The Potential of Natural Products in the Treatment of Triple-negative Breast Cancer

Abstract

Triple-negative breast cancer (TNBC) is a subtype of breast cancer that lacks receptors for targeted therapy. Consequently, chemotherapy is currently the mainstay of systemic treatment options. However, the enrichment of cancer stem cells (CSC, a subpopulation with stem-cell characteristics and tumor-initiating propensity) promotes chemo-resistance and tumorigenesis, resulting in cancer recurrence and relapse. Furthermore, toxic side effects of chemotherapeutics reduce patient wellbeing. Natural products, specifically compounds derived from plants, have the potential to treat TNBC and target CSCs by inhibiting CSC signaling pathways. Literature evidence from six promising compounds were reviewed, including sulforaphane, curcumin, genistein, resveratrol, lycopene, and epigallocatechin-3-gallate. These compounds have been shown to promote cell cycle arrest and apoptosis in TNBC cells. They also could inhibit the epithelial-mesenchymal transition (EMT) that plays an important role in metastasis. In addition, those natural compounds have been found to inhibit pathways important for CSCs, such as NF-κB, PI3K/Akt/mTOR, Notch 1, Wnt/β-catenin, and YAP. Clinicals trials conducted on these compounds have shown varying degrees of effectiveness. Epidemiological case-control studies for the compounds commonly consumed in certain human populations have also been summarized. While in vivo and in vitro data are promising, further basic and clinical investigations are required. Likely, natural products in combination with other drugs may hold great potential to improve TNBC treatment efficacy and patient outcomes.

Molecular and Cellular Mechanisms of Propolis and Its Polyphenolic Compounds against Cancer

“…Several mechanisms have been implicated in the inhibition of cell proliferation: (i) inhibition of the activity of tyrosine-specific protein kinases [ 126 , 127 , 128 ], such as inhibition of PKC, which is one of the key enzymes in the regulation of cellular proliferation and tumor growth; (ii) induction of the differentiation of carcinoma cells [ 3 , 13 , 126 , 127 , 128 , 129 ]; (iii) transcriptional changes in cell cycle- and apoptosis-related genes such as NF-κB, Bcl-X(L) and COX-2; (iv) binding to the estrogen receptor and inhibition of an estrogen receptor-positive human breast cancer cells [ 130 , 131 ]; (v) induction of apoptosis, (vi) downregulation of the expression of mutated H-Ras and p53 tumor suppression gene [ 3 , 13 , 126 ], (vii) modulation of gene methylation and re-expression of tumor suppressors or other genes silenced by aberrant DNA methylation [ 119 , 130 , 131 ], (viii) inhibition of pro-oxidative enzymes xanthine oxidase, cyclooxygenases, or lipooxygenases [ 3 , 13 , 126 , 127 ], and (ix) some flavonoids are a direct poison for topoisomerase II (TopoII), through the stabilization of double strand breaks in the TopoII-DNA cleavage [ 4 , 9 , 10 , 11 , 12 , 13 ].…”

Studies on the mode of action of synthetic diindolylmethane derivatives against triple negative breast cancer cells

“…The combination of natural products with other drugs also has great potential to improve the treatment efficacy of TNBC. [18][19][20] Diindolyl methane (DIM) derivatives are one such naturally derived pharmacophore which have reported anticancer action in various cancer cells. Here, we have subjected a total of 12 synthetic biaryls appended DIM derivatives for cytotoxicity testing against the TNBC cell line MDA-MB-231.…”

“…34 PI3K/Akt/mTOR pathway is an intracellular signalling pathway involved in cell growth/tumour proliferation, and multiple inhibitors targeting this pathway are already in clinical trials. [35][36][37] It can be regulated from the cellular recognition site or at the miRNA level. 38 I3C, DIM and their derivatives have pleiotropic antitumour effects with multiple biological targets.…”

“…Literature evidence suggests many natural products like curcumin, resveratrol, lycopene, and epigallocatechin gallate, which manage TNBC through various mechanisms like induction of apoptosis, cell cycle arrest and inhibiting epithelial to mesenchymal transition, and it targets key cellular pathways involving NF‐κB, PI3K/Akt/mTOR, Notch 1, Wnt/β‐catenin, YAP, etc. The combination of natural products with other drugs also has great potential to improve the treatment efficacy of TNBC 18–20 …”

Curcuminoids as Modulators of EMT in Invasive Cancers: A Review of Molecular Targets With the Contribution of Malignant Mesothelioma Studies

“…More precisely, Buhrmann and colleagues have shown that curcumin had the potential to dramatically decrease the crosstalk between CSCs and stromal fibroblasts (Buhrmann et al, 2014) (Figure 4). Additionally, an important aspect of its pharmacological effects relies on inhibition of several pathways important for CSCs, such as NF-κB, PI3K/Akt/mTOR, Notch, Wnt, and Hippo/YAP (Ke et al, 2021), but also of signaling crosstalks involved in chemoresistance (Vinod et al, 2013). Moreover, unlike other Hedgehog inhibitors that produced some adverse effects in vivo, the combination of curcumin with chemotherapeutics or targeted agents has represented a new therapeutic strategy with low or no toxicity (Li et al, 2012;.…”