Stereoselective Anti-Cancer Activities of Ginsenoside Rg3 on Triple Negative Breast Cancer Cell Models

Abstract

Ginsenoside Rg3 (Rg3) has two epimers, 20(S)-ginsenoside Rg3 (SRg3) and 20(R)-ginsenoside Rg3 (RRg3), and while Rg3 itself has been reported to have anti-cancer properties, few studies have been reported on the anti-cancer effects of the different epimers. The aim was to investigate the stereoselective effects of the Rg3 epimers on triple negative breast cancer (TNBC) cell lines, tested using cell-based assays for proliferation, apoptosis, cell cycle arrest, migration and invasion. Molecular docking showed that Rg3 interacted with the aquaporin 1 (AQP1) water channel (binding score −9.4 kJ mol−1). The Xenopus laevis oocyte expression system was used to study the effect of Rg3 epimers on the AQP1 water permeability. The AQP1 expression in TNBC cell lines was compared with quantitative-polymerase chain reaction (PCR). The results showed that only SRg3 inhibited the AQP1 water flux and inhibited the proliferation of MDA-MB-231 (100 μM), due to cell cycle arrest at G0/G1. SRg3 inhibited the chemoattractant-induced migration of MDA-MB-231. The AQP1 expression in MDA-MB-231 was higher than in HCC1143 or DU4475 cell lines. These results suggest a role for AQP1 in the proliferation and chemoattractant-induced migration of this cell line. Compared to SRg3, RRg3 had more potency and efficacy, inhibiting the migration and invasion of MDA-MB-231. Rg3 has stereoselective anti-cancer effects in the AQP1 high-expressing cell line MDA-MB-231.

Anti-Angiogenic Properties of Ginsenoside Rg3

“…We have shown that blockers of the AQP1 water channel such as AqB013 [ 96 ], AqB050 [ 97 ] and bacopaside II [ 98 ] inhibit tube formation in endothelial cells. We have also shown that SRg3 stereoselectively inhibited AQP1-mediated transport of water [ 12 ]. Decreased expression of AQP1 with Rg3 treatment was also shown in a prostate cancer cell line [ 99 ].…”

“…Rg3 is one of the most studied and pharmacologically active ginsenosides, with stereoselective activities by the epimers SRg3 and RRg3 [ 11 , 12 ]. The chemistry of Rg3 epimers could explain this stereoselective activity.…”

Molecular Targets for Combined Therapeutic Strategies to Limit Glioblastoma Cell Migration and Invasion

“…The expression of AQP1 in the leading edges of migrating cells has been linked to enhanced motility, as documented in neural crest (McLennan et al, 2020) and various types of cancer cells including colon cancer, gliomas, breast cancer, and endothelial cells involved in angiogenic responses (McCoy and Sontheimer, 2007;Pei et al, 2016a;Nakhjavani et al, 2019;Tomita et al, 2019). AQP1 is a dual water and ion channel (Anthony et al, 2000;Yu et al, 2006;Campbell et al, 2012;Kourghi et al, 2018), which has been suggested to accelerate cell migration by enabling parallel water and cation entry (Yool et al, 2009;Pei et al, 2019), promoting the cellular lamellipodial and filopodial extensions needed for forward movement.…”

Pathological role of ion channels and transporters in the development and progression of triple-negative breast cancer

“…Helen et al [32] also reported that the triterpenoid saponins bacopaside I and bacopaside II can synergistically reduce the transcriptional expression of AQP1, and inhibit proliferation, migration and invasion in MDA-MB-231 cells. Similarly, ginsenoside Rg3, a compound with anticancer activity isolated from ginseng, inhibits AQP1 to attenuate cell proliferation through a mechanism that involves downregulation of AQP1 to induce cell cycle arrest in G0/G1 phase by inhibiting cyclin D and E and inhibition of chemoattractant-induced cell migration and invasion by blocking AQP1-mediated water flux in MDA-MB-231 cells [33]. These findings indicate that AQP1 plays an important role in the development and progression of TNBC.…”