Early
attempts at using titanium compounds (derivatives of titanocene dichloride and
budotitane) as anti-cancer treatment were essentially unsuccessful. The main
reason was their rapid hydrolysis in biological media, leading to a variety of
unidentified products that hampered the elucidation of mechanistic aspects.
Lately,
we have introduced a new class of Ti(IV) complexes of “salan” type diamino
bis(phenolato) ligands. These compounds demonstrate substantially enhanced
hydrolytic stability, as well as cytotoxic activity towards a variety of cancer
cell lines in vitro including multi-drug resistant cells. The IC50
of these compounds towards murine mammary carcinoma, lymphoma, multi-drug
resistant lymphoma, as well as human leukemia, melanoma and pancreatic cancer
cell lines, is in the range of 0.6 –
5.7µM, as compared to 70-100µM of the older titanium compounds and to 50-60µM of cisplatin (Manna C.M. et al.
ChemMedChem, 7, 703 (2012)).
One
hydrolysis product of these compounds that has previously been formulated into
nanoparticles to enhance solubility and assist cellular penetration (Meker, S. et al.
Angew. Chem. Int. Ed. 51,10515 (2012)), was active both in
vitro (IC50 -0.45µM) and in vivo (50%
tumor growth inhibition) against a murine lymphoma. Such findings suggest the potential
use of solubilized active titanium compound derivatives as a new class of
anti-cancer agents. One mechanism of action involves activation of the p53
pathway followed by growth arrest at the G1 phase of the cell cycle. Additional
aspects of the molecular mechanisms of action of the above mentioned compounds
will be discussed.
Funding was received from the European
Research Council under the European Community’s Seventh Framework Progrmme
(FP7/2007-2013)/ERC Grant agreement (No.239603)
