Dr. Weeks’ Comment: Green tea fights cancer. Drink up or take BRYT.

Combination of Epigallocatechin-3-gallate and Silibinin: A Novel Approach for Targeting Both Tumor and Endothelial Cells

Somaye Mirzaaghaei,^†Ali M. Foroughmand,*^†Ghasem Saki,^‡ and  Mohammad Shafiei^†

Source of article; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6648523/

Introduction

Since its first suggestion in 1971, anti-angiogenic therapy of cancer has been known as an essential approach in treating many types of the disease.¹ In non-small-cell lung cancer (NSCLC), like other solid tumors, angiogenesis is accompanied with highly invasive and metastatic properties of disease. Treating approaches including anti-angiogenic agents are among the promising therapies in clinical trials. However, there is a critical need for more studies in this area to overcome observed toxicities and drawbacks.²Angiogenesis, the process of creating new blood vessels from preexisting ones, is a key physiological and developmental event to maintain homeostasis. Disrupted regulation of angiogenesis is directly linked to different pathologies and life-threatening diseases, particularly cancer.³ Regardless of the angiogenesis-inducing source, endothelial cell functions such as survival and migration are crucial in angiogenesis. Endothelial cell survival and migration directly depend on vascular endothelial growth factor (VEGF)-mediated pathways, the key target in most available anti-angiogenic therapeutic options.⁴ On targeting this growth factor, its receptors or downstream mediators, by current approaches, not only inhibit tumor angiogenesis but also cause a systemic endothelial cell dysfunction and subsequent toxicity and cardiovascular diseases.⁵ In addition, resistance to VEGF-targeted therapies has been reported in clinical settings.⁶ Therefore, development of novel and safe strategies is an unmet health priority to minimize the side effects of anti-angiogenic therapeutics.

Conclusions

Targeting multiple pathways of tumor angiogenesis along with minimal side effects on normal tissues is a demanding factor in the development of anticancer therapeutic strategies. A variety of flavonoids exhibit anti-angiogenic effects by targeting a wide range of molecular targets in both tumor and endothelial cells.⁹Herein, we have addressed the inhibitory effect of the EGCG and silibinin combination on endothelial cell migration, survival, VEGF–VEGFR2, and miR-17–92 expression, as essential events in angiogenesis. Altogether, our results suggest that the EGCG and silibinin combination may not only beneficially modulate endothelial cell functions but also directly target tumor cells. It could further the anti-angiogenic antitumor properties by widening the target cells, which deserves detailed investigations in the future.

Anti-angiogenic therapy has extensive benefits, which is based on the critical reliance of solid tumors on neoangiogenesis.^7b,56 However, there are a number of challenges in front that encourage researchers to develop more efficient and less toxic approaches.⁶ High distribution of flavonoids in fruits and vegetables and widespread consumption of plant products containing a variety of flavonoids as food or beverage all over the world, in parallel with growing evidence of their antioxidant and anticancer capacity, have made them promising alternatives for anti-angiogenic therapies.⁵⁷

CONCLUSION

In addition, a variety of in vivo studies and human clinical trials on whether oral administration or intravenous injection of some flavonoids introduces an inconsistency with in vitro results which specify a severe concern about the nonsoluble flavonoids in water and the stability of these compounds in physiological conditions.^57,58 This would affect not only the bioavailability of the flavonoid but also degradation by enzymatic reactions, starting from mixing with saliva, and is capable of forming pro-oxidant molecules with possible side effects.⁵⁹ As an example, in the case of EGCG, the peak plasma level of orally administered flavonoid is in sub-micromolar range,⁶⁰ which is very low compare to approved active concentrations in an in vitro situation. To enhance the exploitation of the compound, there are some solutions, among which increasing the intestinal absorption by a nano-drug delivery system using polymeric micelles has been reported to exhibit a variety of benefits.⁶¹ Sustained drug release, increased drug load, enhanced tumor accumulation, and high stability^61,62 are among the welfares of using the polymeric micelle approach, and improved efficacy has been reported for a number of flavonoids including EGCG⁶³ and quercetin.⁶² Low solubility of silibinin in water, however, can be overcome by increasing the administered doses because highly tolerable characteristics of its consumption have been approved in a variety of in vivo and clinical studies. Cumulative uptake amount of this flavonoid in parallel with introducing the novel silibinin formulation can intensify bioavailability and plasma absorption.¹⁹ However, it is beneficial to be cautious about using silibinin in combination with other drugs. In a clinical study of using oral administration of a commercial formula of silibinin, silybin-phytosome, in prostate cancer patients, an improvement in the bioavailability and plasma absorbance of silibinin was observed; however, variability in inter- or intrapatient responses emphasizes the impact of complexity of physiological conditions on its functionality and necessitates wide and detailed preclinical studies prior to using flavonoids in clinical conditions. Altogether, these are suggestive of evaluating promising drug delivery approaches for future studies on EGCG + silibinin in in vivo and further clinical trials.