3-5-bis(3-4-5-trimethoxybenzylidene)-1-methylpiperidine-4-one and Breast-Neoplasms

There is a need for the development of new, safe and efficacious drug therapies for the treatment of estrogen receptor (ER)-negative breast cancers. RL71 is a second-generation curcumin analog that exhibits potent cytotoxicity towards a variety of ER-negative breast cancer cells. Therefore, we have further examined the mechanism of this anticancer activity in three different ER-negative breast cancer cell lines. The mechanistic studies demonstrated that RL71 (1 µM) induced cell cycle arrest in the G2/M phase of the cell cycle. Moreover, RL71 (1 µM) caused 35% of SKBr3 cells to undergo apoptosis after 48 h and this effect was time-dependent. This correlated with an increase in cleaved caspase-3 as shown by western blotting. RL71 (1 µM) also decreased HER2/neu phosphorylation and increased p27 in SKBr3 cells. While in MDA-MB-231 and MDA-MB-468 cells RL71 (1 µM) significantly decreased Akt phosphorylation and transiently increased the stress kinases JNK1/2 and p38 MAPK. In addition, RL71 exhibited anti-angiogenic potential in vitro as it inhibited HUVEC cell migration and the ability of these cells to form tube-like networks. RL71 (8.5 mg/kg) was also orally bioavailable as it produced a peak plasma concentration of 0.405 µg/ml, 5 min after oral drug administration. Thus, our findings provide evidence that RL71 has potent anticancer activity and has potential to be further developed as a drug for the treatment of ER-negative breast cancer.

Topics: Animals; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Caspase 3; Cell Line, Tumor; Cell Movement; Curcumin; Diarylheptanoids; Down-Regulation; Female; G2 Phase Cell Cycle Checkpoints; Human Umbilical Vein Endothelial Cells; Humans; JNK Mitogen-Activated Protein Kinases; Mice; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Proliferating Cell Nuclear Antigen; Proto-Oncogene Proteins c-akt; Receptor, ErbB-2; Receptors, Estrogen; Signal Transduction