Maackiain Modulates miR-374a/GADD45A Axis to Inhibit Triple-Negative Breast Cancer Initiation and Progression

Abstract

Breast cancer ranks as the leading cause of death in lethal malignancies among women worldwide, with a sharp increase of incidence since 2008. Triple negative breast cancer (TNBC) gives rise to the largest proportion in breast cancer-related deaths because of its aggressive growth and rapid metastasis. Hence, searching for promising targets and innovative approaches is indispensable for the TNBC treatment. Maackiain (MA), a natural compound with multiple biological activities, could be isolated from different Chinese herbs, such as Spatholobus suberectus and Sophora flavescens. It was the first time to report the anti-cancer effect of MA in TNBC. MA could suppress TNBC cell proliferation, foci formation, migration, and invasion. MA also exerted a significant inhibitory effect on tumor growth of TNBC. Furthermore, MA could induce apoptosis with an increase of GADD45α and a decrease of miR-374a. In contrast, overexpressing miR-374a would result in at least partly affecting the proapoptotic effect of MA and suppressing GADD45α stimulated by MA. These results reveal the anti-TNBC effect of MA in vitro and in vivo, providing evidence for its potential as a drug candidate utilized in TNBC therapy.

Extracts of Knoxia roxburghii (Spreng.) M. A. Rau Induce Apoptosis in Human MCF-7 Breast Cancer Cells via Mitochondrial Pathways

“…A total of eight compounds, including flavonoids, anthraquinones, and triterpenoids, were identified from the HSF of KR extracts via LC-MS analysis ( Table 2 ). Among these, calycosin, aloe emodin, rhein, and maackiain reportedly exhibit effects against breast cancer [ 29 , 30 , 31 ], while asperuloside, orientin, vicenin-2, and kaempferitrin were proven to exhibit anti-tumor activity [ 32 , 33 , 34 , 35 , 36 ]. Additionally, 3-hydroxymorindone and rubiadin were found to occur in HSF through a comparison with reference compounds.…”

“…They affect estrogen receptors, cellular signaling pathways, cell cycle, apoptosis, and steroid synthesis, and induce DNA damage in cancer cells [ 51 ]. Maackiain could suppress breast cancer cell proliferation, lesion formation, migration, and invasion [ 31 ]. Breast cancer cells were inhibited from invading and migrating by aloe emodin, which inhibited pro-tumorigenic cytokine expression [ 30 ].…”

A Novel Splice Variant of BCAS1 Inhibits β-Arrestin 2 to Promote the Proliferation and Migration of Glioblastoma Cells, and This Effect Was Blocked by Maackiain

“…In cancer therapy, MK can hinder the proliferation, migration, invasion, and foci formation of triple-negative breast cancer cells and thus has a significant inhibitory effect on tumor growth. Furthermore, MK can induce apoptosis by reducing miR-374a, leading to an increase in GADD45α [ 88 ]. In in vitro studies, we found that 1 μM MK was not lethal to GBM cells but could significantly diminish the proliferation and migration of cancer cells.…”

Maackiain Prevents Amyloid-Beta–Induced Cellular Injury via Priming PKC-Nrf2 Pathway

“…Maackiain, a typical isoflavonoid, is extracted from traditional Chinese medicine peony root. Maackiain possesses antioxidative [ 18 ], antiseptic [ 19 ], antitumor [ 20 ], and immunoregulatory properties [ 21 ]. Maackiain has recently been reported to exhibit beneficial effects on preventing and improving diabetes mellitus-related metabolic disturbance [ 18 ].…”

“…Therefore, 10 μM Aβ 42 stimulation for 24 hours was selected as a condition to induce injury to PC12 cells for the following experiments. To determine the protective effects of Maackiain on cell injury induced by Aβ 42 , PC12 cells were pretreated with different doses of Maackiain(10,20, and 50 μM) six hours before 10 μM Aβ 42 stimulation. The results of CCk-8 and LDH activity assay showed that Maackiain prevented Aβ 42 -induced cell injury in a dose-dependent way (Figures1(c) and 1(d)).…”