Identification of an α-Ketoglutarate Analogue as an Anticancer Agent

Abla, Houda (2021) Identification of an α-Ketoglutarate Analogue as an Anticancer Agent, [Dissertation thesis], Alma Mater Studiorum Università di Bologna. Dottorato di ricerca in Biologia cellulare e molecolare, 33 Ciclo. DOI 10.6092/unibo/amsdottorato/9868.
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Often correlated to a poor prognosis and increased mortality in cancer patients, hypoxic adaptation in tumors is mainly endorsed by Hypoxia Inducible Factor (HIF-1α). Under conditions of oxygen scarcity, this transcription factor triggers the expression of specific target genes implicated in glycolysis, neoangiogenesis and survival. Although hypoxia signalling constitutes an interesting target, the development of therapeutics has been limited by the high rate of drug resistance. We showed the lack of respiratory Complex I causes the accumulation of αKG associated to destabilization of HIF-1α that render cancer cells unable to adapt to hypoxia as a result of PHDs stimulation by their substrate αKG, ultimately resulting in a blocked tumor growth in vivo. This project proposes a selective metabolic approach based on the supplementation of αKG as an anticancer agent. To counter αKG limited permeability, the ketoacid was coupled to distinct hydrophobic carriers giving 7 ester analogues of αKG (αKGlogues) generated for the purpose of this study. The analogues were screened for their capacity to oppose to HIF-1α stabilisation under hypoxic conditions and to selectively hamper cancer cells growth without marked toxicity on non-cancer counterparts. This approach allowed us to select αKG-PP as a potent and safe αKGlogue since it limits HIF-1α stabilisation at long term, selectively impairs cancer cells proliferation and their in vitro tumorigenic properties while being well tolerated by the non-cancer counterparts. A synergistic effect of the hydrophobic carrier, independent of HIF-1α, was also unveiled. Metabolomics analysis revealed an intracellular peak in αKG upon treatment coupled to a rearrangement in other TCA cycle intermediates. αKG accumulation correlated with Raptor hyperphosphorylation, suggesting αKGlogue mediates its effect through the block of mTORC1 signalling and protein synthesis. In the perspective of an αKG-based anticancer therapy, the selected analogue displayed anti-proliferative properties on 3D cancer spheroids and a Drosophila melanogaster cancer model.

Tipologia del documento
Tesi di dottorato
Abla, Houda
Dottorato di ricerca
Settore disciplinare
Settore concorsuale
Parole chiave
alpha-ketoglutarate; cancer metabolism; hypoxic adaptation; tumor progression
Data di discussione
9 Giugno 2021

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