Rhabdoid Tumor Growth is Inhibited by Flavopiridol

Abstract

Purpose: Rhabdoid tumors are aggressive and incurable pediatric malignancies. INI1/hSNF5, a tumor suppressor biallelically deleted/inactivated in rhabdoid tumors, directly represses cyclin D1. Rhabdoid tumors and cells are exquisitely dependent on cyclin D1 for genesis and survival, suggesting that targeting the cyclin/cyclin-dependent kinase (cdk) axis may be an effective therapeutic strategy for these tumors. Because cdk inhibitors have not been used for preclinical or clinical testing on rhabdoid tumors, we investigated the effect of flavopiridol, a pan-cdk inhibitor with promising clinical activity, on rhabdoid tumors. Experimental Design: The effect of flavopiridol on rhabdoid cells was tested in vitro using survival, cell cycle, and apoptosis assays. Its effect was assessed in vivo using xenografted rhabdoid tumor models. Immunoblot and immunohistochemical analysis was used to assess the effect of flavopiridol on cyclin D1and p21expression in vitro and in vivo, respectively. Results: Nanomolar concentrations of flavopiridol inhibited rhabdoid cell growth (IC 50 f200 nmol/L), induced G 1 and G 2 arrest, and apoptosis in vitro in a concentration-dependent manner. These effects were correlated with the down-modulation of cyclin D1, up-regulation of p21, and induction of caspase 3/7 activities. Flavopiridol (at 7.5 mg/kg) significantly inhibited the growth of xenografted rhabdoid tumors, and its effect was correlated with the induction of p21 and down-modulation of cyclin D1. Conclusions: Flavopiridol is effective in inducing cell cycle arrest and cytotoxicity in rhabdoid tumors. Its effects are correlated with the down-regulation of cyclin D1and the up-regulation of p21. Flavopiridol is potentially a novel chemotherapeutic agent for rhabdoid tumors.

SMARCB1/INI1 Genetic Inactivation Is Responsible for Tumorigenic Properties of Epithelioid Sarcoma Cell Line VAESBJ

“…Fenretinide (7) and flavopiridol (8) Crystal violet relative absorbance values is significantly decreased after SMARCB1 reexpression versus control (P < 0.001). F, reduced anchorage-independent growth is evident in SMARCB1 expressing cells compared with control (P ¼ 0.019).…”

“…For comparison, selected experiments were conducted in parallel in G401 malignant rhabdoid tumor cell line ( Supplementary Fig. S3), which was previously reported to be affected by SMARCB1 restoration (7,8,20).…”

“…SMARCB1 stimulates the p16/Rb tumor suppressor pathway by activation of CDKN2A and inhibition of Cdk/cyclinD (6). As a result, in MRT cell lines, it has been shown that SMARCB1 loss is associated with responsiveness to Cdk/cyclin inhibitors, such as 4-HPR (7) and flavopiridol (8). In addition, the in vivo spontaneous tumorigenesis in SMARCB1 þ/À knockout mice is increased by TP53-null genetic background (9) and is prevented by CCND1 ablation (10), further supporting the interaction with crucial molecules controlling cell-cycle progression.…”

Aurora AIs a Repressed Effector Target of the Chromatin Remodeling Protein INI1/hSNF5 Required for Rhabdoid Tumor Cell Survival

“…Staining was conducted on paraffin sections of the following tumor samples and normal tissues: (i) 3 human AT/RTs (tbn09-5079, s99-16511, and s06-2106) and a human normal brain tissue adjacent to a tumor as a control; (ii) 2 mouse primary tumors spontaneously developed in Ini1 þ/À mice, HCP04-587E (soft tissue face tumor) and HCPO5-993#2 (brain tumor); and (iii) 1-xenografted tumor (HCPO-597-A1xB) derived from human G401 RT cells developed in the flanks [by subcutaneous injection of the cells (36). For staining INI1, a-INI1 antibodies (BD Biosciences Cat# 612110) was used.…”

The effect of the cyclin-dependent kinase inhibitor flavopiridol on anaplastic large cell lymphoma cells and relationship with NPM-ALK kinase expression and activity

“…31 Competitive inhibitors of both cell-cycle and transcriptional cdk exert a more potent antitumor activity in different preclinical models than compounds with selective cdk inhibitory activity, due perhaps to the functional compensation between cdk family members. [32][33][34][35] Tumor cells engineered to silence cdk2 do not necessarily arrest or die, as they may compensate for lower cdk2 activity with cdk1 or cdk4/6, while cell-cycle arrest caused by combined depletion of cdk1 and cdk2 likely results in cell death, occurring even more rapidly if other cdk are concomitantly impaired. [36][37][38][39] As ALCL cells proliferate rapidly and cell cycle deregulation has recently been shown to contribute to lymphomagenesis, we investigated whether targeting the cyclin/cdk axis could inhibit tumor growth, and assessed this hypothesis using the multiple cdk inhibitor flavopiridol, alone or combined with NPM-ALK kinase inhibitors.…”