Effects of Jaeumkanghwa-tang on tamoxifen responsiveness in preclinical ER+ breast cancer model

Abstract

Resistance to endocrine therapy remains a clinical challenge in the treatment of estrogen receptor-positive (ER+) breast cancer. We investigated if adding a traditional Asian herbal mixture consisting of 12 herbs, called Jaeumkanghwa-tang (JEKHT), to tamoxifen (TAM) therapy might prevent resistance and recurrence in the ER+ breast cancer model of 7,12-dimethylbenz[a]anthracene (DMBA)-exposed Sprague–Dawley rats. Rats were divided into four groups treated as follows: 15 mg/kg TAM administered via diet as TAM citrate (TAM only); 500 mg/kg JEKHT administered via drinking water (JEKHT only group); TAM + JEKHT and no treatment control group. The study was replicated using two different batches of JEKHT. In both studies, a significantly higher proportion of ER+ mammary tumors responded to TAM if animals also were treated with JEKHT (experiment 1: 47% vs 65%, P = 0.015; experiment 2: 43% vs 77%, P < 0.001). The risk of local recurrence also was reduced (31% vs 12%, P = 0.002). JEKHT alone was mostly ineffective. In addition, JEKHT prevented the development of premalignant endometrial lesions in TAM-treated rats (20% in TAM only vs 0% in TAM + JEKHT). Co-treatment of antiestrogen-resistant LCC9 human breast cancer cells with 1.6 mg/mL JEKHT reversed their TAM resistance in dose–response studies in vitro. Several traditional herbal medicine preparations can exhibit anti-inflammatory properties and may increase anti-tumor immune activities in the tumor microenvironment. In the tumors of rats treated with both JEKHT and TAM, expression of Il-6 (P = 0.03), Foxp3/T regulatory cell (Treg) marker (P = 0.033) and Tgfβ1 that activates Tregs (P < 0.001) were significantly downregulated compared with TAM only group. These findings indicate that JEKHT may prevent TAM-induced evasion of tumor immune responses.

Social Isolation Activates Dormant Mammary Tumors, and Modifies Inflammatory and Mitochondrial Metabolic Pathways in the Rat Mammary Gland

“…As we have previously reported [ 19 ], giving rats JGT via drinking water significantly increased the rate of complete responses to tamoxifen in GH rats from 31% to 52% ( n = 23 of a total of 44 tumors, p = 0.004) ( Figure 2 A). Similar results were observed in the SI rats, with the rate of complete responses increasing from 21% to 36% ( n = 16 of a total of 45 tumors, p = 0.03).…”

“…Tamoxifen was administered at a concentration of 340 ppm, which is relevant for human tamoxifen exposure levels via the AIN93G diet, as previously described [ 36 ]. JGT at a dose of 500 mg/kg was administered via drinking water as described previously [ 19 ]. This dose corresponds to 81 mg/kg when converted to a human exposure equivalent [ 37 ] and is less than humans can be safely exposed to over extended time periods [ 38 ].…”

“…If these changes explain the effects of social isolation on breast cancer recurrence, interventions that reverse them could reduce breast cancer mortality. Previously, we found that Jaeumganghwa-tang (JGT), a mixture of 12 herbs commonly and safely used in Asian countries for a wide range of ailments, reduced IL6 expression in mammary tumors and increased sensitivity to tamoxifen therapy in vitro and in an animal model [ 19 ]. Other studies have reported the ability of JGT to inhibit inflammatory cytokines in human mast cells in vitro [ 20 ] and in vivo in mice [ 21 ].…”

Interactions Between Natural Products and Tamoxifen in Breast Cancer: A Comprehensive Literature Review

“…Jaeumkanghwa soup (JEKHT) is a compound composed of 12 traditional herbs ( Jung et al, 2010 ). In antiestrogen-resistant LCC9 human breast cancer cells, the combination of JEKHT with 4-OHT can increase the sensitivity of the cells to TAM ( De Oliveira Andrade et al, 2019 ). All the above evidence shows that natural or plant products can increase the sensitivity of drug-resistant cell lines to TAM.…”

“…JEKHT is a compound consisting of 12 traditional herbs ( Jung et al, 2010 ). In a study adopting DMBA-induced ER+ breast cancer rat model, it was reported that the combined treatment of JEKHT with TAM can reduce risk of recurrence and developing TAM resistance, prevent the development of precancerous endometrial lesions, and prevent the immunosuppressive effects of TAM ( De Oliveira Andrade et al, 2019 ). When compared with the TAM-only group, the combination of JEKHT and TAM significantly downregulated Il-6 , Foxp3 /T regulatory cell (Treg) markers, and Tgfβ 1 that activate Treg ( De Oliveira Andrade et al, 2019 ).…”