a-Chaconine Inhibits Angiogenesis in Vitro

metabolites found in many plants, such as potatoes. Glycoalkaloids are produced in leaves, roots, tubers and sprouts of the potato plant, and are involved in host plant resistance to bacteria, fungi, viruses, and insects. Several reports have showed that glycoalkaloids suppress the growth of cancer cells in human skin, liver, prostate, breast and colon. aChaconine, a trisaccharide glycoalkaloid, is the main steroidal glycoalkaloid in potato (Solanum tuberosum). Recent studies demonstrated that a-chaconine inhibited the growth of human colon (HT29), liver (HepG2), cervical (HeLa), lymphoma (U937), and stomach (AGS and KATO III) cancer cells. a-Chaconine also induced apoptosis of human colon cancer cells through the inhibition of extracellular signal regulating kinase (ERK) phosphorylation and activation of caspase-3. In addition, a-chaconine inhibited migration and invasion of human lung adenocarcinoma A549 cells by reducing matrix metalloproteinase (MMP)-2 and MMP-9 activities through the suppression of phosphatidylinositide-3 kinase/ Akt/nuclear factor kappa B (PI3K/Akt/NF-kB) signaling pathway. Therefore, a-chaconine may possess the potential for cancer chemotherapeutic action. Angiogenesis, a process of new blood vessel formation from a pre-existing microvascular network, plays important roles in many physiological functions including wound healing, embryonic development, and the normal menstrual cycle. Angiogenesis is also involved in pathological conditions, such as ischemia, atherosclerosis, arthritis and carcinogenesis. During tumor development, newly generated vessels are necessary for supplying sufficient oxygen and nutrients to the growing tumor mass, and facilitating the metastatic spreading. The process of angiogenesis includes proliferation, migration, invasion, as well as tube formation of endothelial cells. The process of angiogenesis is promoted by expressing and secreting various proteases that can degrade most extracellular matrix (ECM) components. MMPs, a family of Zn-dependent endopeptidases, are the major proteases in angiogenesis and are closely correlated with invasive and metastatic potentials of cancer cells. Several MMPs, such as MMP-2 and MT1-MMP, are produced by endothelial cells and contribute to the process of angiogenesis. As well as MMPs, the mitogen-activated protein kinases family members (MAPK) are also known to mediate angiogenesis. MAPK family members participate in numerous signaling cascades that play important regulatory roles in cell growth, apoptosis, differentiation, and angiogenesis. The diverse MAPK members are activated in response to various extracellular stimuli and have distinct downstream targets, thus stimulating endothelial cell proliferation and protease production, and acting as positive mediators of angiogenesis. Angiogenesis is also regulated by PI3K/Akt signaling pathway, which has been implicated in a number of cellular functions including cell survival, cell adhesion and metastasis. Moreover, PI3K/Akt and MAPK signaling pathways play a central role in regulating the expression of MMPs by transcriptional factors, including NF-kB. The active NF-kB consists of a dimer of a REL family/p65 subunit and a p50 or p52 subunit. NF-kB is maintained in the cytoplasm in an inactive form, bound by inhibitory pro622 Vol. 33, No. 4