Targeting tumor microenvironment with silibinin: promise and potential for a translational cancer chemopreventive strategy

Abstract

Tumor microenvironment (TME) refers to the dynamic cellular and extra-cellular components surrounding tumor cells at each stage of the carcinogenesis. TME has now emerged as an integral and inseparable part of the carcinogenesis that plays a critical role in tumor growth, angiogenesis, epithelial to mesenchymal transition (EMT), invasion, migration and metastasis. Besides its vital role in carcinogenesis, TME is also a better drug target because of its relative genetic stability with lesser probability for the development of drug-resistance. Several drugs targeting the TME (endothelial cells, macrophages, cancer-associated fibroblasts, or extra-cellular matrix) have either been approved or are in clinical trials. Recently, non-steroidal anti-inflammatory drugs targeting inflammation were reported to also prevent several cancers. These exciting developments suggest that cancer chemopreventive strategies targeting both tumor and TME would be better and effective towards preventing, retarding or reversing the process of carcinogenesis. Here, we have reviewed the effect of a well established hepatoprotective and chemopreventive agent silibinin on cellular (endothelial, fibroblast and immune cells) and non-cellular components (cytokines, growth factors, proteinases etc.) of the TME. Silibinin targets TME constituents as well as their interaction with cancer cells, thereby inhibiting tumor growth, angiogenesis, inflammation, EMT, and metastasis. Silibinin is already in clinical trials, and based upon completed studies we suggest that its chemopreventive effectiveness should be verified through its effect on biological end points in both tumor and TME. Overall, we believe that the chemopreventive strategies targeting both tumor and TME have practical and translational utility in lowering the cancer burden.

Figure 1

The classical and current view of carcinogenesis and chemoprevention targets. Classically, tumor has been viewed as a homogenous mass of rapidly growing cells, though could be of different sizes; while the current view considers tumor as a complex community of interacting heterogeneous population of cells.

Figure 2

Chemical structure of silibinin.

Figure 3

Silibinin exhibits angiopreventive efficacy through targeting the secretion of pro-angiogenic factors by cancer cells (blue arrow); by reducing the recruitment of macrophages in the tumor microenvironment (yellow arrow); and through inhibiting various signaling molecules in endothelial cells, compromising their survival as well as chemotactic movement (purple arrow) towards pro-angiogenic stimuli.

Figure 4

Silibinin targets prostate cancer cell, osteoblast, and osteoclast interaction towards inhibiting the osteoclast activation and differentiation.

Figure 5

Silibinin targets several cellular and non-cellular components in the tumor microenvironment.