Formononetin: A Review of Its Anticancer Potentials and Mechanisms

Abstract

Cancer, a complex yet common disease, is caused by uncontrolled cell division and abnormal cell growth due to a variety of gene mutations. Seeking effective treatments for cancer is a major research focus, as the incidence of cancer is on the rise and drug resistance to existing anti-cancer drugs is major concern. Natural products have the potential to yield unique molecules and combinations of substances that may be effective against cancer with relatively low toxicity/better side effect profile compared to standard anticancer therapy. Drug discovery work with natural products has demonstrated that natural compounds display a wide range of biological activities correlating to anticancer effects. In this review, we discuss formononetin (C₁₆H₁₂O₄), which originates mainly from red clovers and the Chinese herb Astragalus membranaceus. The compound comes from a class of 7-hydroisoflavones with a substitution of methoxy group at position 4. Formononetin elicits antitumorigenic properties in vitro and in vivo by modulating numerous signaling pathways to induce cell apoptosis (by intrinsic pathway involving Bax, Bcl-2, and caspase-3 proteins) and cell cycle arrest (by regulating mediators like cyclin A, cyclin B1, and cyclin D1), suppress cell proliferation [by signal transducer and activator of transcription (STAT) activation, phosphatidylinositol 3-kinase/protein kinase-B (PI3K/AKT), and mitogen-activated protein kinase (MAPK) signaling pathway], and inhibit cell invasion [by regulating growth factors vascular endothelial growth factor (VEGF) and Fibroblast growth factor 2 (FGF2), and matrix metalloproteinase (MMP)-2 and MMP-9 proteins]. Co-treatment with other chemotherapy drugs such as bortezomib, LY2940002, U0126, sunitinib, epirubicin, doxorubicin, temozolomide, and metformin enhances the anticancer potential of both formononetin and the respective drugs through synergistic effect. Compiling the evidence thus far highlights the potential of formononetin to be a promising candidate for chemoprevention and chemotherapy.

Keywords: anti-metastasis; anticancer; antitumor; apoptosis; formononetin.

Figure 1

Chemical structure of formononetin.

Figure 2

Graphical summary of the anticancer mechanisms of formononetin. Formononetin acts on multiple signaling pathways in cancer cells. It induces apoptosis via classical caspase-dependent pathway and modulation of Bcl-2 family of proteins. It induces cell cycle arrest by modulating the cycle regulatory proteins. It inactivates signaling pathways, namely, JAK/STAT pathway, PI3K/AKT pathway, as well as MAPK (ERK1/2) pathways. Formononetin also modulates several miRNA expressions as well as supresses cell migration, invasion, and angiogenesis (Li et al., 2014; Liu et al., 2014b; Yang et al., 2014; Hu and Xiao, 2015; Guo et al., 2016; Qi et al., 2016; Wu et al., 2017; Kim et al., 2018a; Park et al., 2018; Wang et al., 2018; Zhang et al., 2018a). NAG-1, nonsteroidal anti-inflammatory drug (NSAID)-activated gene-1; IAP, inhibitors of apoptosis proteins; IL-6, interleukin-6; PARP, poly(ADP-ribose) polymerase; GSH, glutathione; GSSG, oxidized glutathione; GR, glutathione reductase; PTEN, phosphatase and tensin; HIFα, hypoxia inducible factor α; miR, microRNA; TIMP, tissue inhibitors of metalloproteinases; ER, estrogen receptor; MMP, matrix metalloproteinases; CDK, cyclin dependent kinases; STAT, signal transducer and activator of transcription; PI3K, phosphatidylinositol 3-kinase; AKT, protein kinase B; VEGF, vascular endothelial growth factor; FGF, fibroblast growth factor; FGFR, fibroblast growth factor receptor; IGF-1R, insulin-like growth factor 1 receptor; ERK, extracellular signal-regulated kinase; JAK, Janus kinase; ROS, reactive oxygen species.