NSC348884, a nucleophosmin inhibitor disrupts oligomer formation and induces apoptosis in human cancer cells

Abstract

Nucleophosmin (NPM), a multifunctional nucleolar phosphoprotein is dysregulated in human malignancies leading to anti-apoptosis and inhibition of differentiation.We evaluated the precise three-dimensional structure of NPM based on the highly conserved structure of Xenopus NO38 and its requirement to form dimers and pentamers via its N-terminal domain (residues, 1-107). We hypothesized that a small molecular inhibitor (SMI) that could disrupt the formation of dimers would inhibit aberrant NPM function(s) in cancer cells. Molecular modeling, pharmacophore design, in silico screening and interactive docking identified NSC348884 as a putative NPM SMI that disrupts a defined hydrophobic pocket required for oligomerization. NSC348884 inhibited cell proliferation at an IC 50 of 1.7-4.0 lM in distinct cancer cell lines and disrupted NPM oligomer formation by native polyacrylamide gel electrophoresis assay. Treatment of several different cancer cell types with NSC348884 upregulated p53 (increased Ser15 phosphorylation) and induced apoptosis in a dose-dependent manner that correlated with apoptotic markers: H2AX phosphorylation, poly(ADPribose) polymerase cleavage and Annexin V labeling. Further, NSC348884 synergized doxorubicin cytotoxicity on cancer cell viability. The data together show that NSC348884 is an SMI of NPM oligomer formation, upregulates p53, induces apoptosis and synergizes with chemotherapy. Hence, an SMI to NPM may be a useful approach to anticancer therapy.

RNA aptamers interfering with nucleophosmin oligomerization induce apoptosis of cancer cells

“…Similar to our findings, Qi et al (2008) have identified a small molecule, NSC348884, as an NPM inhibitor. Although NSC348884 possibly binds to the N terminus of NPM, which is different from where NPM aptamers bind to, it can disrupt NPM oligomerization and cause an upregulation of p53 as do NPM aptamers.…”

Nucleolar stress is an early response to myocardial damage involving nucleolar proteins nucleostemin and nucleophosmin

“…This result validates the importance of NS and NPM in regulating rRNA biogenesis and controlling p53 pathway. Pharmacologic inhibition of NPM with NSC348884 (NPMi), previously reported to induce apoptosis in cancer cells (33), also significantly increases apoptosis in NRCMs (Fig. 3C), thus confirming a key role of NPM for cell survival.…”

A Simple Approach to Cancer Therapy Afforded by Multivalent Pseudopeptides That Target Cell-Surface Nucleoproteins

“…Studies using a peptide derived from Rev protein, which binds nucleophosmin, suppressed tumor growth through apoptosis by upregulating the transcriptional activity of p53. Recently, NSC348884, a pharmacophore that targets nucleophosmin, has been shown to inhibit the proliferation of various cancer cell lines through the induction of apoptosis (35). Likewise, it has been shown that C in the presence of 0.02% sodium azide and then fixed with methanol.…”

“…This stretch of basic residues interacts with the N-terminal globular domain of nucleophosmin, which has been shown to be involved in nucleophosmin pentamer formation and chaperone activity. It is noteworthy that molecules that interact with the N-terminal domain of nucleophosmin, such as the Rev peptide (37) or the small molecule NSC 348884 (35), disrupt nucleophosmin oligomer formation and induce apoptosis. From this set of results, we can hypothesize that N6L, which is a pseudopeptide rich in Lys and Arg residues and displays high affinity for nucleophosmin, disrupts its oligomerization and/or the formation of complexes between nucleolin, nucleophosmin, and oncoproteins.…”