A cytostatic ruthenium(II)-platinum(II) bis(terpyridyl) anticancer complex that blocks entry into S phase by up-regulating p27KIP1

Cytostatic agents that interfere with specific cellular components to prevent cancer cell growth offer an attractive alternative, or complement, to traditional cytotoxic chemotherapy. Here, we describe the synthesis and characterization of a new binuclear RuII-PtII complex [Ru(tpy)(tpypma)Pt(Cl)(DMSO)]3+ (tpy = 2,2':6',2''-terpyridine and tpypma = 4-([2,2':6',2''-terpyridine]-4'-yl)-N-(pyridin-2-ylmethyl)aniline), VR54, which employs the extended terpyridine tpypma ligand to link the two metal centres. VR54 binds DNA in vitro by non-intercalative reversible mechanisms (Kb = 1.3 x 105 M-1) and does not irreversibly bind guanosine. Cellular studies reveal VR54 suppresses proliferation of A2780 ovarian cancer cells with no cross-resistance in the A2780CIS cisplatin-resistant cell line. Through the preparation of mononuclear RuII and PtII structural derivatives we determine both metal centres are required for this anti-proliferative activity. In stark contrast to cisplatin, VR54 does not activate the DNA damage response network nor induces significant levels of cell death. Instead, VR54 is cytostatic and inhibits cell proliferation by up-regulating the cyclin-dependent kinase inhibitor p27KIP1 and inhibition of Rb phosphorylation; which blocks entry into S phase and results in G1 cell cycle arrest. Thus, VR54 inhibits cancer cell growth via a gain of function at the G1 restriction point. This is the first metal coordination compound to demonstrate such activity