHereditary spastic paraplegia (HSP) leads to progressive gait disturbances with lower limb muscle weakness and spasticity. Mutations in SPAST are a major cause of adult-onset, autosomal-dominant HSP. Spastin, the protein encoded by SPAST, is a microtubule-severing protein that is enriched in the distal axon of corticospinal motor neurons, which degenerate in HSP patients. Animal and cell models have identified functions of spastin and mutated spastin but these models lack the gene dosage, mutation variability and genetic background that characterize patients with the disease. In this study, this genetic variability is encompassed by comparing neural progenitor cells derived from biopsies of the olfactory mucosa from healthy controls with similar cells from HSP patients with SPAST mutations, in order to identify cell functions altered in HSP. Patient-derived cells were similar to control-derived cells in proliferation and multiple metabolic functions but had major dysregulation of gene expression, with 57% of all mRNA transcripts affected, including many associated with microtubule dynamics. Compared to control cells, patient-derived cells had 50% spastin, 50% acetylated α-tubulin and 150% stathmin, a microtubule-destabilizing enzyme. Patient-derived cells were smaller than control cells. They had altered intracellular distributions of peroxisomes and mitochondria and they had slower moving peroxisomes. These results suggest that patient-derived cells might compensate for reduced spastin, but their increased stathmin expression reduced stabilized microtubules and altered organelle trafficking. Sub-nanomolar concentrations of the microtubule-binding drugs, paclitaxel and vinblastine, increased acetylated α-tubulin levels in patient cells to control levels, indicating the utility of this cell model for screening other candidate compounds for drug therapies.

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Section: Discussionmentioning

confidence: 99%

A patient-derived stem cell model of hereditary spastic paraplegia with SPAST mutations

Abrahamsen

Fan

Matigian

et al. 2013

Disease Models &Amp; Mechanisms

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“…This synergism is thought to be due to differences in the binding mode of the compounds and the mechanism by which they cause stabilization of the MTs. In addition, PTX and some of its derivatives can synergize with MT destabilizing agents, for example, PTX and vinorelbine [48], PTX and vinblastine when administered sequentially [49], and PTX with 2-methoxyestradiol both in vivo and in vitro [50,51]. Thus, if two compounds target tubulin at different binding sites they are more likely to synergize with one another.…”

Section: Discussionmentioning

confidence: 99%

Zampanolide, a Microtubule-Stabilizing Agent, Is Active in Resistant Cancer Cells and Inhibits Cell Migration

Field

Northcote

Paterson

et al. 2017

IJMS

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Zampanolide, first discovered in a sponge extract in 1996 and later identified as a microtubule-stabilizing agent in 2009, is a covalent binding secondary metabolite with potent, low nanomolar activity in mammalian cells. Zampanolide was not susceptible to single amino acid mutations at the taxoid site of β-tubulin in human ovarian cancer 1A9 cells, despite evidence that it selectively binds to the taxoid site. As expected, it did not synergize with other taxoid site microtubule-stabilizing agents (paclitaxel, ixabepilone, discodermolide), but surprisingly also did not synergize in 1A9 cells with laulimalide/peloruside binding site agents either. Efforts to generate a zampanolide-resistant cell line were unsuccessful. Using a standard wound scratch assay in cell culture, it was an effective inhibitor of migration of human umbilical vein endothelial cells (HUVEC) and fibroblast cells (D551). These properties of covalent binding, the ability to inhibit cell growth in paclitaxel and epothilone resistant cells, and the ability to inhibit cell migration suggest that it would be of interest to investigate zampanolide in preclinical animal models to determine if it is effective in vivo at preventing tumor growth and metastasis.

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“…For example, paclitaxel can act synergistically with vinblastine [11], and estramustine [16]. Estramustin plus vinblastine [17,18], and vinorelbine plus docetaxel [19] are more effective than either drug alone, and vinorelbine plus paclitaxel [20], and docetaxel plus CI-980 [21], are superior to single agents.…”

Section: Discussionmentioning

confidence: 99%

“…Cells were then treated with ABZ, 2ME, and their combination. After 24 hours incubation with the drugs, a quantitative tubulin polymerization assay was performed as described previously [11]. …”

Section: Methodsmentioning

confidence: 99%

Combination of Albendazole and 2-Methoxyestradiol significantly improves the survival of HCT-116 tumor-bearing nude mice

et al. 2013

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BackgroundAlbendazole (ABZ) is a microtubule-targeting anthelmintic with a remarkable activity against a variety of human cancer cells. In this study, we examined if the antitumor activity of ABZ could be enhanced by its combination with other microtubule-binding agents.MethodsThe interactions between ABZ and microtubule-binding agents, paclitaxel, vinblastine, colchicine, and 2-methoxyestradiol were characterized using median effect analysis method in HCT-116 colorectal cancer cells and DU145 prostate cancer cell line. The mechanism underlying the synergistic interaction related to tubulin polymerization and apoptosis was then investigated. Finally, the effect of the combination therapy on the survival of HCT-116 tumor-bearing nude mice was evaluated.ResultsAmong the tested drugs, a synergistic anti-proliferative effect was observed with the combination of low concentrations of ABZ plus colchicine and ABZ plus 2-methoxyestradiol (2ME). Exploring the mechanism of the interaction between ABZ and 2ME revealed that the combination therapy synergistically activated the extrinsic pathway of apoptosis. Consistent with in vitro results, the combination of low concentration of ABZ with 2ME prolonged the survival of mice-bearing HCT-116 tumors. High concentration of ABZ in combination with 2ME, however, proved to be less effective than ABZ alone.ConclusionsThe combination of low doses of ABZ and 2ME has shown promising results in our pre-clinical model. Additionally, the finding that the combination of two microtubule-binding agents that share the same binding site can act synergistically may lead to the development of new therapeutic strategies in cancer treatment.

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Combinations of pacliataxel and vinblastine and their effects on tublin polymerization and cellular cytotoxicity: Characterization of a synergistic schedule

Cited by 54 publications

References 17 publications

A patient-derived stem cell model of hereditary spastic paraplegia with SPAST mutations

A patient-derived stem cell model of hereditary spastic paraplegia with SPAST mutations

Zampanolide, a Microtubule-Stabilizing Agent, Is Active in Resistant Cancer Cells and Inhibits Cell Migration

Combination of Albendazole and 2-Methoxyestradiol significantly improves the survival of HCT-116 tumor-bearing nude mice

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