Lactate dehydrogenase downregulation mediates the inhibitory effect of diallyl trisulfide on proliferation, metastasis, and invasion in triple‐negative breast cancer

Abstract

The Warburg effect plays a critical role in tumorigenesis, suggesting that specific agents targeting Warburg effect key proteins may be a promising strategy for cancer therapy. Previous studies have shown that diallyl trisulfide (DATS) inhibits proliferation of breast cancer cells by inducing apoptosis in vitro and in vivo. However, whether the Warburg effect is involved with the apoptosis-promoting action of DATS is unclear. Here, we show that the action of DATS is associated with downregulation of lactate dehydrogenase A (LDHA), an essential protein of the Warburg effect whose upregulation is closely related to tumorigenesis. Interestingly, inhibition of the Warburg effect by DATS in breast cancer cells did not greatly affect normal cells. Furthermore, DATS inhibited growth of breast cancer cells, particularly in MDA-MB-231, a triple-negative breast cancer (TNBC) cell, and reduced proliferation and migration; invasion was reversed by over-expression of LDHA. These data suggest that DATS inhibits breast cancer growth and aggressiveness through a novel pathway targeting the key enzyme of the Warburg effect. Our study shows that LDHA downregulation is involved in the apoptotic effect of DATS on TNBC. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1390-1398, 2017.

Pkcδ Activation is Involved in ROS-Mediated Mitochondrial Dysfunction and Apoptosis in Cardiomyocytes Exposed to Advanced Glycation End Products (Ages)

“…Cell viability was measured using the MTT assay as previously described [ 27 ], and based on the 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT, M2003; Sigma, St. Louis, MO, USA) conversion into formazan crystals using mitochondrial dehydrogenases. The prepared H9c2 cells suspension was seeded into 96-well plates at a density of 1 × 10 4 cells/well and incubated at 37 °C for 24 h. Then the cells were treated with (0-300 μg/ml) AGEs as indicated for (0-36 h).…”

“…The protein levels of cultured cells were performed as previously described [ 27 ]. Cultured H9c2 cell were scraped and washed twice with DPBS, then cell suspension was spun down, and cell pellets were lysed for 30min in lysis buffer (50mM Tris (pH 7.5), 0.5M NaCl, 1.0mM EDTA (pH 7.5), 10% glycerol.…”

Triple Isozyme Lactic Acid Dehydrogenase Inhibition in Fully Viable MDA-MB-231 Cells Induces Cytostatic Effects That Are Not Reversed by Exogenous Lactic Acid

“…That said, the only adverse anticancer effect of LDH inhibition appears to be in attenuation of cell proliferation, independent of (+) lactic acid production. The anti-mitotic effect of various LDH inhibitors (of independent isoforms) has been observed in diverse models [ 18 ], some using natural LDH inhibitors such as saffron [ 19 , 20 ], diallyl trisulfide (DATS) [ 21 ], galloflavin derivative’s [ 22 ] PGG, novel synthetic bifunctional nanoparticles, and drugs [ 23 , 24 , 25 ]. LDH inhibition causing anti-mitotic effects is consistently reported in a variety of cancer models [ 24 , 26 ], including 2D or 3D cultures and xenograft transplants in nude mice [ 27 , 28 , 29 , 30 , 31 ] and, in many instances, can augment the efficacy of chemo- or radiation-resistant cancers [ 32 , 33 , 34 ] and impede EMT, migration, or clonogenicity [ 35 ].…”

Gene Expression Changes by Diallyl Trisulfide Administration in Chemically-induced Mammary Tumors in Rats

“…The antitumor effect of garlic/onions is attributable to organosulfur compounds that are generated upon cutting or chewing of these edible plants [ 11 ]. Diallyl trisulfide (DATS) is one such component of garlic that exhibits antitumor activity in breast cancer in vitro and in vivo [ 12 - 23 ]. The antitumor characteristics of DATS in breast cancer include inhibition of cell proliferation, apoptosis induction, cell cycle arrest, suppression of self-renewal of breast cancer-stem like cells, and inhibition of metastasis properties in vitro and/or in vivo [ 12 - 23 ].…”

“…Diallyl trisulfide (DATS) is one such component of garlic that exhibits antitumor activity in breast cancer in vitro and in vivo [ 12 - 23 ]. The antitumor characteristics of DATS in breast cancer include inhibition of cell proliferation, apoptosis induction, cell cycle arrest, suppression of self-renewal of breast cancer-stem like cells, and inhibition of metastasis properties in vitro and/or in vivo [ 12 - 23 ]. Several oncogenic pathways are also inhibited by DATS treatment in breast cancer cells in vitro, and the examples include NF-κB, HIF-1α, Wnt/β-catenin, leptin, STAT3, etc.…”