Zoledronic acid is unable to induce apoptosis, but slows tumor growth and prolongs survival for non-small-cell lung cancers

Baumgart

Journal of Biological Chemistry

et al. 2011

The aminobisphosphonate zoledronic acid has elicited significant attention due to its remarkable anti-tumoral activity, although its detailed mechanism of action remains unclear. Here, we demonstrate the existence of a nuclear GSK-3␤-NFATc2 stabilization pathway that promotes breast and pancreatic cancer growth in vitro and in vivo and serves as a bona fide target of zoledronic acid. Specifically, the serine/threonine kinase GSK-3␤ stabilizes nuclear NFATc2 through phosphorylation of the serine-rich SP2 domain, thus protecting the transcription factor from E3-ubiquitin ligase HDM2-mediated proteolysis. Zoledronic acid disrupts this NFATc2 stabilization pathway through two mechanisms, namely GSK-3␤ inhibition and induction of HDM2 activity. Upon nuclear accumulation, HDM2 targets unphosphorylated NFATc2 for ubiquitination at acceptor lysine residues Lys-684/Lys-897 and hence labels the factor for subsequent proteasomal degradation. Conversely, mutagenesis-induced constitutive serine phosphorylation (Ser-215, Ser-219, and Ser-223) of the SP2 domain prevents NFATc2 from HDM2-mediated ubiquitination and degradation and consequently rescues cancer cells from growth suppression by zoledronic acid. In conclusion, this study demonstrates a critical role of the GSK-3␤-HDM2 signaling loop in the regulation of NFATc2 protein stability and growth promotion and suggests that double targeting of this pathway is responsible, at least to a significant part, for the potent and reliable anti-tumoral effects of zoledronic acid.

mentioning

confidence: 65%

Disruption of a Nuclear NFATc2 Protein Stabilization Loop Confers Breast and Pancreatic Cancer Growth Suppression by Zoledronic Acid

Baumgart

Journal of Biological Chemistry

et al. 2011

Biochemical Pharmacology

“…These authors showed that reduction in prostate cell growth was mainly mediated by cell cycle prolongation. Other two papers related to breast and lung cancer [50,51] [38,39]. A few years ago it was reported that the enhanced Bcl-2 expression alters the threshold for apoptosis in a cholangiocarcinoma cell line [52].…”

Section: Discussionmentioning

confidence: 99%

Zoledronic acid determines S-phase arrest but fails to induce apoptosis in cholangiocarcinoma cells

Romani

Desenzani

Morganti

et al. 2009

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. In conclusion, our study indicates that zoledronic acid induces S-phase arrest and cell-narrowing, both reversed by GGOH and, by changing the delicate balance between pro-apoptotic and antiapoptotic proteins, allows survival of cholangiocarcinoma cells.

“…2A). The model is based on established pharmacodynamics and known effects of each of the agents [21][22][23][24][25][26][27][28][29] on the cell cycle for 10 tumor types [31][32][33][34][35][36][37][38] and for erythroblasts 39 (erythroblasts have the highest proliferative index of marrow (Fig. 2B).…”

Section: Drug Selectionmentioning

confidence: 99%

Novel phase I study combining G1 phase, S phase, and G2/M phase cell cycle inhibitors in patients with advanced malignancies

et al. 2015

PURPOSE:Cancer is a manifestation of aberrant cellular proliferation, and the cell cycle is one of the most successfully drugged targets in oncology. No prior study has been reported that simultaneously targets the 3 principal cell cycle phases populated by proliferating cells -G 1 , S, and G 2 /M.METHODS: Temsirolimus (G 1 inhibitor), topotecan (S inhibitor), and bortezomib (G 2 /M inhibitor) were administered in combination to patients with advanced malignancies using a 3+3 dose escalation schedule to assess the safety and establish the maximum tolerated dose (primary endpoints) of this cell cycle targeting approach. An in silico pharmacodynamic model using established effects of each of these agents on the cell cycle was used to validate the regimen and to guide the dosing regimen.RESULTS: Sixty-two subjects were enrolled. The most common adverse events and dose-limiting toxicities were cytopenias, consistent with the cell cycle targeting approach employed. All cytopenias resolved to baseline values upon holding study drug administration. The maximum tolerated dose was temsirolimus 15 mg/kg IV D1, 8, 15; topotecan 2.8 mg/m 2 IV D1, 8; and bortezomib 0.9 mg/m 2 IV D1, 4, 8, 11 of a 21-day cycle. In silico modeling suggests the regimen induces cell population shifts from G 2 /M and S phases to G 1 phase and the quiescent G 0 phase. Eighteen percent of subjects (11/62) achieved partial response (n D 2, serous ovarian and papillary thyroid) or stable disease for > 6 months (n D 9).