Multi-Anticancer Activities of Phytoestrogens in Human Osteosarcoma

Abstract

Phytoestrogens are plant-derived bioactive compounds with estrogen-like properties. Their potential health benefits, especially in cancer prevention and treatment, have been a subject of considerable research in the past decade. Phytoestrogens exert their effects, at least in part, through interactions with estrogen receptors (ERs), mimicking or inhibiting the actions of natural estrogens. Recently, there has been growing interest in exploring the impact of phytoestrogens on osteosarcoma (OS), a type of bone malignancy that primarily affects children and young adults and is currently presenting limited treatment options. Considering the critical role of the estrogen/ERs axis in bone development and growth, the modulation of ERs has emerged as a highly promising approach in the treatment of OS. This review provides an extensive overview of current literature on the effects of phytoestrogens on human OS models. It delves into the multiple mechanisms through which these molecules regulate the cell cycle, apoptosis, and key pathways implicated in the growth and progression of OS, including ER signaling. Moreover, potential interactions between phytoestrogens and conventional chemotherapy agents commonly used in OS treatment will be examined. Understanding the impact of these compounds in OS holds great promise for developing novel therapeutic approaches that can augment current OS treatment modalities.

Keywords: anticancer effects; estrogen receptors; osteosarcoma; phytoestrogens.

Figure 1

Basic chemical structures of the major classes of phytoestrogens. The different types of phytoestrogens share a structural similarity with 17β-Estradiol. In green, the flavonoid skeleton showing rings A, B, and C and the numbering.

Figure 2

Intracellular mediators of the effects of phytoestrogens on cancer cells. Phytoestrogen can interact with the two types of ER, the intracellular ERα and Erβ, and membrane-associated mERs and GPER, activating downstream genomic and non-genomic effects which ultimately affect cell cancer phenotypes. The genomic pathway can involve ER interactions with other transcription factors (TFs), such as CREB, AP-1, Sp1, and NF-κB. Phytoestrogens can also act through ER-independent mechanisms which induce oxidative stress-mediated signaling by generating ROS, as well as interacting with other nuclear receptors, such as PPARs and ERRα/γ.

Figure 3

Chemical structure of the most common isoflavones and some of their possible targets in OS cells. Isoflavones, especially genistein, bind ERβ with a significant higher affinity than ERα. Downward arrows represent downregulation or reduction. Upward arrows represent upregulation or increase.

Figure 4

Chemical structure of flavonoids discussed throughout the text.

Figure 5

Downregulation of various pathways involved in the anti-OS activity of the stilbene resveratrol, and its glycosidic form polydatin.