1. Autophagic flux blockage by accumulation of weakly basic tenovins leads to elimination of B-Raf mutant tumour cells that survive vemurafenib.
- Author
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Ladds MJGW, Pastor-Fernández A, Popova G, van Leeuwen IMM, Eng KE, Drummond CJ, Johansson L, Svensson R, Westwood NJ, McCarthy AR, Tholander F, Popa M, Lane DP, McCormack E, McInerney GM, Bhatia R, and Laín S
- Subjects
- Antineoplastic Agents chemistry, Benzamides chemistry, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Drug Resistance, Neoplasm drug effects, Drug Synergism, Gene Expression Regulation, Neoplastic drug effects, Humans, Melanoma drug therapy, Molecular Structure, Mutation, Sirtuins genetics, Tumor Suppressor Protein p53 genetics, Vemurafenib, Antineoplastic Agents pharmacology, Autophagy drug effects, Benzamides pharmacology, Indoles pharmacology, Melanoma genetics, Proto-Oncogene Proteins B-raf genetics, Sulfonamides pharmacology
- Abstract
Tenovin-6 is the most studied member of a family of small molecules with antitumour activity in vivo. Previously, it has been determined that part of the effects of tenovin-6 associate with its ability to inhibit SirT1 and activate p53. However, tenovin-6 has also been shown to modulate autophagic flux. Here we show that blockage of autophagic flux occurs in a variety of cell lines in response to certain tenovins, that autophagy blockage occurs regardless of the effect of tenovins on SirT1 or p53, and that this blockage is dependent on the aliphatic tertiary amine side chain of these molecules. Additionally, we evaluate the contribution of this tertiary amine to the elimination of proliferating melanoma cells in culture. We also demonstrate that the presence of the tertiary amine is sufficient to lead to death of tumour cells arrested in G1 phase following vemurafenib treatment. We conclude that blockage of autophagic flux by tenovins is necessary to eliminate melanoma cells that survive B-Raf inhibition and achieve total tumour cell kill and that autophagy blockage can be achieved at a lower concentration than by chloroquine. This observation is of great relevance as relapse and resistance are frequently observed in cancer patients treated with B-Raf inhibitors.
- Published
- 2018
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