Russelioside A, a Pregnane Glycoside from Caralluma tuberculate, Inhibits Cell-Intrinsic NF-κB Activity and Metastatic Ability of Breast Cancer Cells.

Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a potential target for inflammatory-breast cancer treatment as it participates in its pathogenesis, such as tumor initiation, progression, survival, metastasis, and recurrence. In this study, we aimed to discover a novel anti-cancer treatment from natural products by targeting NF-κB activity. Using the 4T1-NFκB-luciferase reporter cell line, we tested three pregnane glycosides extracted from the herb Caralluma tuberculata and discovered that Russelioside A markedly suppressed NF-κB activity in breast cancer. Russelioside A inhibited NF-κB (p65) transcriptional activity and its phosphorylation. Following NF-κB inhibition, Russelioside A exerted anti-proliferative and anti-metastatic effects in breast cancer cells in vitro. Moreover, it inhibited the NF-κB constitutive expression of downstream pathways, such as VEGF-b, MMP-9, and IL-6 in 4T1 cells. In addition, it reduced the metastatic capacity in a 4T1 breast cancer model in vivo. Collectively, our conclusions reveal that Russelioside A is an attractive natural compound for treating triple-negative breast cancer growth and metastasis through regulating NF-κB activation.

Design and synthesis of 2-Substituted-4-benzyl-5-methylimidazoles as new potential Anti-breast cancer agents to inhibit oncogenic STAT3 functions.

STAT3 signaling is known to be associated with tumorigenesis and further cancer cell-intrinsic activation of STAT3 leads to altered regulation of several oncogenic processes. Given the importance of STAT3 in cancer development and progression particularly breast cancer, it is crucial to discover new chemical entities of STAT3 inhibitor to develop anti-breast cancer drug candidates. Herein, 4-benzyl-2-benzylthio-5-methyl-1H-imidazole (2a) and 4-benzyl-5-methyl-2-[(2,6-difluorobenzyl)thio]-1H-imidazole (2d) from a group of thirty imidazole-bearing compounds showed greater STAT3 inhibition than their lead compounds VS1 and the oxadiazole derivative MD77. Within all tested compounds, ten derivatives effectively inhibited the growth of the two tested breast cancer cells with IC50 values ranging from 6.66 to 26.02 µM. In addition, the most potent derivatives 2a and 2d inhibited the oncogenic function of STAT3 as seen in the inhibition of colony formation and IL-6 production of breast cancer cell lines. Modeling studies provided evidence for the possible interactions of the synthesized compounds with the key residues of the STAT3-SH2 domain. Collectively, our present study suggests 2-substituted-4-benzyl-5-methylimidazoles are a new class of anti-cancer drug candidates to inhibit oncogenic STAT3 function.

Synthetic E-guggulsterone derivative GSD-1 inhibits NF-κB signaling and suppresses the metastatic potential of breast cancer cells.

Guggulsterone (GS) [4,17(20)-pregnadiene-3,16-dione], is the main active phytosterol constituent in guggul, the gum resin of Commiphora wightii (Arnott.) Bhand./Commiphora mukul Engl. tree, and is known for its medicinal effects. In this study, we report that GSD-1, a structurally-related synthetic GS derivative, strongly inhibits NF-κB activation induced by TNF-α. GSD-1 prevented the nuclear translocation of p65 through the blockade of IκBα degradation and p65 phosphorylation, and further inhibited the activation of upstream kinases, including transforming growth factor-ß activated kinase 1 (TAK1), IκB kinase (IKK) α, and IKKß. Furthermore, GSD-1 inhibited the cell-intrinsic activation of NF-κB, and exerted its direct anti-cancer and anti-metastatic effects in both murine and human breast cancer cell lines. This study demonstrated GSD-1 to be an attractive compound to target NF-κB activation that has potential for treating breast cancer growth and metastasis.

Inhibition of cell-intrinsic NF-κB activity and metastatic abilities of breast cancer by aloe-emodin and emodic-acid isolated from Asphodelus microcarpus.

Anthraquinones are a major class of compounds naturally occurring in Asphodelus microcarpus. The pharmacological actions of anthraquinones in cancer cells are known to induce apoptosis or autophagy, and revert multidrug resistance. In this study, five anthraquinone-type analogs were isolated from the methanol extract of A. microcarpus leaves and identified as, emodin, rhein, physcion, aloe-emodin, and emodic acid. Among them, aloe-emodin and emodic-acid strongly inhibited the proliferation, cells-intrinsic NF-κB activity and metastatic ability of breast cancer. Although aloe-emodin inhibited p38 and ERK phosphorylation, emodic-acid more markedly inhibited JNK, in addition to p38 and ERK phosphorylation. Both aloe-emodin and emodic-acid inhibited the secretion of the pro-tumorigenic cytokines IL-1ß and IL-6, and VEGF and MMP expression, and subsequently inhibited the invasive and migratory potential of 4T1 cells. Thus, our study demonstrated the effects of aloe-emodin and emodin-acid in controlling the migratory and invasive ability of 4T1 breast cancer cells, in addition to inhibiting NF-κB activity and the expression of its downstream target molecules.

Protective role of probiotic lactic acid bacteria against dietary fumonisin B1-induced toxicity and DNA-fragmentation in sprague-dawley rats.

The genus Fusarium, especially F. verticillioides and F. proliferatum, has been found in several agricultural products worldwide, especially in maize. Regardless the occurrence of symptoms, the presence of Fusarium in maize constitutes an imminent risk due to its ability to produce fumonisins, mycotoxins with proven carcinogenic effect on rats, swine, and equines and already classified as possible carcinogens to humans. The toxicity of incremental levels of fumonisin B1 (FB1), that is, 50, 100, and 200 mg FB1/kg diet, and the role of Lactobacillus delbrueckii subsp. lactis DSM 20076 (LL) and Pediococcus acidilactici NNRL B-5627 (PA) supplementation in counteracting the FB1 effects in intoxicated rats were monitored over a period of 4 weeks. Effects on the feed intake and body weight gain were noticed. A significant (p ≤ 0.05) increase in the level of liver and kidney functions markers and DNA fragmentation was also noticed in rat groups T100 and T200. The lactic acid bacteria (LAB) supplementation could bring back the normal serum biochemical parameters in rats fed on fumonisin B1-contaminated diets (T50 and T100) compared to FB1-treated groups. In rats of high-dosage dietary groups supplemented with LAB (T200-LL and T200-PA), the supplementation reduced the serum activity levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and creatinine by 11.3, 11.9, 32, and 20%, respectively. DNA fragmentations were observed in the rat group treated with 200 mg FB1 after 3 weeks, while fragmentation was noticed in treated groups with 100 and 200 mg FB1 after 4 weeks. No DNA fragmentation was apparent in FB1-treated rats co-administered the LL or PA strain. These results suggest that in male rats consuming diets containing FB1, there is a time- and dose-dependent increase in serum enzyme activities and DNA lesions. Moreover, Lb. delbrueckii subsp. lactis (LL) and P. acidilactici (PA) strains have a protective effect against antigenotoxicity and precancerous lesions.