PEER-REVIEWED ARTICLE
Antiangiogenic Phytochemicals Best Poised for Clinical Trial Testing A literature review of the most promising natural agents for treating cancer ABSTRACT
Angiogenesis is a normal physiological process involving the production and organization of blood vessels, a process required for wound healing and general health maintenance. In the case of cancer, however, the angiogenic process becomes an enabling characteristic that allows tumors to grow and metastasize more effectively. As 1 of the hallmarks of cancer, angiogenesis is also a vulnerable point for malignancy that is susceptible to influence by external modulators. Conventional treatments have the capacity to help hinder cancer growth and spread through antiangiogenic agents; however, they also have associated toxicity that can create side effects that limit their application. A number of natural health products have shown promise in clinical application against cancer through antiangiogenic mechanisms. In this paper we explore a few of these agents that have some of the strongest related research for application. We discuss some of the clinical evidence that currently exists and, importantly, how to enable effective research to further explore this topic.
INTRODUCTION & BACKGROUND Angiogenesis Process
Similar to normal tissue, malignant tumors require a sustained delivery of nutrients and removal of waste to subsist. Delivery and removal are primarily achieved through tumor neovascularization via a process called angiogenesis, which involves the formation of new blood vessels from existing vasculature. Unlike normal tissue, malignancies circumvent the ordinarily quiescent and well-organized nature of angiogenesis and exploit the process to facilitate unimpeded malignant growth.1,2 The process of cancer-related angiogenesis is heavily influenced by mediators in the tumor environment and is accelerated by localized tissue breakdown. Amongst other angiogenic
Athanasios Psihogios, ND, and Dugald Seely, ND, MSc, FABNO mediators, vascular endothelial growth factor (VEGF) is the primary signal protein implicated in the process of angiogenesis.1,3 As a ligand, it stimulates VEGF receptor 2 (VEGFR-2), which is highly expressed by endothelial cells engaging in angiogenesis.3 Binding results in up-regulation of genes that mediate proliferation and migration of endothelial cells, while promoting survival and permeability of the vasculature.3 Angiogenesis in Modern Cancer Care
In the early 1970s, Dr Judah Folkman theorized that angiogenesis could serve as a potential therapeutic target,4 with the first approved pharmaceutical agents coming out in the early 2000s.3-6 Bevacizumab, a monoclonal antibody that binds circulating VEGF, was the first FDA-approved angiogenesis inhibitor, which when combined with standard chemotherapy, improved survival for patients with metastatic colorectal cancer.7 Similarly, patients with advanced non-small-cell lung cancer (NSCLC) experienced a survival benefit with bevacizumab in combination with standard chemotherapy.8 Overall, pharmaceutical VEGF inhibitors have shown modest benefit when added to standard care and have proven to be a valuable addition to standard care in certain circumstances.3 Based on 33 randomized controlled clinical trials (RCTs) (N= 17,396 NSCLC participants), the addition of approved angiogenesis inhibitors significantly improved progression-free survival (PFS; HR: 0.81, 95% CI 0.76–0.85, P<0.001), overall survival (OS; HR: 0.95, 95% CI 0.92–0.98, P= 0.004), objective response rate (ORR; RR: 1.54, 95% CI 1.37–1.73 P<0.001), and disease control rate (DCR; RR: 1.18, 95% CI 1.10–1.27, P<0.001) compared to non-angiogenesis inhibitor treatments.9 Approved angiogenesis inhibitors have also demonstrated improved survival outcomes for patients with ovarian10 and gastric11 cancers. In contrast, a meta-analysis of 7 RCTs (N=1,322 participants) exploring use of angiogenesis inhibitors in small-cell lung cancer (SCLC) found angiogenesis inhibitors did not significantly improve prognosis,12 indicating the potential for cancer-type specificity related to clinical impact.
22 ©2020 NATURAL MEDICINE JOURNAL. ALL RIGHTS RESERVED. NMJ, OCTOBER 2020 SUPPLEMENT—VOL. 12, NO. 101 (SUPPL)
