Abstract

Ribosome-inactivating proteins (RIPs) are found in several edible plants and are well characterized. Many studies highlight their use in cancer therapy, alone or as immunoconjugates, linked to monoclonal antibodies directed against target cancer cells. In this context, we investigate the cytotoxicity of quinoin, a novel type 1 RIP from quinoa seeds, on human continuous and primary glioblastoma cell lines. The cytotoxic effect of quinoin was assayed on human continuous glioblastoma U87Mg cells. Moreover, considering that common conventional glioblastoma multiforme (GBM) cell lines are genetically different from the tumors from which they derive, the cytotoxicity of quinoin was subsequently tested towards primary cells NULU and ZAR (two cell lines established from patients’ gliomas), also in combination with the chemotherapeutic agent temozolomide (TMZ), currently used in glioblastoma treatment. The present study demonstrated that quinoin (2.5 and 5.0 nM) strongly reduced glioblastoma cells’ growth. The mechanisms responsible for the inhibitory action of quinoin are different in the tested primary cell lines, reproducing the heterogeneous response of glioblastoma cells. Interestingly, primary cells treated with quinoin in combination with TMZ were more sensitive to the treatment. Overall, our data highlight that quinoin could represent a novel tool for glioblastoma therapy and a possible adjuvant for the treatment of the disease in combination with TMZ, alone or as possible immunoconjugates/nanoconstructs.

Highlights

  • What is reported in the breast cancer cell line MCF7 and glioblastoma cell line U87-Mg, type-II Ribosome-inactivating proteins (RIPs) Riproximin showed a recovery/resistance following longer exposure periods

  • We can explain this interesting aspect with the assumption that a portion of the cell population developed a resistant mechanism to quinoin through the proposed mechanisms as previously reported [33]

  • The chemotherapeutic agent TMZ, used in current glioblastoma treatment, improves overall survival, it does not provide an effective treatment for the disease

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Summary

Introduction

Ribosome-inactivating proteins (RIPs) are a group of toxins essentially retrieved in flowering plants [1] These toxins are enzymes (N-glycosylase; EC: 3.2.2.22) able to remove a single adenine (A4324 in rat) located at a universally conserved stem and loop sequence on the large rRNA, known as the α-sarcin-ricin loop (SRL) [2]. The loss of this specific adenine causes conformational changes in the SRL structure, after which the EF-G (in prokaryotes) and eEF-2 (in eukaryotes) elongation factors are unable to interact with ribosomes during mRNA-tRNA translocation, blocking translocation during protein synthesis [3]. Type 1 RIPs are monomeric proteins (~30-kDa) with N-glycosylase activity while type 2 RIPs are dimeric proteins (~60-kDa) consisting of an enzymatic A-chain homologous to type 1 RIPs, linked through a disulphide bond to a

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