The Seco-Taxane IDN5390 Is Able to Target Class III β-Tubulin and to Overcome Paclitaxel Resistance

Ferlini, Cristiano; Raspaglio, Giuseppina; Mozzetti, Simona; Cicchillitti, Lucia; Filippetti, Flavia; Gallo, Daniela; Fattorusso, Caterina; Campiani, Giuseppe; Scambia, Giovanni

doi:10.1158/0008-5472.can-04-3065

Cited by 100 publications

(56 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It has been reported that selective in vitro pressure by antitubulin agents is able to force tumor cells to develop drug resistance by overexpressing h III tubulin isotype (10,12,32). Conversely, we observed a decrease in the percentage of h III tubulin positivity in posttreatment tissue samples regardless of response to chemotherapy.…”

Section: Discussioncontrasting

confidence: 61%

Class III β-Tubulin Overexpression Is a Marker of Poor Clinical Outcome in Advanced Ovarian Cancer Patients

Ferrandina

Zannoni²,

Martinelli

et al. 2006

Clinical Cancer Research

Self Cite

214

171

View full text Add to dashboard Cite

Purpose: Overexpression of h III tubulin has been involved in paclitaxel resistance in several experimental models. We investigated the role of h III tubulin as predictor of clinical outcome in ovarian cancer patients given platinum/paclitaxel treatment. We also investigated whether h III tubulin expression could be modified after the selective pressure represented by chemotherapy in vivo. Experimental Design: The study was designed to include a series of consecutive ovarian cancer patients with unresectable disease at time of first surgery, who underwent interval debulking surgery with pathologic assessment of response to treatment with platinum/ paclitaxel chemotherapy. Immunostaining was done on formalin-fixed, paraffin-embedded tissue sections from pretreatment and posttreatment tissue biopsies by using the polyclonal rabbit anti^class III h-tubulin antibody. Results: h III Tubulin immunoreaction was observed in 51 of 62 (82.2%) cases. h III Tubulin positivity was neither associated with clinicopathologic variables nor with pathologic response to chemotherapy. Significantly lower percentages of h III tubulin positivity were observed in posttreatment (range, 5-80%; median, 20%) versus pretreatment (range 10-100%; median, 40%) tissue biopsies (P = 0.0011). Cases with high h III tubulin expression showed a worse overall survival with respect to cases with low h III tubulin expression (median overall survival, 25 versus 46 months; P = 0.002). Multivariate analysis showed that high content of h III tubulin remains independently associated with a worse prognosis. Conclusions: Assessment of h III tubulin could be useful to identify poor prognosis ovarian cancer patients candidates to more aggressive and/or targeted therapy.

show abstract

Section: Discussioncontrasting

confidence: 61%

Class III β-Tubulin Overexpression Is a Marker of Poor Clinical Outcome in Advanced Ovarian Cancer Patients

Ferrandina

Zannoni²,

Martinelli

et al. 2006

Clinical Cancer Research

Self Cite

214

171

View full text Add to dashboard Cite

show abstract

“…Orobol suppressed all isotypes of ß-tubulin with the strongest effect on ß4a and caused the structural changes in microtubles resulting in increased levels of apoptosis although the rate of apoptotic cells did not correspond well to the level of the orobolsensitization effect. While ß3 tubulin overexpression is highlighted in PX-resistant cells in some studies (25)(26)(27), the lower level of ß1, ß3 and ß4a in PX-sensitive cells is consistent with the data of Kavallaris et al (12) and Shalli et al (28). They documented that PX-resistant cells displayed a significant increase in ß1, ß3, and ß4a isotypes.…”

Section: Discussionsupporting

confidence: 83%

Differential regulation of the cytotoxicity activity of paclitaxel by orobol and platelet derived growth factor in human ovarian carcinoma cells

Isonishi

Saitou²,

Yasuda³

et al. 2007

Oncol Rep

View full text Add to dashboard Cite

Abstract. Paclitaxel (PX) binds to and stabilizes tubulin, preventing depolymerization, and resulting in cell death. Based on a previous report showing the activity of phosphatidylinositol kinase (PIK) on tubulin, we investigated the effect of the PI4K inhibitor orobol and the PI3K activator platelet derived growth factor (PDGF) on PX sensitivity. Drug sensitivity was examined by classical colony forming assay. Tubulin isotype expression was determined by semiquantitative RT-PCR. Microtubule texture was observed by laser confocal microscope using anti-ß-tubulin antibody. Apoptotic activity was estimated by frequency of condensed nuclear chromatin with Hoechst 33342 stain. Orobol enhanced PX sensitivity of human ovarian carcinoma 2008 cells by 18.9±1.2-fold (N=3; P<0.01). In contrast, pretreatment with PDGF rendered cells resistant to PX by 2.3±0.4-fold (N=3; P<0.01). Neither orobol nor PDGF showed any effect on cell growth. Orobol produced a 2.5-fold sensitization in cisplatinresistant 2008/C13 * 5.25 (C13) cells, and PDGF rendered the cells 2.3-fold resistant to PX. Orobol suppressed the ß4a-tubulin isotype expression by 85% and other isotypes by 20%. In contrast, PDGF induced ß4a-tubulin isotype expression by 1.3-fold, while it supressed all the other isotypes by 20-40%. Orobol produced thick microtubules and PDGF generated ring condensed microtubules. Orobol promoted PX-induced apoptosis, while PDGF caused 50% reduction of apoptosis. These results indicate that orobol and PDGF regulate PX sensitivity by reciprocally altering the proportion of tubulin isotype expression and PX-induced apoptotic signaling. IntroductionThe antimicrotubule agent paclitaxel (PX) has shown some efficacy in the treatment of ovarian and metastatic breast cancers, and particularly encouraging is its utility in advanced ovarian cancers that are refractory to DNA damage-based chemotherapy (1). In contrast to tubulin depolymerizing toxins such as nocodazole or colcemid, PX stabilizes microtubule formation and, in continuous treatment, it prevents completion of mitosis, resulting in cell-cycle blockage in mitosis and activation of apoptosis. PX reversibly binds to microtubules in vitro and apparently does not bind to free tubulin (2,3). PX strongly stimulates the rate and extent of microtubule polymerization and reduces the concentration of soluble tubulin (4). Additionally, PX also inhibits tubulin exchange at microtubule ends and reduces the fluxral rigidity of them (5). At subnanomolar concentrations, PX suppresses microtubule dynamics by affecting shortening of microtubules (6). At higher concentrations, PX suppresses dynamics by inhibiting the growing and shortening of microtubules (7). Little is known about how microtubule dynamics are regulated in cells. In vitro and in cells, microtubule ends switch between states of growing and shortening, a process known as 'dynamic instability', apparently due to the gain and loss of a stabilizing GTP-or GDP-Pi-liganded tubulin cap at the microtubule ends. Net growing of microtubules can occur ...

show abstract

“…Therefore, TUBB3 appears an attractive target and TUBB3 targeting agents could improve our therapeutic arsenal against drug resistance. A first example of this is represented by the seco-taxane IDN5390, a compound able to selectively target TUBB3 (9). This drug exhibits unique properties of cytotoxic, antiangiogenic agent and inhibitor of cell motility (10) and is currently undergoing preclinical development.…”

Section: Introductionmentioning

confidence: 99%

From plasma membrane to cytoskeleton: a novel function for semaphorin 6A

Prislei¹,

Mozzetti²,

Filippetti

et al. 2008

Molecular Cancer Therapeutics

Self Cite

View full text Add to dashboard Cite

Class III B-tubulin (TUBB3) overexpression has been reported in ovary, lung, breast, and gastric cancer patients. Currently, no clinical drugs are available for a specific targeting of TUBB3, whereas the investigational drug IDN5390 specifically interacts with TUBB3. To gain insight into the pathways leading to TUBB3 up-regulation, we did a human genome microarray analysis in A2780 cells made resistant to IDN5390 to identify selected pathways specifically disrupted in resistant cells. Using this approach, we discovered that semaphorin 6A (SEMA6A) is down-regulated not only in IDN5390-resistant cells but also in cells made resistant to cisplatin, topotecan, and doxorubicin, whereas no changes were noticed in paclitaxel-and gemcitabine-resistant cells. Acute treatment with IDN5390 was able to down-regulate SEMA6A in cells unselected for drug resistance. TUBB3 expression was assessed in A2780 clones with stable overexpression of SEMA6A and in a panel of clones in which silencing of the protein was obtained. Quantitative PCR was then used to check the modulation of SEMA6A as well as to assess the expression of TUBB3. TUBB3 was increased (median value, 5.4) and reduced (median value, 0.47) in cells with overexpression and silencing of SEMA6A, respectively. Thus, the findings indicate a correlation between the expression of SEMA6A and TUBB3. Then, we found that a form of 83 kDa of SEMA6A is expressed in the cytoskeleton in association with B-actin. These findings suggest for SEMA6A a novel function in the cytoskeleton and a role in modulating tubulin isotype composition and microtubule dynamics.

show abstract

The Seco-Taxane IDN5390 Is Able to Target Class III β-Tubulin and to Overcome Paclitaxel Resistance

Cited by 100 publications

References 26 publications

Class III β-Tubulin Overexpression Is a Marker of Poor Clinical Outcome in Advanced Ovarian Cancer Patients

Class III β-Tubulin Overexpression Is a Marker of Poor Clinical Outcome in Advanced Ovarian Cancer Patients

Differential regulation of the cytotoxicity activity of paclitaxel by orobol and platelet derived growth factor in human ovarian carcinoma cells

From plasma membrane to cytoskeleton: a novel function for semaphorin 6A

Contact Info

Product

Resources

About