Angiogenesis an increasing interest during the past decade. It

Angiogenesis is a process of formation of new blood vessels from
pre-existing vessels. Although, it’s a physiological process in growth and
wound healing, it plays important role in pathologic condition as well, such as
tumor progression and metastasis (1-3). In fact, tumor mass above 2 to 3 mm3
needs extra vascularization due to nutrition and oxygen supplying and removal
of metabolic wastes from tumor microenvironment (1, 2). There are several steps which are essential
for angiogenesis and blood capillary formation such as endothelial cell
survival, proliferation, migration and tube formation. In addition to that, each
steps can be targeted by different anti-angiogenic compounds and the efficacy
of that will be directly related with a number of these steps being affected by
the agent. Anti-vascular
therapy and angio-prevention is a promising strategy for cancer treatment which
has been an increasing interest during the past decade. It provides the chance
of destroying of the existing tumor microvasulature and consequently makes
massive shutdown of tumor blood flow (4). Currently, there are some anti-angiogenic
agents under clinical trials which are surprisingly small molecule natural compounds
(5).  

The
genus Combretum belongs to the Combretaceae family which distributed
throughout the South Africa. Combretastatin A-4 obtained from the bark of the
South African tree “Combretum caffrum”. It is believed the first isolation from
this plant go back to 1982 by Pettit et al (6). It
is known that CA-4 as a tubulin binding agent with the ability of disruption of
microtubule formation, is one of the most prominent agent in anti-vascular
therapy. Microtubule formation is vital important for intracellular protein
trafficking, cell movement and mitotic cell division. Furthermore, CA-4 can
potentially decrease blood stream to solid tumor by binding to endothelial cell
tubulin and then leading to extensive tumor cell necrosis (7,
8). However,
while the molecular mechanism of anti-angiogenic effects of CA-4 isn’t clearly
understandable, it affects angiogenic response in different ways. CA-4 can
really has an extremely negative impact on VEGF induced endothelial cell proliferation,
migration and remodeling into capillary-like structure (tube formation) in so
far as it  plays a major role in
VEGF/VEGFR-2 signaling pathway. VEGF is one of the most potent mediator of
angiogenesis among 30 known endogenous pro-angiogenic factors. The in vivo
angiogenic response to VEGF is specially mediated through activation of VEGF
receptor 2 (VEGFR-2)8.
When VEGF binds to VEGFR-2, it might undergo phosphorylation at the surface of
endothelial cell. Then the downstream signal pathways of VEGFR-2 may be
activated and sequentially promotes angiogenesis9,10.Consequently, interruption of VEGF/VEGFR-2
signaling pathway is considered to be a promising method interfering with
stable tumor angiogenesis and tumor development. Some studies demonstrated that
CA-4 can inhibite tumor neovascularization via interference with vascular
endothelial-cadherin signaling 16. The other study which was conducted recently by Ren et al.
showed that anti-angiogenic effect of CA-4 was correlated with the Raf-MEK-ERK
and Rho/Rho kinas signaling pathways 17

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