Novel tyrosine kinase inhibitors, sorafenib and sunitinib, are able to block multiple tyrosine kinase pathways, resulting in decreases in
expression of pro-angiogenic factors, inhibition of angiogenesis, and reductions in tumor growth. Clinical trials suggest 30% to 40% partial
response rates in patients with metastatic renal cell carcinoma. It is likely that these agents will have to be combined with other agents that
target blood vessels by other mechanisms to make further gains in survival. The use of COX-2 inhibitors in benign conditions such as
arthritis have received much negative publicity for their side effects; however, their potential as anticancer agents continue to be explored.
COX-2 inhibitors can reduce endothelial proliferation. Lee et al. investigated a second potential antiangiogenic mechanism of COX-2:
endothelial cell trafﬁcking with pericytes/vascular mural cells, which is critical for vessel survival. The treatment of xenograft of Wilms
tumors with the COX-2 inhibitor SC-236 results in decreased expression of the chemokine receptor CXCR4 in tumor vessels, which is
consistent with defective homing of vascular progenitor cells, decreased phosphorylation of platelet-derived growth factor receptor, and
diminished phosphorylated Akt, indicating decreased survival signaling. Given the diverse mechanisms by which SC-236 inhibits vascular
development, there is a large potential for combining COX-2 inhibitors with the recently introduced tyrosine kinase inhibitors.
Joel W. Slaton, M.D.
Small molecules that reactivate p53 in renal cell carcinoma reveal a NF-kappaB-dependent mechanism of p53 suppression in
tumors. Gurova KV, Hill JE, Guo C, Prokvolit A, Burdelya LG, Samoylova E, Khodyakova AV, Ganapathi R, Ganapathi M, Tararova ND,
Bosykh D, Lvovskiy D, Webb TR, Stark GR, Gudkov AV, Department of Molecular Genetics, The Cleveland Clinic Foundation, Cleveland,
Proc Natl Acad Sci USA 2005;102:17448–53
Renal cell carcinomas (RCC) commonly retain wild-type but functionally inactive p53, which is repressed by an unknown dominant
mechanism. To help reveal this mechanism, we screened a diverse chemical library for small molecules capable of restoring p53-dependent
transactivation in RCC cells carrying a p53-responsive reporter. Among the compounds isolated were derivatives of 9-aminoacridine (9AA),
including the antimalaria drug quinacrine, which strongly induced p53 function in RCC and other types of cancer cells. Induction of p53
by these compounds does not involve genotoxic stress and is mediated by suppression of NF-kappaB activity. In contrast to agents that target
IkappaB kinase 2, 9AA and quinacrine can effectively suppress both basal and inducible activities of NF-kappaB, representing inhibitors
of a previously undescribed type that convert NF-kappaB from a transactivator into a transrepressor, leading to accumulation of inactive
nuclear complexes with unphosphorylated Ser-536 in the p65/RelA subunit. p53 function in RCC can be restored by ectopic expression of
a superrepressor of IkappaB as effectively as by 9AA-derived compounds. These ﬁndings suggest that the complete or partial repression
of p53 observed in many tumors can be the result of constitutive activation of NF-kappaB. The results demonstrate, in principle, the
possibility to kill cancer cells selectively through simultaneous inhibition of NF-kappaB and activation of p53 by a single small molecule
and suggest anticancer applications for the well known antimalaria drug quinacrine.
Despite the improved response rates in patients with metastatic renal cancer by the introduction of tyrosine kinase inhibitors, other
therapeutic strategies are needed for those patient who fail to respond or become resistant to these agents. The protein p53 controls genetic
stability and reduces the risk of cancer through induction of growth arrest or apoptosis in response to deoxyribonucleic acid damage or
deregulation of protooncogenes. RCC expresses wild-type p53 suppressor gene that is functionally inactive. The investigators show that
9AA, a derivative of quinacrine, can induce p53, simultaneously inhibiting NF-kappaB in renal carcinoma. The fact that quinacrine and
similar drugs have a long history of human use as anti-malaria and anti-arthritis agents, and that the drugs have favorable pharmacologic
and toxicologic properties, provides the opportunity for rapid clinical evaluation of these drugs as inhibitory agents of RCC.
Joel W. Slaton, M.D.
464 J.W. Slaton / Urologic Oncology: Seminars and Original Investigations 24 (2006) 457– 464