The "Yin and Yang" of Natural Compounds in Anticancer Therapy of Triple-Negative Breast Cancers

Abstract

Among the different types of breast cancers, triple-negative breast cancers (TNBCs) are highly aggressive, do not respond to conventional hormonal/human epidermal growth factor receptor 2 (HER2)-targeted interventions due to the lack of the respective receptor targets, have chances of early recurrence, metastasize, tend to be more invasive in nature, and develop drug resistance. The global burden of TNBCs is increasing regardless of the number of cytotoxic drugs being introduced into the market each year as they have only moderate efficacy and/or unforeseen side effects. Therefore, the demand for more efficient therapeutic interventions, with reduced side effects, for the treatment of TNBCs is rising. While some plant metabolites/derivatives actually induce the risk of cancers, many plant-derived active principles have gained attention as efficient anticancer agents against TNBCs, with fewer adverse side effects. Here we discuss the possible oncogenic molecular pathways in TNBCs and how the purified plant-derived natural compounds specifically target and modulate the genes and/or proteins involved in these aberrant pathways to exhibit their anticancer potential. We have linked the anticancer potential of plant-derived natural compounds (luteolin, chalcones, piperine, deguelin, quercetin, rutin, fisetin, curcumin, resveratrol, and others) to their ability to target multiple dysregulated signaling pathways (such as the Wnt/β-catenin, Notch, NF-κB, PI3K/Akt/mammalian target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK) and Hedgehog) leading to suppression of cell growth, proliferation, migration, inflammation, angiogenesis, epithelial-mesenchymal transition (EMT) and metastasis, and activation of apoptosis in TNBCs. Plant-derived compounds in combination with classical chemotherapeutic agents were more efficient in the treatment of TNBCs, possibly with lesser side effects.

Keywords: anticancer therapy; apoptosis; chemotherapy; natural compounds; signaling pathways; triple-negative breast cancers.

Figure 1

Oncogenic signaling in triple-negative breast cancers (TNBCs). Aberrant signaling pathways (Wnt/β-catenin, Notch, NF-κB, PI3K/AkT/mTOR, MAPK and Hedgehog) significant in TNBCs and specific pathway-associated components, target genes, and the dysregulated proteins involved in the various signaling pathways leading to cancer progression by supporting cell proliferation, survival and migration, inflammation, angiogenesis, epithelial-mesenchymal transition (EMT) and metastasis, and inhibition of apoptosis. The upward white arrows indicate activation/upregulation while the downward red arrows indicate inhibition/downregulation.

Figure 2

Chemical structures of the natural compounds. Image (Part 1) shows the chemical structures of the natural compounds (A. Luteolin, B. Chalcone, C. Piperine, D. Deguelin, E. Quercetin, F. Rutin, G. Fisetin, H. Resveratrol, I. Curcumin, J. Maximiscin, K. Cyclopamine, L. Capsaicin, and M. Genistein) with potential anticancer properties in TNBCs. Image Part 2 (in red box) shows the chemical structure of N. Asparagine which supports the growth and metastasis of TNBCs.

Figure 3

Natural compounds as anticancer agents in TNBCs: Mode(s) of Action. Aberrant signaling pathways (Wnt/β-catenin, Notch, NF-κB, PI3K/AkT/mTOR, MAPK, and Hedgehog) and pathway components that are targeted by natural compounds (highlighted in red). Phytochemicals have a broad range of action and a single anticancer phytochemical can target multiple pathways that determine cell fate. These compounds can suppress proliferation, growth, and migration; cause cell cycle arrest; induce apoptosis; inhibit angiogenesis; suppress EMT; and inhibit metastasis by targeting and modulating different pathway components and thereby regulating gene transcription and translation. This figure represents membrane, cytoplasmic; and nuclear targets of the selected natural compounds which show potential anticancer properties in TNBCs (see text for detailed mode(s) of action for the natural compounds mentioned).

Figure 4

Natural compounds as pro-apoptotic agents in TNBCs: Mode(s) of Action. Apoptotic signaling in three different cell conditions. Apoptosis is regulated by several proteins including caspases, proteins that promote apoptosis such as Smac/Diablo/Bax/Bad (positive regulators), and proteins that inhibit apoptosis such as survivin/Bcl2/Bcl-xL/IAPs/XIAP (negative regulators). In a non-cancerous cell, after completion of the normal life span, the cell undergoes apoptosis/programmed cell death. Inhibition of apoptosis is a hallmark of all cancers and is characterized by abnormal expression patterns of different proteins involved in the apoptotic signaling, including an increase in levels of negative regulators, a decrease in the levels of positive regulators, and inactivation of caspases. Treatment of cancers with natural compounds/phytochemicals that possess anticancer properties can block pro-survival signals from the aberrant signaling pathways involved in oncogenesis, decrease the levels of negative regulators, increase the levels of positive regulators, and activate caspases, ultimately inducing apoptosis in cancer cells (see text for detailed mode(s) of action for the natural compounds mentioned).

Figure 5

Role of asparagine in promoting growth, EMT, and metastasis in TNBCs. Asparagine, a non-essential amino acid, is synthesized in the body from aspartate in the presence of asparagine synthetase. Asparagine can act as an amino acid exchange factor regulating the uptake of other amino acids such as arginine, histidine, and serine into the cell. This amino acid exchange increases protein and nucleotide synthesis through the activation of mTORC1, which in turn favors and promotes TNBC cell proliferation. Increase in the bioavailability of asparagine (from dietary asparagine and the asparagine synthesized by the body) leads to an upregulation of EMT-up genes and asparagine-enriched EMT proteins (such as Twist1) with a decrease in the levels of E-cadherin, thereby promoting epithelial-mesenchymal transition (EMT) and supporting TNBC metastasis.