Broad targeting of angiogenesis for cancer prevention and therapy

Abstract

Deregulation of angiogenesis – the growth of new blood vessels from an existing vasculature – is a main driving force in many severe human diseases including cancer. As such, tumor angiogenesis is important for delivering oxygen and nutrients to growing tumors, and therefore considered an essential pathologic feature of cancer, while also playing a key role in enabling other aspects of tumor pathology such as metabolic deregulation and tumor dissemination/metastasis. Recently, inhibition of tumor angiogenesis has become a clinical anti-cancer strategy in line with chemotherapy, radiotherapy and surgery, which underscore the critical importance of the angiogenic switch during early tumor development. Unfortunately the clinically approved anti-angiogenic drugs in use today are only effective in a subset of the patients, and many who initially respond develop resistance over time. Also, some of the anti-angiogenic drugs are toxic and it would be of great importance to identify alternative compounds, which could overcome these drawbacks and limitations of the currently available therapy. Finding “the most important target” may, however, prove a very challenging approach as the tumor environment is highly diverse, consisting of many different cell types, all of which may contribute to tumor angiogenesis. Furthermore, the tumor cells themselves are genetically unstable, leading to a progressive increase in the number of different angiogenic factors produced as the cancer progresses to advanced stages. As an alternative approach to targeted therapy, options to broadly interfere with angiogenic signals by a mixture of non-toxic natural compound with pleiotropic actions were viewed by this team as an opportunity to develop a complementary anti-angiogenesis treatment option. As a part of the “Halifax Project” within the “Getting to know cancer” framework, we have here, based on a thorough review of the literature, identified 10 important aspects of tumor angiogenesis and the pathological tumor vasculature which would be well suited as targets for anti-angiogenic therapy: (1) endothelial cell migration/tip cell formation, (2) structural abnormalities of tumor vessels, (3) hypoxia, (4) lymphangiogenesis, (5) elevated interstitial fluid pressure, (6) poor perfusion, (7) disrupted circadian rhythms, (8) tumor promoting inflammation, (9) tumor promoting fibroblasts and (10) tumor cell metabolism/acidosis. Following this analysis, we scrutinized the available literature on broadly acting anti-angiogenic natural products, with a focus on finding qualitative information on phytochemicals which could inhibit these targets and came up with 10 prototypical phytochemical compounds: (1) oleanolic acid, (2) tripterine, (3) silibinin, (4) curcumin, (5) epigallocatechin-gallate, (6) kaempferol, (7) melatonin, (8) enterolactone, (9) withaferin A and (10) resveratrol. We suggest that these plant-derived compounds could be combined to constitute a broader acting and more effective inhibitory cocktail at doses that would not be likely to caus...

Hepatocellular carcinoma is accelerated by NASH involving M2 macrophage polarization mediated by hif-1αinduced IL-10

“…43,44 Hypoxiainducible factor 1 (HIF-1) controls oxygen delivery (via angiogenesis) to cancer tissues. 45,46 Our previous data using hif-1adPA mice showed that hif-1a over-expression in hepatocytes led to increased steatosis, while hif-1a deletion in hepatocytes protected mice from alcohol-induced liver injury.…”

Nutraceuticals: Curative Integrative Cancer Treatment

“…Flavonoids are antioxidants, anti-angiogenic, anti-proliferative, active oxygen species scavengers, electrophiles, metal chelators, hydrogen peroxide producers, nitrosation inhibitors, and phase I detoxification enzyme modulators [25,26,43]. Flavones, flavanones, flavonols, flavanonols, isoflavones, flavanols, anthocyanidins and anthocyanins comprise the flavonoid category.…”

“…Anthocyanidins and anthocyanins: This group includes cyanidin, delphinidin, malvidin, peonidin, and petunidin, which are found in blueberries [43,46]. Carob fruit contains delphinidin, pelargonidin and cyanidin [47].…”

“…Apigenin and luteolin have other sources, including celery and parsley [43]. Polymethoxyflavones (PMF) are unique to citrus species' peels, thus used in TCM [52].…”

“…Flavonols: Tea is the source of several flavanols: Epicatechin (EC), epigallocatechin (EGC), epicatechin-3-gallate (ECG), EGCG, galloyl polyphenol, thearubigin, and theaflavins [43]. Green tea derived galloyl polyphenol and EGCG decrease retinoblastoma protein (Rb) phosphorylation, arresting cells in G1 phase [55].…”