Ranpirnase Interferes with NF- B Pathway and MMP9 Activity, Inhibiting Malignant Mesothelioma Cell Invasiveness and Xenograft Growth

Abstract

The ribonuclease ranpirnase (Onconase) has been used empirically to treat malignant mesothelioma (MM) patients, and some of them had prolonged survivals. The aim of this study was to investigate the mechanisms of the therapeutic function of ranpirnase in MM cells. The effects of ranpirnase were studied in vivo and in vitro on 2 MM cell lines (epithelioid REN and sarcomatoid PPM-Mill). We found that ranpirnase was able to inhibit NF-κB nuclear translocation, evaluated by cell fractionation and immunoblotting as well as by immunofluorescence. Also, MMP9 secretion by MM cells was decreased by ranpirnase treatment, as assessed by the reduction of metalloproteinase activity, evaluated by zymography on culture-conditioned media. Ranpirnase induced apoptosis of MM cells in vitro and in vivo, causing a powerful inhibition of MM tumor growth in SCID xenografts, determined by In Vivo Imaging System (IVIS) of tumor cells engineered by lentiviral transduction of the luciferase gene. Finally, mice treated with ranpirnase showed a significantly prolonged survival. Our data provide a mechanistic rationale to explain the beneficial antitumor activity observed in some patients treated with ranpirnase and demonstrate that ranpirnase interferes with the NF-κB pathway, thus influencing MM tumor cell invasiveness and survival. It is hoped that this information will also facilitate the identification of those patients who are more likely to benefit from this drug and will also open a new frontier for the use of this drug in tumor types other than MM.

Mesothelin Overexpression Promotes Mesothelioma Cell Invasion and MMP-9 Secretion in an Orthotopic Mouse Model and in Epithelioid Pleural Mesothelioma Patients

“…These data provide evidence that MSLN promotes MMP secretion contributing to tumor aggressiveness. A recent report further highlights the role of MMP-9-mediated invasion in MPM and the beneficial therapeutic efficacy of suppressing MMP-9 expression(42). In addition to MMP-9, we have observed increased in vitro secretion of MMP 1, 2, and 7 with MSLN overexpression – consistent with published observations that in promoting cancer cell invasion MMPs can influence each other directly(41, 43).…”

Designing Hybrid Onconase Nanocarriers for Mesothelioma Therapy: A Taguchi Orthogonal Array and Multivariate Component Driven Analysis

“…6 It has been reported previously that ONC is a potent inhibitor of TNF-a dependent NF-κB activity in MM cells. 5 ONC inhibited NF-κB activity and MMP9 secretion, which induced apoptosis in MM cells and decreased MM invasion. 5 Moreover, it was found that ONC inhibited MM tumor growth in a severe combined immunodeficiency (SCID) xenograft mouse model.…”

“…5 ONC inhibited NF-κB activity and MMP9 secretion, which induced apoptosis in MM cells and decreased MM invasion. 5 Moreover, it was found that ONC inhibited MM tumor growth in a severe combined immunodeficiency (SCID) xenograft mouse model. 5 These unique mechanisms of action of ONC together with a lack of immunogenicity make ONC a promising alternative to current chemotherapies for MM therapy.…”

Recombinant expression, different downstream processing of the disulfide-rich anti-tumor peptide Ranpirnase and its effect on the growth of human glioma cell line SHG-44

“…1). Ranpirnase is the smallest member of the ribonuclease (RNase A) superfamily, and appears to be a promising drug with broad clinical application in tumor treatment due to its moderate cytotoxicity, unique synergy, low immunogenicity and few side effects (1)(2)(3)(4)(5)(6)(7)(8)(9)(10). Between 1996 and 2004, Tamir Biotechnology, Inc. (formerly Alfacell Corporation) successively conducted clinical investigations regarding the effects of ranpirnase on breast cancer, pancreatic cancer, renal cell carcinoma, non-small cell lung cancer and malignant mesothelioma, for which the therapeutic effect was the most significant with few side effects.…”