The βI/βIII‐tubulin isoforms and their complexes with antimitotic agents

Magnani, Matteo; Ortuso, Francesco; Soro, Simonetta; Alcaro, Stefano; Tramontano, Anna; Botta, Maurizio

doi:10.1111/j.1742-4658.2006.05340.x

Cited by 57 publications

(56 citation statements)

References 34 publications

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“…Such mutations have been extensively found with epothilones in previous studies, including also the R282Q mutation (14), which is mapped directly in the drug binding site (26). No clinical studies have elucidated the frequency of point mutations in patients treated with epothilones.…”

Section: Discussionmentioning

confidence: 99%

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Molecular Mechanisms of Patupilone Resistance

et al. 2008

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Patupilone is an epothilone in advanced clinical development that has shown promising efficacy in heavily pretreated patients. This study aimed at characterizing the mechanisms of patupilone activity in resistant patients. To this end, we generated patupilone-resistant cells using two cellular models, the first characterized by high chemosensitivity and low class III B-tubulin (TUBB3) expression (A2780), and the second by low chemosensitivity and high TUBB3 expression (OVCAR-3). The obtained cell lines were named EPO3 and OVCAR-EPO, respectively. The same selection procedure was done in A2780 cells to generate a paclitaxel-resistant cell line (TAX50). Factors of resistance are expected to increase in the drugresistant cell lines, whereas factors of drug sensitivity will be down-regulated. Using this approach, we found up-regulation of TUBB3 in TAX50, but not EPO3, cells, showing that TUBB3 mediates the resistance to paclitaxel but not to patupilone. Moreover, TUBB3 was a factor of patupilone sensitivity because OVCAR-EPO cells exhibited a dramatic reduction of TUBB3 and a concomitant sensitization to hypoxia and cisplatin-based chemotherapy. To identify the mechanisms underlying patupilone resistance, tubulin genes were sequenced, thereby revealing that a prominent mechanism of drug resistance is represented by point mutations in class I B-tubulin. Overall, these results suggest that paclitaxel and patupilone have nonoverlapping mechanisms of resistance, thus allowing the use of patupilone for those patients relapsing after paclitaxel-based chemotherapy. Furthermore, patupilone represents a promising first-line option for the treatment of high-risk ovarian cancer patients, who exhibit high TUBB3 levels and poor response to standard paclitaxelplatin chemotherapy.

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Section: Discussionmentioning

confidence: 99%

“…This is supported by the dramatic reduction evident in OVCAR-EPO cells and by the reappearance of cells in which TUBB3 is newly inducible by hypoxia. In a modeling study, Magnani and colleagues (26) predicted that TUBB3 would be targeted more specifically by patupilone than by paclitaxel. Therefore, this study is in line with this model.…”

Section: Discussionmentioning

confidence: 99%

Molecular Mechanisms of Patupilone Resistance

et al. 2008

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“…The epothilones appear to decrease III-tubulin expression and restore sensitivity of tumor cells to other chemotherapeutic agents including cisplatin and taxanes. In breast cancer cells, ixabepilone appears to be less sensitive to mutational changes within the III-tubulin gene that impair taxane binding, 22 and better at suppressing the overall dynamicity of III-tubulin compared with paclitaxel non-taxane resistant breast cancer cells. Also, in vitro data suggests that ixabepilone may overcome taxane resistance in breast cancer cell lines through preferential binding to the III-tubulin isoform.…”

Section: Nsclcmentioning

confidence: 98%

Lung Cancer: Biomarkers, Tyrosine Kinase Inhibitors and Monoclonal Antibodies

Semadhi

Prasojo

Widarini

2017

Mol Cell Biomed Sci

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Lung cancer is the most contributor of cancer cause death in the world. Lung cancer is related to cigarette consumption and genetic factor. Nicotine derived nitrosamine ketone is the most important inducer of lung cancer associated with DNA Mutations resulting in the activation of Kirsten rat sarcoma viral (KRAS) oncogenes. DNA Mutation in Lung cancer is mostly presence by epidermal growth factor receptor (EGFR) mutations. There were seven potential biomarkers to detect early lung cancer, whereas carcinoembryonic antigen (CEA), neuron specific enolase (NSE), cytokeratin-19 fragments (CYFRA 21-1), alpha-fetoprotein (AFP), cancer antigen 125 (CA-125), CA-199 and ferritin. The use of biomarkers in combination can improve the accuracy in diagnosing lung cancer. Other biomarkers include KRAS mutations, B-type Raf kinase (BRAF) mutation, mesenchymal-epithelial transition factor (MET) amplification and Excision repair cross-complementing group 1 (ERCC1) can be used to see whether there are any genetic mutations that lead to lung cancer. Treatment of lung cancer with chemotherapy can be done using tyrosine kinase inhibitors and monoclonal antibodies.

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“…The configuration of the pocket binding epothilone B (patupilone) in class III beta-tubulin differs from the one present in class I beta-tubulin, the most abundantly expressed beta-tubulin (Magnani et al, 2006;Ferlini et al, 2005). Therefore, cells with high expression of class III beta-tubulin appears more sensitive to patupilone .…”

Section: Therapeutic Approaches With Class III Beta-tubulinmentioning

confidence: 99%

Class III beta-tubulin, drug resistance and therapeutic approaches in cancers

Karki¹,

Ferlini²

2014

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Class III beta-tubulin is one of the critical proteins associated with microtubule assembly, important to many cellular functions including mitochondrial respiration and intracellular trafficking. Widely regarded as a specific neuronal marker in developmental neurobiology and stem cell research, it is also highly expressed in a wide range of tumors of both neuronal and non-neuronal origin. The expression of class III beta-tubulin is tightly controlled at multiple levels with tissue-dependent mechanisms of regulation. For instance, class III beta-tubulin expression is under the control of estrogens in breast cancer cells but is influenced by exposure to hypoxia and poor-nutrient supply in ovarian cancer. In some but not all cancers, class III beta-tubulin expression is purely a prognostic biomarker, predicting poor outcome of patients regardless of chemotherapy treatment. Moreover, the expression of class III beta-tubulin does not confer an aggressive phenotype by itself. Instead, class III betatubulin functions like a cytoskeletal gateway, which enhances the incorporation of pro-survival kinases into the cytoskeleton and protects them from degradation. The associations of class III beta-tubulin with survival kinase PIM-1, RNA-binding protein HuR, microRNAs are examples highlighting the functional complexity of this protein. The utility of class III beta-tubulin as a prognostic biomarker can also greatly improve if combined with these pro-survival partners. Subsequently, pharmacogenetic approaches, designed to counteract and target these pathways and associated-factors concurrently, might lead to better therapies and prognostic tools for class III beta-tubulin expressing cancers.

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The βI/βIII‐tubulin isoforms and their complexes with antimitotic agents

Cited by 57 publications

References 34 publications

Molecular Mechanisms of Patupilone Resistance

Molecular Mechanisms of Patupilone Resistance

Lung Cancer: Biomarkers, Tyrosine Kinase Inhibitors and Monoclonal Antibodies

Class III beta-tubulin, drug resistance and therapeutic approaches in cancers

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