Dottore di ricerca

ciclo: XXXVI

relatore: Prof. Gianluca Canettieri
co-supervisore: Prof. Gianluca Canettieri

Titolo della tesi: Dose-dependent effect of polyamines on cancer cell proliferation and viability

Spermidine (SPD) is a polyamine that is involved in various cellular processes, including proliferation, viability, and translation. Because cancer cells contain higher concentrations of polyamines than normal cells, their biosynthesis is considered an attractive target for cancer therapy. In contrast, toxic by-products of SPD, such as aldehydes including acrolein and H2O2, have been shown to induce cytotoxicity in vitro, and recent research has reported the potential use of SPD to limit intestinal tumorigenesis in vivo (Gobert et al., 2022). Therefore, the administration of exogenous polyamines appears to induce distinct cellular outcomes in a concentration-dependent manner, although this issue has not been addressed in detail. Here, I investigated the mechanisms underlying changes in cell proliferation and viability associated with the administration of exogenous SPD in colorectal cancer cell lines. Upon polyamine depletion by difluoromethylornithine (DFMO), SPD treatment resulted in a dose-dependent, bidirectional effect. At lower doses (< 20 µM), SPD induced cell proliferation via DHPS and EIF5A hypusination. Conversely, at higher doses, SPD (> 100 µM) induced cytotoxicity independently of DHPS. Fetal bovine serum (FBS) in the culture medium was essential for the cytotoxic effect of high SPD as it contains bovine serum amine oxidase (BSAO), and the addition of exogenous BSAO, which has amine oxidase activity equivalent to that of FBS, restored SPD toxicity. Of note, the DHPS (Deoxyhypusine Synthase) inhibitor GC7 prevented the cytotoxic effect of high SPD by inhibiting BSAO in a non-competitive inhibitory manner, as evaluated by cell-free biochemical assays. Together, these results reveal the concentration-dependent survival and cytotoxic effects of SPD in cancer cells and provide a novel target for the widely used DHPS inhibitor, GC7.

Produzione scientifica

11573/1652233 - 2022 - Bovine serum amine oxidase and polyamine analogues: chemical synthesis and biological evaluation integrated with molecular docking and 3-D QSAR studies
Ragno, Rino; Anna, Minarini; Proia, Eleonora; Antonini, Lorenzo; Andrea, Milelli; Vincenzo, Tumiatti; Marco, Fiore; Fino, Pasquale; Rutigliano, Lavinia; Fioravanti, Rossella; Tahara, Tomoaki; Pacella, Elena; Greco, Antonio; Canettieri, Gianluca; Maria Luisa Di Paolo, ; Agostinelli, Enzo - 01a Articolo in rivista
rivista: JOURNAL OF CHEMICAL INFORMATION AND MODELING (AMER CHEMICAL SOC, 1155 16TH ST, NW, WASHINGTON, USA, DC, 20036) pp. 3910-3927 - issn: 1549-9596 - wos: WOS:000844671100001 (0) - scopus: 2-s2.0-85136242905 (0)

11573/1569360 - 2021 - Enzymatic spermine metabolites induce apoptosis associated with increase of p53, caspase-3 and miR-34a in both neuroblastoma cells, SJNKP and the N-Myc-amplified form IMR5
Kanamori, Yuta; Finotti, Alessia; Di Magno, Laura; Canettieri, Gianluca; Tahara, Tomoaki; Timeus, Fabio; Greco, Antonio; Tirassa, Paola; Gasparello, Jessica; Fino, Pasquale; Di Liegro, Carlo Maria; Proia, Patrizia; Schiera, Gabriella; Di Liegro, Italia; Gambari, Roberto; Agostinelli, Enzo - 01a Articolo in rivista
rivista: CELLS (Basel: mdpi-Molecular Diversity Preservation International) pp. 1950- - issn: 2073-4409 - wos: WOS:000688873300001 (8) - scopus: 2-s2.0-85115044573 (9)

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