New Inhibitors of Angiogenesis with Antitumor Activity in Vivo

Angiogenesis is a requirement for
the sustained growth and proliferation
of solid tumors, and the development of new compounds that induce
a sustained inhibition of the proangiogenic signaling generated by
tumor hypoxia still remains as an important unmet need. In this work,
we describe a new antiangiogenic compound (22) that inhibits
proangiogenic signaling under hypoxic conditions in breast cancer
cells. Compound 22 blocks the MAPK pathway, impairs cellular
migration under hypoxic conditions, and regulates a set of genes related
to angiogenesis. These responses are mediated by HIF-1α, since
the effects of compound 22 mostly disappear when its
expression is knocked-down. Furthermore, administration of compound 22 in a xenograft model of breast cancer produced tumor growth
reductions ranging from 46 to 55% in 38% of the treated animals without
causing any toxic side effects. Importantly, in the responding tumors,
a significant reduction in the number of blood vessels was observed,
further supporting the mechanism of action of the compound. These
findings provide a rationale for the development of new antiangiogenic
compounds that could eventually lead to new drugs suitable for the
treatment of some types of tumors either alone or in combination with
other agents.