NDUFS3 knockout cancer cells and molecular docking reveal specificity and mode of action of anti-cancer respiratory complex I inhibitors.
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| Abstract |
Inhibition of respiratory complex I (CI) is becoming a promising anti-cancer strategy, encouraging the design and the use of inhibitors, whose mechanism of action, efficacy and specificity remain elusive. As CI is a central player of cellular bioenergetics, a finely tuned dosing of targeting drugs is required to avoid side effects. We compared the specificity and mode of action of CI inhibitors metformin, BAY 87-2243 and EVP 4593 using cancer cell models devoid of CI. Here we show that both BAY 87-2243 and EVP 4593 were selective, while the antiproliferative effects of metformin were considerably independent from CI inhibition. Molecular docking predictions indicated that the high efficiency of BAY 87-2243 and EVP 4593 may derive from the tight network of bonds in the quinone binding pocket, although in different sites. Most of the amino acids involved in such interactions are conserved across species and only rarely found mutated in human. Our data make a case for caution when referring to metformin as a CI-targeting compound, and highlight the need for dosage optimization and careful evaluation of molecular interactions between inhibitors and the holoenzyme.
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| Authors | Ivana Kurelac, Beatrice Cavina, Manuela Sollazzo, Stefano Miglietta, Agnese Fornasa, Monica De Luise, Maria Iorio, Eleonora Lama, Daniele Traversa, Hamid Razi Nasiri, Anna Ghelli, Francesco Musiani, Anna Maria Porcelli, Luisa Iommarini, Giuseppe Gasparre |
| Journal | Open biology (Open Biol) Vol. 12 Issue 11 Pg. 220198 (11 2022) ISSN: 2046-2441 [Electronic] England |
| PMID | 36349549 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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