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Elucidation of the cell death pathways induced by aqueous‐stable Titanium(IV) compounds as potential anticancer agents
Author(s) -
Delgado Yamixa,
Vázquez Alexandra,
Kowaleff Martin,
Saxena Manoj,
Torres Zally,
Tinoco Arthur
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.609.12
Subject(s) - phosphatidylserine , chemistry , lability , apoptosis , intracellular , combinatorial chemistry , ligand (biochemistry) , cytotoxic t cell , programmed cell death , stereochemistry , biophysics , biochemistry , in vitro , membrane , receptor , biology , phospholipid
Titanium(IV)‐based compounds are excellent anticancer drug candidates with a broad spectrum of effect. Even when these compounds have excellent promise to supplant platinum‐based drugs, no compound has yet in the market due to their aqueous instability issues and lability. Recently we developed aqueous stable and cytotoxic Ti(IV) compounds by the coupling of the 3,5‐Bis(2‐hydroxyphenyl)‐1,2,4‐triazole based ligands i.e., Deferasirox( B ) , BHPT( C ) and HBED( D ). These ligands mimic the transferrin (Tf) protein metal binding site ( Figure 1A) favorable for Ti(IV) coordination facilitating the anticancer effect of the metal by preventing its lability and more importantly exhibiting higher intracellular affinity for iron. However, the cell dead pathways of these novel Ti(IV) complexes, and its cellular localization for potential therapeutic use, are still unknown. In this study our goal is elucidate the cytotoxic mechanism induced by Ti(HBED), Ti(BHPT) 2 and Ti(Def) 2 compared with their ligands. Preliminary results showed that all of our Ti compounds and ligands induce the externalization of the phosphatidylserine characteristic of the apoptotic machinery activation. Interestingly Ti(Def) 2 showed a low caspase‐3 activity, strong ROS production and membrane disruption compared to the other compounds, surprisingly even to its parent Def ligand. These results confirm our initial hypothesis that the Tf mimicking‐based Titanium(IV) ligands trigger controlled cell death and thus are very promising candidates for cancer treatment. Support or Funding Information The authors would like to thank: REU PR CLIMB (NSF Award #1560278), UPR Score, NIH SC1 (1SC1CA190504‐01), and NIH‐NIGMS (P20GM103642). 1(A) Transferrin (Tf) metal binding site comparing Ti‐bound vs Fe‐bound conformation; Chemical Tf mimetic (cTfm) 3,5‐Bis(2‐hydroxyphenyl)‐1,2,4‐triazole based ligands: (B) Def, (C) BHPT and (D) HBED. Binding atoms are labeled in red. Ti(IV) bound to all these ligands form octahedral complexes.