Rhein Augments Antiproliferative Effects of Atezolizumab Based on Breast Cancer (4T1) Regression

Abstract

Rhein, an anthraquinone extracted from rhubarb, is used in traditional Chinese medicine for diuresis, diarrhoea, inflammation, and immune regulation. Atezolizumab, a programmed cell death ligand 1 monoclonal antibody, is mainly used to treat bladder cancer and non-small cell lung cancer unresponsive to chemotherapy. We explored the effects of rhein and atezolizumab in combination on breast cancer. Mice with established 4T1 breast cancer xenografts were administered rhein (10 mg/kg) and atezolizumab (10 mg/kg), alone and in combination, and the effects on tumour growth were evaluated. The proportion of CD8+ T cells in the spleen and tumour tissue, the levels of TNF-α, and interleukin-6 in serum as well as the mRNA levels of apoptotic factors (caspase-3, caspase-8, caspase-9, and Bax/Bcl-2) were also evaluated. All of the treatment groups had inhibitory effects on the xenograft tumour growth, with results that were significantly different from those in the control group. In addition, the proportion of CD8+ T cells in the spleen and tumour was significantly increased in the combination therapy group and was significantly different from the other treatment groups. The serum levels of TNF-α and IL-6 were significantly increased in the rhein and combination therapy groups. Finally, the levels of various apoptotic factors in tumour tissues were significantly higher in the combination treatment group than those in the other groups. Administration of rhein, atezolizumab, or their combination all had therapeutic effects on 4T1 breast cancer xenografts in mice, with the combination treatment having stronger effects.

The Interplay Between Regular T Cells and Immunotherapy in Cervical Cancer

“…Previous studies showed that IL6 and Tumor necrosis factor α (TNFα) could promote Tregs proliferation in tumor sites. The recent study reported that anti-PD-L1 treatment or the Rhein and combination therapy groups upregulated the IL6 level established 4T1 breast cancer xenografts [24]. Consistently, we also observed the slightly increase of IL6 in the tumor tissue after anti-PD-L1 therapy (data not show).…”

Therapeutic Emergence of Rhein as a Potential Anticancer Drug: A Review of Its Molecular Targets and Anticancer Properties

“…This compound suppressed proliferation and inhibited breast cancer in mice. For instance, the administration of rhein has been shown to suppress tumor growth in 4T1-cell-induced mouse xenografts [146]. This study also showed that rhein in combination with atezolizumab synergistically elevated the expression of apoptotic protein such as Bax and caspases-3, -8, and -9, and decreased that of Bcl-2 [146].…”

“…For instance, the administration of rhein has been shown to suppress tumor growth in 4T1-cell-induced mouse xenografts [146]. This study also showed that rhein in combination with atezolizumab synergistically elevated the expression of apoptotic protein such as Bax and caspases-3, -8, and -9, and decreased that of Bcl-2 [146]. In another study, it was reported that rhein inhibited the phosphorylation of Akt and activated FOXO3a and further stimulated the activity of the pro-apoptotic protein Bim, which led to the cleavage of caspase proteins and subsequent induction of apoptosis in MCF-7 cells [144].…”

“…These cancerous cells in lymphoblasts or acute lymphoblastic leukemia (ALL) are the cause of 25% of all childhood cancers [167]. The antileukemic effect of rhein was studied on the acute promyelocytic leukemia cell lines NB4 and HL-60 [146,163]. Rhein was shown to target the Bid protein, which caused the loss of mitochondrial potential due to Cyt c efflux and induced the cleavage of an apoptotic executioner caspase, caspase-3, in HL-60 cells [145].…”

The Complex Roles and Therapeutic Implications of m6A Modifications in Breast Cancer

“…In 2019, one study evaluated rhein's function in vivo. Rhein enhanced the apoptotic effect of atezolizumab on 4T1 BC cells (Shen et al, 2019). Treatment with a combination of rhein (10 mg/kg) and atezolizumab (10 mg/kg) inhibited 4T1 xenograft tumor growth and increased serum levels of tumor necrosis factor α and interleukin-6, the CD8 + T-cell ratio, apoptotic factors (e.g., caspase-3, caspase-8, and caspase-9), and Bax/Bcl-2 mRNA levels compared with rhein or atezolizumab treatment alone.…”