Anti-angiogenic effects of purine inhibitors of cyclin dependent kinases

Abstract

Small molecular inhibitors of Cyclin dependent kinases (Cdks) are currently being developed as anticancer therapeutics due to their antiproliferative properties. The purine Cdk specific inhibitor (R)-roscovitine (seliciclib, CYC202) represents one of the most promising of these compounds. It is currently evaluated in clinical trials concerning cancer therapy. Recently, we have shown that roscovitine exerts potent antiangiogenic effects and elucidated Cdk5 as a new player in angiogenesis. These findings introduce Cdk5 as novel target for antiangiogenic therapy, and Cdk5 inhibitors as an attractive therapeutic approach. Here, we present the antiangiogenic profile of 15 derivatives of roscovitine in vitro and in vivo and provide structure activity relationships of the roscovitine analogs. The (S)-isomer LGR561 and the respective (R)- and (S)-isomers LGR848 and LGR849 strongly inhibited proliferation and cell cycle progression, induced cell death, and reduced migration of endothelial cells in vitro. In comparison to roscovitine, these compounds showed an increased potency to inhibit Cdk2, Cdk5, Cdk7, and Cdk9. By analyzing the effects of LGR561, LGR848, and LGR849 on endothelial cell tube formation, mouse aortic ring sprouting, angiogenesis in the chick chorioallantoic membrane, and neovessel formation in the mouse cornea, we elucidate the two (S)-isomers LGR561 and LGR849 as highly potent inhibitors of angiogenesis. This study provides first information on how to modify roscovitine to develop Cdk inhibitors with increased antiangiogenic activity and suggests the application of existing and the development of new Cdk inhibitors to inhibit both, cancer cell proliferation and angiogenesis.

Cdk5 controls lymphatic vessel development and function by phosphorylation of Foxc2

“…As Cdk5 is ubiquitously expressed throughout the vasculature ( Supplementary Figs 1 and 3), and our own previous studies indicated functions of Cdk5 in blood vessel endothelial cells in vitro [19][20][21] , we checked whether blood vessels were affected by endothelial Cdk5 knockdown. Although knockdown of Cdk5 by the Tie2Cre driver resulted in Cdk5 downregulation in both lymphatic as well as blood endothelial cells (Fig.…”

New Molecular Targets for Anti-Angiogenic Therapeutic Strategies

“…Given the importance of cell cycle management in the prevention of uncontrolled cell growth, studies that shed light on the function of CDKs in tumorigenesis have gained recent momentum. A number of smallmolecule inhibitors have been developed to alter the CDK deregulation that is frequently observed in human cancers (Baker, 2010;Liebl et al, 2011;Liebl et al, 2010). Success with one of the earliest CDK inhibitors, olomoucine, led to the widespread search for more specific compounds that would preclude aberrant CDK activity in tumors.…”

“…Success with one of the earliest CDK inhibitors, olomoucine, led to the widespread search for more specific compounds that would preclude aberrant CDK activity in tumors. To date, multiple CDK inhibitors have demonstrated anti-proliferative effects in cultured and xenografted myeloma, leukemia, colon cancer, lung cancer, and breast cancer cells (Baker, 2010;Liebl et al, 2011;Liebl et al, 2010). Recently, the CDK inhibitor roscovitine (Table 1), was shown to arrest human estrogen receptor alpha (ER-) positive MCF-7 breast cancer cells in the G(2) phase of the cell cycle and induce p53-dependent apoptosis (Wesierska-Gadek et al, 2011).…”

“…Recently, the CDK inhibitor roscovitine (Table 1), was shown to arrest human estrogen receptor alpha (ER-) positive MCF-7 breast cancer cells in the G(2) phase of the cell cycle and induce p53-dependent apoptosis (Wesierska-Gadek et al, 2011). Based on its anti-cancer activity both in vitro and in vivo, roscovitine is being evaluated in phase 2 clinical trials for the treatment of non-small cell lung cancer and nasopharyngeal cancer (Baker, 2010;Liebl et al, 2011;Liebl et al, 2010). Aside from its ability to impede tumor cell division, anti-angiogenic properties have also been discovered for this CDK inhibitor.…”

“…Surprisingly, only a few prior reports have denoted a role for CDKs in tumor angiogenesis. To understand the molecular basis of these cell cycle and transcriptional regulators in tumor blood vessel formation, Liebl et al, assessed the effects of CDK inhibition in human umbilical vein endothelial cells (HUVEC) (Liebl et al, 2011;Liebl et al, 2010). In response to treatment with roscovitine, endothelial migration and tubule formation was significantly reduced.…”