Cell cycle checkpoint efficiency and cellular response to paclitaxel in prostate cancer cells

Lanzi, Cinzia; Cassinelli, Giuliana; Cuccuru, Giuditta; Supino, Rosanna; Zuco, Valentina; Ferlini, Cristiano; Scambia, Giovanni; Zunino, Franco

doi:10.1002/pros.1105

Cited by 64 publications

(37 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The excellent tolerability of IDN 5390 was an unexpected finding, since in in vitro systems the derivative is only slightly less cytotoxic than PTX and the effects on tubulin polymerisation are comparable to those of PTX at equitoxic concentrations. Again, the effects of IDN 5390 and PTX on pathways involving Bcl-2 and Raf phosphorylation were comparable, thus suggesting a common mechanism of action at the cellular level, with tubulin as the primary cellular target and activation of biochemical pathways that typically characterise the cellular response to microtubule damage Lanzi et al, 2001).…”

Section: Discussionmentioning

confidence: 84%

IDN 5390: an oral taxane candidate for protracted treatment schedules

et al. 2003

View full text Add to dashboard Cite

The recognition of the antiangiogenic properties of taxanes provides a basis for novel therapeutic approaches. A prolonged exposure to low drug concentrations has been proposed to be the most suitable approach to exploit the antiangiogenic potential of cytotoxic agents. Such schedule is required to target preferentially slowly dividing endothelial cells. The protracted use of taxanes could benefit from the availability of a taxane endowed with a favourable tolerability profile. Among compounds of a novel series of C-seco taxanes, IDN 5390 was originally selected on the basis of its potent antimotility activity and poor cytotoxicity on endothelial cells. The aim of the study was to investigate the preclinical pharmacologic profile of IDN 5390 in a variety of human tumour xenografts, including ovarian and colon carcinoma and a glioblastoma. IDN 5390, delivered by s.c. injection, daily for 5 days per week, exhibited a high activity against all tumours investigated (tumour growth inhibition was always 485%) in the range of well-tolerated doses. The maximum tolerated dose/injection (MTD), with no signs of systemic or local vesicant toxicity, was 120 mg kg À1 . In contrast, paclitaxel, delivered according to the same schedule, exhibited a variable antitumour efficacy associated with a substantial local toxicity (MTD ¼ 10 mg kg À1 ). Considering the remarkable efficacy of IDN 5390 delivered s.c. by protracted treatment schedule, the oral route of administration was further investigated, as the most suitable for daily treatment. Indeed, a good bioavailability of oral IDN 5390 was found. Oral IDN 5390 maintained a substantial efficacy against human tumour xenografts, including paclitaxel-resistant tumours, without loss of potency with respect to s.c. administration. In conclusion, the therapeutic advantages of IDN 5390, over paclitaxel, in protracted daily treatment schedules are represented by the oral efficacy and the high tolerability, which are favourable features to exploit the antiangiogenic potential and to design combinations with other effective agents.

show abstract

Section: Discussionmentioning

confidence: 84%

IDN 5390: an oral taxane candidate for protracted treatment schedules

et al. 2003

View full text Add to dashboard Cite

show abstract

“…It has also been described that PC3 cells treated with 50 ng/mL of paclitaxel during 24 hours and then withdrawn exit from mitosis without cytokinesis, leading to the appearance of polyploid cells. In this context, cell death was a slow and delayed process (a sub-G 1 population appeared after 72 hours of treatment), occurring after DNA endoreduplication (27). Also, PC3 cells have been shown to exit from mitosis after a prolonged mitotic arrest induced by 150 nmol/L paclitaxel, and remained in an abnormal G 1 -like state for extended period of time (28).…”

Section: Discussionmentioning

confidence: 99%

Prostate Cancer Cell Response to Paclitaxel Is Affected by Abnormally Expressed Securin PTTG1

Castilla

Medina

et al. 2014

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

PTTG1 protein, the human securin, has a central role in sister chromatid separation during mitosis, and its altered expression has been reported in many tumor types. Paclitaxel is a widely used chemotherapeutic drug, whose mechanism of action is related to its ability to arrest cells in mitosis and the subsequent induction of the intrinsic apoptotic pathway. By using two prostate cancer cell lines with different responses to paclitaxel treatment, we have identified two situations in which PTTG1 influences cell fate differentially. In slippageprone PC3 cells, both PTTG1 downregulation and overexpression induce an increase in mitotic cells that is associated with diminished apoptosis after paclitaxel treatment. In LNCaP cells, however, PTTG1 downregulation prevents mitotic entry and, subsequently, inhibits mitosis-associated, paclitaxel-induced apoptosis. In contrast, PTTG1 overexpression induces an increase in mitotic cells and apoptosis after paclitaxel treatment. We have also identified a role for Mcl-1 protein in preventing apoptosis during mitosis in PC3 cells, as simultaneous PTTG1 and Mcl-1 silencing enhances mitosis-associated apoptosis after paclitaxel treatment. The finding that a more efficient mitotic arrest alone in PC3 cells is not enough to increase apoptosis was also confirmed with the observation that a selected paclitaxel-resistant PC3 cell line showed an apoptosis-resistant phenotype associated with increased mitosis upon paclitaxel treatment. These findings could contribute to identify putative responsive and nonresponsive cells and help us to approach incomplete responses to paclitaxel in the clinical setting. Mol Cancer Ther; 13(10); 2372-83. Ó2014 AACR.

show abstract

“…Cancer cells, in the presence of SNCG, have a reduced ability to initiate and maintain proper mitotic arrest, which leads to antimicrotubule drug resistance by premature exit, before cells initiate apoptosis. The inhibitory effect of SNCG on BubR1 function may explain the induced resistance against antimicrotubule drugs in breast (48), prostrate (49), and lung (50) cancers. However, the relationship between antimicrotubule drug resistance and SNCG is likely to be complex.…”

Section: Discussionmentioning

confidence: 99%

Synuclein γ Compromises Spindle Assembly Checkpoint and Renders Resistance to Antimicrotubule Drugs

Miao

Zhang

et al. 2014

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Defects in the spindle assembly checkpoint (SAC) have been proposed to contribute to the chromosomal instability in human cancers. One of the major mechanisms underlying antimicrotubule drug (AMD) resistance involves acquired inactivation of SAC. Synuclein g (SNCG), previously identified as a breast cancer-specific gene, is highly expressed in malignant cancer cells but not in normal epithelium. Here, we show that SNCG is sufficient to induce resistance to AMD-caused apoptosis in breast cancer cells and cancer xenografts. SNCG binds to spindle checkpoint kinase BubR1 and inhibits its kinase activity. Specifically, the C-terminal (Gln106-Asp127) of SNCG binds to the N-terminal TPR (tetratricopeptidelike folds) motif of BubR1. SNCG-BubR1 interaction induces a structure change of BubR1, attenuates its interaction with other key checkpoint proteins of Cdc20, and thus compromises SAC function. SNCG expression in breast cancers from patients with a neoadjuvant clinical trial showed that SNCG-positive tumors are resistant to chemotherapy-induced apoptosis. These data show that SNCG renders AMD resistance by inhibiting BubR1 activity and attenuating SAC function. Mol Cancer Ther; 13(3); 699-713. Ó2014 AACR.

show abstract

Cell cycle checkpoint efficiency and cellular response to paclitaxel in prostate cancer cells

Cited by 64 publications

References 37 publications

IDN 5390: an oral taxane candidate for protracted treatment schedules

IDN 5390: an oral taxane candidate for protracted treatment schedules

Prostate Cancer Cell Response to Paclitaxel Is Affected by Abnormally Expressed Securin PTTG1

Synuclein γ Compromises Spindle Assembly Checkpoint and Renders Resistance to Antimicrotubule Drugs

Contact Info

Product

Resources

About