Sorafenib was the first small

Sorafenib was the first small RTK inhibitor drug to be developed and was initially approved against renal cell carcinoma, then against hepatocellular carcinoma (HCC) and more recently for differentiated thyroid treatment [111]. Sunitinib soon followed, being approved for gastrointestinal stromal tumors, rare stomach cancers and renal cell carcinoma [106], [112]. Other RTK inhibitors approved for antiangiogenic clinical use includes: pazopanib, approved against advanced renal cell carcinoma and soft tissue sarcoma; vandetanib, approved against advanced medullary thyroid cancer situations that cannot be removed by surgery; carbozoantinib also approved against medullary thyroid cancer and renal cell carcinoma and vandetanib, approved against medullary thyroid cancer [107]. Thalidomide is a drug used for several decades for the treatment of various diseases, but was only approved as an anticancer drug in 2006, being approved against multiple myeloma. The precise mechanism of its antiangiogenic activity was not yet fully elucidated, although several activities that probably account for its activity, including TNF-α, IL-6 Wortmannin receptor inhibition and NF-κB and COX-2 direct inhibition, were observed [113]. Lenalodomide belongs to the same type of inhibitors as thalidomine, being also used against multiple myeloma by inhibiting VEGF expression (Table 1) [114]. Despite the various molecules involved in the angiogenic process, most of these drugs have greater affinity for acting on tyrosine kinases, particularly the VEGF and respective receptor [104], [105]. For example, bevacizumab is a monoclonal antibody that specifically recognize and binds to VEGF, making this growth factor unable to activate the receptor [108]. Other inhibitors bind to receptors, at the surface of endothelial cells, or to other proteins in the downstream signaling pathways that block their activities [112]. A common problem when using antiangiogenic drugs is the common situation of drug resistance. Although initially there is a positive response to the drugs, and the tumor angiogenesis is blocked, eventually the tumor acquires resistance and circumvents the pathway that is blocked, normally the VEGF/VEGFR2 target pair. Resistance is usually acquired when the tumor is able to growth, by enabling VEGF/VEGFR-2 independent pathways, thus promoting tumor angiogenesis [112]. An alternative to overcome the antiangiogenic drugs resistance is by their combination with other conventional therapies, including chemotherapy or radiation [19]. Combined therapies may have a synergistic effect when compared to the single drug therapies [115]. For example, bevacizumab sometimes is used with other drugs such as 5-fluorouracil or chemotherapy, to enhance treatment against various types of cancers [116]. Another factor to highlight is the toxicity that antiangiogenic drugs have in the body, contributing to side effects and leading sometimes to serious injuries [112]. The more common effects experienced by patients are hypertension, diarrhea, decrease of white blood cells, fatigue, taste modification and appetite reduction, weight loss, nausea, abdominal pain, skin reactions and hypocalcemia [110], [112], [117], and more frequent complications include hepatic toxicity, arterial and venous thrombotic events, gastric cancer and stroke [110], [112]. Still, each drug is administered to different types of cancer and at distinct doses among patients, they result in more or fewer side effects in the body. In this sense, it becomes essential to develop new drugs with lower or no toxicity, and with the ability to prevent pathological angiogenesis [19]. Researchers have thus focused in antiangiogenic molecules that occur naturally in plants. These compounds are accessible, have low or minimal toxicity, and have been traditionally used for many years in the treatment of various diseases [47].
Natural sources of antiangiogenic compounds