Dietary Compound Isoliquiritigenin, an Antioxidant from Licorice, Suppresses Triple-Negative Breast Tumor Growth via Apoptotic Death Program Activation in Cell and Xenograft Animal Models

Abstract

Patients with triple-negative breast cancer have few therapeutic strategy options. In this study, we investigated the effect of isoliquiritigenin (ISL) on the proliferation of triple-negative breast cancer cells. We found that treatment with ISL inhibited triple-negative breast cancer cell line (MDA-MB-231) cell growth and increased cytotoxicity. ISL reduced cell cycle progression through the reduction of cyclin D1 protein expression and increased the sub-G1 phase population. The ISL-induced apoptotic cell population was observed by flow cytometry analysis. The expression of Bcl-2 protein was reduced by ISL treatment, whereas the Bax protein level increased; subsequently, the downstream signaling molecules caspase-3 and poly ADP-ribose polymerase (PARP) were activated. Moreover, ISL reduced the expression of total and phosphorylated mammalian target of rapamycin (mTOR), ULK1, and cathepsin B, whereas the expression of autophagic-associated proteins p62, Beclin1, and LC3 was increased. The decreased cathepsin B cause the p62 accumulation to induce caspase-8 mediated apoptosis. In vivo studies further showed that preventive treatment with ISL could inhibit breast cancer growth and induce apoptotic and autophagic-mediated apoptosis cell death. Taken together, ISL exerts an effect on the inhibition of triple-negative MDA-MB-231 breast cancer cell growth through autophagy-mediated apoptosis. Therefore, future studies of ISL as a supplement or alternative therapeutic agent for clinical trials against breast cancer are warranted.

Characterization and Cytotoxic Activity of <i>Dalbergia latifolia</i> Wood Extract

“…With licorice isoliquiritigenin it was reported that pretreatment of mice showed least chances rate of getting cancer attack [17]. Also consequently, there was a reduction in cell proliferation and also the induction of Ki-67 protein which also reduces the cell proliferation and the proteins like caspase-3 and p62 proteins formation were reduced [20][21][22][23][24]. This denotes that the cancerous cells were underwent autophagy.…”

Perspectives on the Role of Isoliquiritigenin in Cancer

“…Lin et al (2017) demonstrated that treatment with ISL alone or in combination with doxorubicin is highly effective in sensitizing doxorubicin-resistant cancer cells, resulting in the reduced survival of cancer cells [ 142 ]. Moreover, ISL not only inhibits cancer cell growth by inducing apoptosis and autophagy, but can also enhance chemosensitivity [ 40 , 66 , 67 , 69 ]. It has also been reported that doxorubicin triggers an epithelial-to-mesenchymal transition (EMT) in TNBC through mediating the PI3K/AKT pathway.…”

“…It has also been reported that doxorubicin triggers an epithelial-to-mesenchymal transition (EMT) in TNBC through mediating the PI3K/AKT pathway. Interestingly, ISL also can inhibit the PI3K/AKT pathway and thus suppresses EMT and increases the antiproliferative effect [ 40 , 66 , 67 , 69 ]. ISL or its derivatives show a greater influence by regulating the miR-374a/BAX axis, the -374a/PTEN/AKT axis, or the autophagy-mediated apoptosis (p62/caspase-8) pathway, especially in TNBC [ 33 , 67 , 69 ].…”

“…Interestingly, ISL also can inhibit the PI3K/AKT pathway and thus suppresses EMT and increases the antiproliferative effect [ 40 , 66 , 67 , 69 ]. ISL or its derivatives show a greater influence by regulating the miR-374a/BAX axis, the -374a/PTEN/AKT axis, or the autophagy-mediated apoptosis (p62/caspase-8) pathway, especially in TNBC [ 33 , 67 , 69 ]. Recent studies have also demonstrated that ISL causes chemosensitization and induces autophagy following the degradation of the ABCG2 autophagy–lysosome pathway or the miR-25-mediating ULK1 (a kinase involved in autophagy) [ 40 , 56 ].…”

“…The other first-line chemotherapies for breast cancer are epirubicin, 5-FU, and Taxol. Remarkably, previous studies have also shown that ISL can interact synergistically with these first-line chemotherapy drugs through mediating cell death (apoptosis) and autophagy and suppressing breast CSCs [ 40 , 56 , 69 ]. In a preclinical study, ISL was able to shed a novel light on reversing the epigenetic changes of Wnt inhibitory factor 1 (WIF-1), which induced the demethylation of WIF-1 promoter and subsequently prevented tumor initiation by inhibiting CSCs [ 51 ].…”